Methods and systems using peptides for targeting and mapping human nerves in image guided surgery, diagnostics and therapeutic delivery

Abstract

To provide agents for labeling and locating renal nerve.SOLUTION: A provided agent comprises human neuron or nerve-targeting molecule to be used by a method comprising: (a) contacting the renal nerve in the renal arterial wall with an agent, thereby labeling the renal nerve in the renal artery wall; and (b) illuminating the cargo through the renal artery wall in the kidney; receiving fluorescent light from the cargo; and using the received fluorescent light to determine the position of renal nerve in the renal artery wall during operation of a subject; and (c) using the position of the renal nerve in the renal artery wall for irradiating or guiding ablation of the renal nerve in the renal artery wall.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Sequence Listing Description The sequence listing associated with this application is provided in text form in lieu of a written document and is hereby incorporated by reference. The text file containing the sequence listing is named 110267_402WO_SEQUENCE_LISTING.txt. The text file is 37.1 KB, was created on October 8, 2020, and was provided electronically via EFS-Web. [Background technology]

[0002] Background of the Invention Because accidental severing of neurons or nerves results in significant morbidity, preservation of human neurons and nerves is one of the most important goals of any surgical procedure. Nerves are typically identified by their elongated, whitish appearance and relationship to nearby structures or by electrophysiological testing. However, in cases of trauma, tumor involvement, inflammation, or infection, nerve identification using these criteria can be difficult. Therefore, there is a need for a method for reliably and definitively identifying neurons or nerves that overcomes the deficiencies in the art.

[0003] Identification of neurons or nerves before direct exposure during surgery, or confirmation of neuron or nerve identity after direct exposure in cases of uncertainty, is achieved by electromyography (EMG) monitoring. However, this technique has the disadvantage of not providing visual feedback to the surgeon. Thus, even if a nerve is identified at one location, either by accidental or intentional stimulation, there is no visual guide for the surgeon as to how far the nerve is from the stimulation site or the direction in which the nerve leaves the stimulation site. Furthermore, EMG tracks only motor pathways, not sensory fibers. EMG fails when neuron or nerve conduction or neuromuscular transmission is temporarily blocked somewhere far from the recording site. Such blockage can easily occur due to neuron or nerve compression, trauma, local anesthetics, or neuromuscular blocking agents.

[0004] Labeling neurons or nerves primarily relies on retrograde or anterograde tracing of individually identified axonal tracts via the use of fluorescent dyes. However, labeling neurons or nerves with locally applied fluorescent tracers has several disadvantages. First, this technique can only label one neuron or nerve fiber tract at a time, depending on the location where the dye is injected. Second, because retrograde axonal tracers typically accumulate in the neuronal cell body, this technique results in limited labeling of the fluorescent dye along the axonal tract. Third, retrograde transport is relatively slow (on the order of a few millimeters per day); therefore, it takes a long time to label human neurons or nerves, which are often longer than one meter, as in the case of sciatic neurons or nerves and their dendritic branches. Fourth, application of fluorescent dye to innervation targets, such as direct intramuscular injection to label motor neurons or nerves, is typically contaminated with varying amounts of tracer dye remaining at the injection site. Because neuron or nerve dissection relies on accurate visualization before reaching adjacent structures, a surgical site contaminated with fluorescent dye is undesirable. Finally, direct injection of the fluorescent dye itself may damage the target organ or the neuron or nerve of interest, either through mechanical injury or through very high local concentrations of dye and vehicle at the injection site. Summary of the Invention [Problem to be solved by the invention]

[0005] There is a need in the art to identify peptides that can bind to human nerves and neurons to facilitate surgical procedures and human neuroprotection.

[0006] Neurohoming peptide sequences have previously been identified for their ability to bind to mouse nerves for laboratory studies. However, the peptide sequences described in this application are identified for their ability to bind to human nerves after systemic intravenous injection into human patients, and as such, these peptides fulfill a need for peptides that can bind to human nerves more specifically and effectively than previous sequences. The present invention provides peptide sequences that selectively bind to human nerves and / or neurons, as well as methods of using such sequences in surgical procedures (e.g., to preserve nerves and / or avoid nerve damage during such procedures). [Means for solving the problem]

[0007] Disclosed herein, in certain embodiments, is a targeting molecule comprising a peptide that specifically binds to human neurons, human nerves, or components of either. In some embodiments, the peptide is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 7), and Ac-QVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 8). -N-2; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C with a GGC linker; SEQ ID NO: 11), -2; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWE EPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4;SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), No. 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), FAM-QVPW EEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVK KGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124) and / or combinations thereof;

[0008] In some embodiments, a human neuron or nerve targeting molecule that specifically binds to a human neuron or nerve or any component, the targeting molecule being selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 7), -N-2; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C with a GGC linker; SEQ ID NO: 11), -2; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWE EPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4;SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 1 20), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), 5FAM-QVPWEEP YYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (G HNP401-C-2 with a G linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124) and / or combinations thereof;

[0009] In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3).

[0010] In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21), and SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25).

[0011] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1).

[0012] In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2).

[0013] In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3).

[0014] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4).

[0015] In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5).

[0016] In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6).

[0017] In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7).

[0018] In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8).

[0019] In some embodiments, the targeting molecule comprises the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9).

[0020] In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10).

[0021] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11).

[0022] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12).

[0023] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13).

[0024] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14).

[0025] In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20).

[0026] In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21).

[0027] In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22).

[0028] In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23).

[0029] In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24).

[0030] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25).

[0031] In some embodiments, the targeting molecule comprises SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26).

[0032] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27).

[0033] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28).

[0034] In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118).

[0035] In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119).

[0036] In some embodiments, the targeting molecule comprises the peptide PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120).

[0037] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121).

[0038] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122).

[0039] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123).

[0040] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124).

[0041] In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104).

[0042] In some embodiments, the human neuron or neural targeting molecule further comprises a cargo, hi some embodiments, the cargo is a drug, a fluorescent moiety, a photosensitizer, or a combination thereof.

[0043] In some embodiments, the human neuron or neural targeting molecule further comprises a drug.

[0044] In some embodiments, the human neuron or neural targeting molecule further comprises a drug selected from the group consisting of an antihistamine, a GABA receptor modulator, a neurotransmitter reuptake inhibitor, a local anesthetic, an anticholinergic, a sodium channel blocker, a calcium channel blocker, a thyrotropin-releasing hormone, a gamma-secretase inhibitor, an AMPA receptor agonist or antagonist, an NMDA receptor agonist or antagonist, an mGlu receptor agonist or antagonist, a growth factor, an antiemetic, a corticosteroid, a cytotoxic agent, an antioxidant, an iron chelator, a mitochondrial modulator, a sirtuin modulator, a nitric oxide (NO) and / or nitric oxide synthase (NOS) modulator, a potassium channel agonist or antagonist, a purinergic receptor agonist or antagonist, and / or a combination thereof.

[0045] In some embodiments, the human neuron or neural targeting molecule is selected from the group consisting of benzocaine, carticaine, cinchocaine, cyclomethycaine, lidocaine, prilocaine, propoxycaine, proparacaine, tetracaine, tocainide and trimecaine, methotrexate, cyclophosphamide, thalidomide, paclitaxel, pemetrexed, pentostatin, pipobroman, pixantrone, plicamycin, platonin, procarbazine, raltitrexed, rebeccamycin, rubitecan, SN-38, salinosporamide A, satraplatin, streptozotocin, swainsonine, tariquidar, taxanes, tegafur-uracil, temozolomide, testolactone, thioTEPA, thioguanidine, thiazolinone ... In some embodiments, the therapeutic agent further comprises a drug selected from the group consisting of benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzoyl peroxidase, benzoyl peroxidase (POP), benzocaine, benzoyl peroxidase (POX), benzocaine, benzoyl peroxidase (PPER ...

[0046] In some embodiments, the human neuron or neural targeting molecule further comprises a fluorescent moiety.

[0047] In some embodiments, the human neuron or neural targeting molecule further comprises a fluorescent moiety selected from the group consisting of a fluorescent protein, a fluorescent peptide, a fluorescent dye, and / or a combination thereof.

[0048] In some embodiments, the human neuron or neural targeting molecule further comprises a fluorescent moiety selected from the group consisting of xanthene, bimane, coumarin, aromatic amine, benzofuran, fluorescent cyanine, carbazole, dicyanomethylenepyran, polymethine, oxabenzanthrane, pyrylium, carbostyl, perylene, acridone, quinacridone, rubrene, anthracene, coronene, phenanthracene, pyrene, butadiene, stilbene, porphyrin, phthalocyanine, lanthanide metal chelate complexes, rare earth metal chelate complexes, derivatives thereof, and / or combinations thereof.

[0049] In some embodiments, the human neuron or neural targeting molecule is selected from the group consisting of 5-carboxyfluorescein, fluorescein-5-isothiocyanate, 6-carboxyfluorescein, 5(6)-carboxyfluorescein, tetramethylrhodamine-6-isothiocyanate, 5-carboxytetramethylrhodamine, 5-carboxyrhodol derivatives, tetramethyl and tetraethylrhodamine, diphenyldimethyl and diphenyldiethylrhodamine, dinaphthylrhodamine, rhodamine 101 sulfonyl chloride, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, indocyanine green, IR800CW, cyan fluorescent protein ( CFP), EGFP, 6-FAM, FAM, fluorescein, 5,6-dicarboxyfluorescein, 5-(and 6)-sulfofluorescein, sulfonefluorescein, succinylfluorescein, 5-(and 6)-carboxySNARF-1, carboxyfluorescein sulfonate, carboxyfluorescein zwitterion, carboxyfluorescein quaternary ammonium, carboxyfluorescein phosphonate, carboxyfluorescein GABA, carboxyfluorescein-cis-Cy5, 5'(6')-carboxyfluorescein, fluorescein glutathione, and / or combinations thereof.

[0050] In some embodiments, the human neuron or neural targeting molecule further comprises a photosensitizer.

[0051] In some embodiments, the human neuron or neural targeting molecule further comprises a photosensitizer selected from the group consisting of porphyrins, chlorins, and dyes.

[0052] In some embodiments, the human neuron or neural targeting molecule further comprises a photosensitizer selected from the group consisting of porphyrin, protoporphyrin IX, purlitin, verteporfin, HPPH, temoporfin, methylene blue, photofrin, protofrin, hematoporphyrin, talaporfin, benzoporphyrin derivative monoacid, 5-aminolevulinic acid, lutetium texaphyrin, metallophthalocyanine, metallonaphthalocyanine sulfobenzo-porphyrazine, metallonaphthalocyanine, zinc tetrasulfophthalocyanine, bacteriochlorin, metallochlorin, chlorine derivative, tetra(m-hydroxyphenyl)chlorin (mTHPC), pheophorbide, dibromofluorescein (DBF), IR700DX, naphthalocyanine, porphyrin derivative, and / or combinations thereof.

[0053] In some embodiments, a method of identifying a human neuron or nerve is provided, comprising contacting the human neuron or nerve with a targeting molecule comprising (a) a peptide that specifically binds to the neuron or nerve or a component of either, and (b) a fluorescent moiety, wherein the targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEE PYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), No. 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24);SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPW EEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104) and / or combinations thereof;

[0054] In some embodiments, the human neuronal or neural targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2) and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3).

[0055] In some embodiments, the human neuronal or neural targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21), and SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25).

[0056] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1).

[0057] In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2).

[0058] In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3).

[0059] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4).

[0060] In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5).

[0061] In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6).

[0062] In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7).

[0063] In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8).

[0064] In some embodiments, the targeting molecule comprises the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9).

[0065] In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10).

[0066] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11).

[0067] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12).

[0068] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13).

[0069] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14).

[0070] In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16).

[0071] In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20).

[0072] In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21).

[0073] In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22).

[0074] In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23).

[0075] In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24).

[0076] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25).

[0077] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26).

[0078] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27).

[0079] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28).

[0080] In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118).

[0081] In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119).

[0082] In some embodiments, the targeting molecule comprises the peptide PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120).

[0083] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121).

[0084] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122).

[0085] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123).

[0086] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124).

[0087] In some embodiments, the fluorescent moiety is selected from the group consisting of a fluorescent protein, a fluorescent peptide, a fluorescent dye, and / or combinations thereof.

[0088] In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104).

[0089] In some embodiments, the fluorescent moiety is selected from the group consisting of xanthene, bimane, coumarin, aromatic amine, benzofuran, fluorescent cyanine, carbazole, dicyanomethylenepyran, polymethine, oxabenzanthrane, pyrylium, carbostyl, perylene, acridone, quinacridone, rubrene, anthracene, coronene, phenanthracene, pyrene, butadiene, stilbene, porphyrin, phthalocyanine, lanthanide metal chelate complexes, rare earth metal chelate complexes, derivatives thereof, and / or combinations thereof.

[0090] In some embodiments, the fluorescent moiety is 5-carboxyfluorescein (5-FAM), fluorescein-5-isothiocyanate, 6-carboxyfluorescein (6-FAM), 5(6)-carboxyfluorescein, tetramethylrhodamine-6-isothiocyanate, 5-carboxytetramethylrhodamine, 5-carboxyrhodol derivatives, tetramethyl and tetraethylrhodamine, diphenyldimethyl and diphenyldiethylrhodamine, dinaphthylrhodamine, rhodamine 101 sulfonyl chloride, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, indocyanine green, IR800CW, cyan fluorescent protein, The carboxyfluorescein may be selected from the group consisting of carboxyfluorescein (CFP), EGFP, 6-FAM, FAM, fluorescein, 5,6-dicarboxyfluorescein, 5-(and 6)-sulfofluorescein, sulfonefluorescein, succinylfluorescein, 5-(and 6)-carboxySNARF-1, carboxyfluorescein sulfonate, carboxyfluorescein zwitterion, carboxyfluorescein quaternary ammonium, carboxyfluorescein phosphonate, carboxyfluorescein GABA, carboxyfluorescein-cis-Cy5, 5'(6')-carboxyfluorescein, fluorescein glutathione, and / or combinations thereof.

[0091] In some embodiments, a method of delivering a drug to a human neuron or nerve is provided, comprising contacting the human neuron or nerve with a human neuron or nerve targeting molecule comprising (a) a peptide that specifically binds to the neuron or nerve or a component of either, and (b) the drug, wherein the targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEE PYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), No. 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24);SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPW EEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104) and / or combinations thereof;

[0092] In some embodiments, the drug is selected from the group consisting of an antihistamine, a GABA receptor modulator, a neurotransmitter reuptake inhibitor, a local anesthetic, an anticholinergic, a sodium channel blocker, a calcium channel blocker, a thyrotropin-releasing hormone, a gamma-secretase inhibitor, an AMPA receptor agonist or antagonist, an NMDA receptor agonist or antagonist, an mGlu receptor agonist or antagonist, a growth factor, an antiemetic, a corticosteroid, a cytotoxic agent, an antioxidant, an iron chelator, a mitochondrial modulator, a sirtuin modulator, a nitric oxide (NO) and / or nitric oxide synthase (NOS) modulator, a potassium channel agonist or antagonist, a purinergic receptor agonist or antagonist, and / or a combination thereof.

[0093] In some embodiments, the drug is selected from the group consisting of benzocaine, carticaine, cinchocaine, cyclomethycaine, lidocaine, prilocaine, propoxycaine, proparacaine, tetracaine, tocainide and trimecaine, methotrexate, cyclophosphamide, thalidomide, paclitaxel, pemetrexed, pentostatin, pipobroman, pixantrone, plicamycin, procarbazine, raltitrexed, rebeccamycin, rubitecan, SN-38, salinosporamide A, satraplatin, streptozotocin, swainsonine, tariquidar, taxanes, tegafur-uracil, temozolomide, testolactone, thioTEPA, thioguanine, topotecan,

[0033] The therapeutic agent is selected from the group consisting of rabectedin, tretinoin, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, zosuquidar, carbamazepine, oxcarbazepine, phenytaine, valproic acid, sodium valproate, cinnarizine, flunarizine, nimodipine, brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3, neurotrophin-4, fibroblast growth factor (FGF) receptor, insulin-like growth factor (IGF), and / or combinations thereof.

[0094] In some embodiments, a method of delivering a photosensitizer to a human neuron or nerve is provided, comprising contacting the human neuron or nerve with a human neuron or nerve targeting molecule comprising (a) a peptide that specifically binds to the neuron or nerve or a component of either, and (b) a photosensitizer, wherein the targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEE PYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), No. 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24);SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPW EEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104) and / or combinations thereof;

[0095] In some embodiments, the method further comprises exposing the human neuron or nerve to a light source that activates the photosensitizer.

[0096] In some embodiments, the photosensitizer is selected from the group consisting of porphyrins, chlorins, and dyes.

[0097] In some embodiments, the photosensitizer is selected from the group consisting of porphyrin, protoporphyrin IX, purlitin, verteporfin, HPPH, temoporfin, methylene blue, photofrin, protofrin, hematoporphyrin, talaporfin, benzoporphyrin derivative monoacid, 5-aminolevulinic acid, lutetium texaphyrin, metallophthalocyanine, metallonaphthalocyanine sulfobenzo-porphyrazine, metallonaphthalocyanine, zinc tetrasulfophthalocyanine, bacteriochlorin, metallochlorin, chlorine derivative, tetra(m-hydroxyphenyl)chlorin (mTHPC), pheophorbide, dibromofluorescein (DBF), IR700DX, naphthalocyanine, porphyrin derivative and / or combinations thereof.

[0098] In some embodiments, the human neuronal or neural targeting molecule is administered by systemic intravenous injection to the human subject.

[0099] In some embodiments, the human neuron or neural targeting molecule is administered prior to a surgical procedure. In some embodiments, the surgical procedure is a cancer surgical procedure. In some embodiments, the surgical procedure is a prostate cancer surgical procedure.

[0100] In some embodiments, a pharmaceutical composition is provided comprising: (a) a peptide that specifically binds to a human neuron, a human nerve, or a component of either; and (b) a pharmaceutically acceptable excipient, wherein the human neuron or nerve targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), No. 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2;SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (G HNP401-C-2 with a G linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104) and / or combinations thereof.

[0101] In some embodiments of the composition, the peptide is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2) and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3).

[0102] In some embodiments of the composition, the peptide is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21) and SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25).

[0103] In some embodiments of the composition, the peptide comprises SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1).

[0104] In some embodiments of the composition, the peptide comprises WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2).

[0105] In some embodiments of the composition, the peptide comprises DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3).

[0106] In some embodiments of the composition, the peptide comprises Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4).

[0107] In some embodiments of the composition, the peptide comprises Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5).

[0108] In some embodiments of the composition, the peptide comprises Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6).

[0109] In some embodiments of the composition, the peptide comprises Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7).

[0110] In some embodiments of the composition, the peptide comprises Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8).

[0111] In some embodiments of the composition, the peptide comprises Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9).

[0112] In some embodiments of the composition, the peptide comprises Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10).

[0113] In some embodiments of the composition, the peptide comprises Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11).

[0114] In some embodiments of the composition, the peptide comprises Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12).

[0115] In some embodiments of the composition, the peptide comprises Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13).

[0116] In some embodiments of the composition, the peptide comprises Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14).

[0117] In some embodiments of the composition, the peptide comprises DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16).

[0118] In some embodiments of the composition, the peptide comprises QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20).

[0119] In some embodiments of the composition, the peptide comprises QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21).

[0120] In some embodiments of the composition, the peptide comprises PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22).

[0121] In some embodiments of the composition, the peptide comprises EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23).

[0122] In some embodiments of the composition, the peptide comprises PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24).

[0123] In some embodiments of the composition, the peptide comprises SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25).

[0124] In some embodiments of the composition, the peptide comprises SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26).

[0125] In some embodiments of the composition, the peptide comprises SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27).

[0126] In some embodiments of the composition, the peptide comprises SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28).

[0127] In some embodiments of the composition, the peptide comprises PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118).

[0128] In some embodiments of the composition, the peptide comprises EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119).

[0129] In some embodiments of the composition, the peptide comprises PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120).

[0130] In some embodiments of the composition, the peptide comprises SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121).

[0131] In some embodiments of the composition, the peptide comprises SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122).

[0132] In some embodiments of the composition, the peptide comprises SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123).

[0133] In some embodiments of the composition, the peptide comprises SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124).

[0134] In some embodiments of the composition, the peptide comprises 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104).

[0135] In some embodiments of the composition, the peptide is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1).

[0136] In some embodiments of the composition, the peptide is WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2).

[0137] In some embodiments of the composition, the peptide is DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3).

[0138] In some embodiments of the composition, the peptide is Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4).

[0139] In some embodiments of the composition, the peptide is Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5).

[0140] In some embodiments of the composition, the peptide is Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6).

[0141] In some embodiments of the composition, the peptide is Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7).

[0142] In some embodiments of the composition, the peptide is Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8).

[0143] In some embodiments of the composition, the peptide is Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9).

[0144] In some embodiments of the composition, the peptide is Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10).

[0145] In some embodiments of the composition, the peptide is Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11).

[0146] In some embodiments of the composition, the peptide is Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12).

[0147] In some embodiments of the composition, the peptide is Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13).

[0148] In some embodiments of the composition, the peptide is Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14).

[0149] In some embodiments of the composition, the peptide is DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16).

[0150] In some embodiments of the composition, the peptide is QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20).

[0151] In some embodiments of the composition, the peptide is QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21).

[0152] In some embodiments of the composition, the peptide is PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22).

[0153] In some embodiments of the composition, the peptide is EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23).

[0154] In some embodiments of the composition, the peptide is PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24).

[0155] In some embodiments of the composition, the peptide is SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25).

[0156] In some embodiments of the composition, the peptide is SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26).

[0157] In some embodiments of the composition, the peptide is SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27).

[0158] In some embodiments of the composition, the peptide is SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28).

[0159] In some embodiments of the composition, the peptide is 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104).

[0160] In some embodiments of the composition, the peptide is PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118).

[0161] In some embodiments of the composition, the peptide is EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119).

[0162] In some embodiments of the composition, the peptide is PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120).

[0163] In some embodiments of the composition, the peptide is SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121).

[0164] In some embodiments of the composition, the peptide is SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122).

[0165] In some embodiments of the composition, the peptide is SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123).

[0166] In some embodiments of the composition, the peptide is SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124).

[0167] In some embodiments of the composition, the peptide is conjugated to a cargo, hi some embodiments, the cargo is a drug, a photosensitizer, or a fluorescent moiety.

[0168] In some embodiments, methods are provided for nerve labeling and mapping and map-guided surgery, more particularly in the bronchi or kidney, using neural targeting molecules or compositions as further described herein. [Brief explanation of the drawings]

[0169] [Figure 1] Fluorescence images of exposed sciatic nerves in live wild-type mice after administration of 450 nmol of HNP401 in three mice (left) and NP41 (two mice, right). Both left and right sciatic nerves are shown. FAM is fluorescein conjugated to the C-terminal lysine of each peptide sequence. Images were acquired on a Zeiss Lumar.

[0170] [Figure 2] Quantification of images from Figure 1 shows that HNP401 has similar contrast (nerve fluorescence intensity / muscle fluorescence intensity) to NP41 (6.2-fold compared to 6.7-fold), with higher intensity labeling of both nerve and adjacent muscle tissue. A total of 6 nerves, 3 mice for HNP401 and 2 mice (4 nerves) for NP41. Y-axis = mean fluorescence (515 nm emission) intensity calculated in Image J.

[0171] [Figure 3]Topical application of nerve-binding peptides to human nerve slices showing high binding of HNP401. For HNP401, the exposure gain was reduced (from 30 to 10) compared to the other standards because exposure under the same settings reached saturation due to the high signal.

[0172] [Figure 4] Fluorescence from human nerve sections after topical application of NP41, HNP401, and HNP404. 100 μM of peptide was applied for 20 minutes, followed by washing with PBS and imaging with a Nikon A1 confocal microscope. All images are leveled.

[0173] [Figure 5] In vivo labeling of rat sciatic nerve with HNP401.

[0174] [Figure 6] Fluorescent labeling of rat prostate cavernous nerves in live rats. HNP301 is an early generation nerve-binding peptide that does not exhibit comparable contrast for prostate nerve labeling compared to HNP401.

[0175] [Figure 7] In vivo labeling of prostatic neurovascular bundles with HNP401. HNP401 labeling of autonomic nerve bundles in live rats.

[0176] [Figure 8]Screening of human nerve-binding peptides identified by phage display. Topical application of 100 mM human nerve-binding peptides FAM-HNP401 (A), FAM-HNP402 (B), and FAM-HNP403 (C) to serial sections of fresh, viable human sural nerve (top image) and human temporalis muscle (bottom image). For comparison, topical application of 100 mM carboxy-FAM (D) and peptides screened for binding to mouse nerve NP41-FAM (E). H&E of nerve and muscle staining (F). All fluorescent images were acquired with a Lumar microscope at 34x magnification, 2-second exposure, and leveled equally for comparison. NTQTLAKAPEHT (NP41, SEQ ID NO: 15 from U.S. Pat. No. 8,685,372 or International Patent Publication No. WO2010121023A2).

[0177] [Figure 9] Comparison of FAM-HNP401 and FAM-NP41 in binding and labeling of the human sural nerve. Topical application of 100 mM HNP401-FAM to 10 mm sections of unfixed human brachial plexus nerve tissue (A) and human temporalis muscle tissue (D) held adjacently on the same glass slide and imaged by confocal microscopy with a 488 nm excitation laser. For comparison, NP41-FAM was applied to human nerve (B) and muscle (C) under identical conditions as those described for (A and D). H&E staining of nerve (C) and muscle (F). Signal intensity of the perineurium of nerve tissue treated with HNP401-FAM (n = 4) compared to NP41-FAM (n = 4) (G). Nerve-to-muscle contrast of the peptides topically applied to human tissue sections (n ​​= 4) (H).

[0178] [Figure 10]Differential binding of nerve-binding peptides to human and mouse tissues. Human tissue: Determination of optimal dose-response by topical application of HNP401-FAM to human sural nerve sections at final concentrations of 375 mM (A), 100 mM (B), 50 mM (C), 10 mM (D), and 1 mM (E). Imaged by confocal microscopy with identical parameters and leveled for comparison. **Images were brightened 2x for visualization. Nerve and muscle contrast at the higher concentration of 375 mM for FAM-NP41 (F and G) and FAM-HNP401 (H and I). Imaged by confocal microscopy and leveled for direct comparison. Mouse tissue: Mouse facial nerve (red arrow) with surrounding muscle treated with 375 mM (J) and 100 mM (K) FAM-NP41 or 375 mM (L) and 100 mM (M) FAM-HNP401. The bottom image is equivalent and was acquired on a Lumar imaging scope with the same parameters. FAM-HNP401 shows high muscle binding in mouse tissue with lower contrast compared to FAM-NP41.

[0179] [Figure 11]In vivo imaging of nerve-binding peptides in rodents, including pharmacokinetic profiles after intravenous injection. In vivo fluorescence images of the sciatic nerve of a 6-month-old SKH1-Elite mouse, where 450 nmol of FAM-HNP401 (A) or FAM-NP41 (B) was intravenously injected and imaged with a Lumar imaging scope 2 hours after injection. Sciatic nerve intensity measured in Image J shows a 2.3-fold increase in binding of the peptide screened for binding to human nerve (HNP401) versus the peptide screened for binding to mouse nerve (NP41) (C). However, nerve-to-surrounding muscle contrast for the two peptides is comparable: 5.79 ± 0.81 for FAM-HNP401 and 6.63 ± 1.63 for FAM-NP41 in the mouse thigh (D). In vivo fluorescence images of the prostatic nerve plexus using a real-time custom surgical imaging system (E) and a Lumar small animal microscope (F) 5 hours after systemic injection of 2 μmol of HNP401-FAM in a 100 gm male Sprague Dawley rat. The sciatic nerve in the rat was imaged 5 hours after systemic injection of 2 μmol of FAM-HNP401 (G). Blood clearance curves show the FAM signal obtained from equal volumes of blood drawn from five SKH1-Elite male mice. Each mouse was intravenously injected with 100 nmol of FAM-HNP401 before blood collection at 1 minute, 10 minutes, 20 minutes, 30 minutes, 1 hour, and 2 hours (H).

[0180] [Figure 12]HNP401 binds to human nerves (corpus cavernosum and medial anterobrachial). Fluorescence imaging after topical application of 100 μM FAM-HNP401 or FAM-NP41 to 10 μm sections on cryosectioning tape from a human intraprostatic nerve (top row, A and B) or a medial anterobrachial human nerve (bottom row, B and F). The nerves were imaged immediately after sectioning and application of the peptides using a confocal microscope. Immunohistochemical analysis with double labeling for neurofilament antibody SMI312 (red) and DAPI-stained nuclei (blue) on fixed nerve sections (C and G) and corresponding H&E staining on glass slides (D and H).

[0181] [Figure 13] HNP401 binds to human cavernous nerves. Using confocal microscopy, topical application of 100 μM FAM-HNP401 (A) or FAM-NP41 (B) to 10 μm sections on cryosection tape of unfixed, freshly viable nerves from the prostate gland was observed. Immunofluorescence (C) of neurofilament antibody SMI312 on fixed sections of nerves from the prostate gland and corresponding H&E staining on glass slides (D). These images are from a different patient than the one shown in Figure 5 herein.

[0182] [Figure 14] Determination of the human nerve-binding domain of HNP401 by serial deletion. Representative fluorescence images of unfixed human sural nerves treated locally with 100 μM FAM-labeled HNP401 (A), HNP401-N-2 (B), HNP401-N4 (C), HNP401-N6 (D), HNP401-N8 (E), HNP401-N4 C-2 (F), HNP401-N4 C-4 (G), HNP401-N4 C-6 (H), and HNP401-N4 C-8 (I).

[0183] [Figure 15] Quantification of neural connectivity for deletion variants of HNP401. Quantification of neural connectivity for each HNP401 variant shown in Figure 7 (n=5).

[0184] [Figure 16]In vivo fluorescent labeling of autonomic nerves in rodents. (A) Low-magnification fluorescent image showing the bladder, vas deferens, and urethra in a mouse, with adjacent autonomic nerves running through the prostate labeled with FAM-NP41. (B) Higher-magnification white-light reflectance image of the autonomic nerves running adjacent to the urethra and corresponding fluorescent grayscale image (C). (D) Quantification of autonomic nerve detection by fluorescence compared to white-light detection in a mouse. (D) Nerve-to-muscle contrast for reflectance / fluorescence was plotted for individual nerve branches. Values ​​to the right of the line indicate improved visualization with fluorescence compared to reflected light. (E-G) Images are similar to (A-C), except they highlight FAM-NP41-dependent labeling of autonomic nerves in the rat prostate versus the mouse, and white-light imaging shows invisible nerves (F). (H) FAM-NP41-labeled prostate nerves are also detectable using a clinical-grade Zeiss Pentero Surgical Microscope.

[0185] [Figure 17] Comparison of FAM-HNP401 and FAM-NP41 in binding and labeling of the human sural nerve. Topical application of 100 μM FAM-HNP401 to 10 μm sections of unfixed human sural nerve tissue (A) and human temporalis muscle tissue (E) held adjacently on the same glass slide and imaged by confocal microscopy with a 488 nm excitation laser. For comparison, FAM-NP41 was applied to serial sections of human nerve (B) and muscle (F) under identical conditions as those mentioned for (A and E). H&E staining of nerve (C) and muscle (G). Signal intensity of the perineurium of nerve tissue treated with FAM-HNP401 (n = 4) compared to FAM-NP41 (n = 4) (D). Nerve-to-muscle contrast of the peptide applied topically to human tissue sections (n ​​= 4) (H).

[0186] [Figure 18]In vivo imaging of nerve-binding peptides in mice and rats, including pharmacokinetics. In vivo fluorescence images of the sciatic nerve from a 6-month-old SKH1 mouse previously intravenously injected with 450 nmol of FAM-HNP401 [approximately 48.4 mg / kg] (A) or FAM-NP41 [approximately 39 mg / kg] (B). Sciatic nerve intensity, measured and quantified in Image J, showed a 2.3-fold increase for FAM-HNP401 compared to FAM-NP41 (C). Nerve-to-muscle contrast for the two peptides was comparable: 5.79 ± 0.81 for FAM-HNP401 and 6.63 ± 1.63 for FAM-NP41 (D). In vivo fluorescence image of a rat sciatic nerve 5 hours after intravenous injection of 2 μmol of FAM-HNP401 [approximately 54 mg / kg] (E). Rat prostate nerves imaged with a real-time custom surgical imaging system (F) and a Lumar small animal microscope (G) 5 hours after intravenous injection of 2 μmol of FAM-HNP401. Blood clearance curves show the FAM signal obtained from equal volumes of blood drawn from five SKH1-Elite male mice (H). Each mouse was intravenously injected with 100 nmol [approximately 11 mg / kg] of FAM-HNP401 before blood collection at 1 minute, 10 minutes, 20 minutes, 30 minutes, 1 hour, and 2 hours.

[0187] [Figure 19] HNP401 binds to freshly viable nerves from the prostate and to the medial anteroposterior human nerve. Fluorescence imaging after topical application of 100 μM FAM-HNP401 or FAM-NP41 to 10 μm sections on cryosectioning tape from nerves within the human prostate (top row, A and B) or from the medial anteroposterior human nerve (bottom row, E and F). Nerves were imaged immediately after sectioning and application of the peptides using a confocal microscope. Immunohistochemical analysis with double labeling for neurofilament antibody SMI312 (red) and DAPI-stained nuclei (blue) of fixed sections of nerves (C and G) and corresponding H&E staining on glass slides (D and H).

[0188] [Figure 20]Comparison of cleavage sequences to determine binding efficiency. Representative fluorescence images of unfixed human sural nerves treated locally with 100 μM FAM-labeled N-2 (A), N-4 (B), N-6 (C), N-8 (D), C-2 (E), C-4 (F), C-6 (G), C-8 (H), or HNP401 (I). Due to low solubility, for local testing, C-6 had a final concentration of *73 μM, and C-8 had a final concentration of **80.6 μM. To test for improved binding, a comparison of peptide signal intensities normalized to FAM-HNP401 was performed (J). Normalized sural nerve versus temporalis muscle contrast was determined for FAM-HNP401 and FAM-HNP401-N-2 (Student's t-test, unpaired, one-tailed, p=0.011) (K).

[0189] [Figure 21]Food dyes efficiently quench FAM-NP41 bladder fluorescence. A fluorescence plate reader assay was used to demonstrate dose-dependent quenching of FAM-NP41 fluorescence. Erythrosine Extruded Blue (Santa Cruz Biotechnology, Inc.) was the most efficient quencher, achieving >80% quenching at a 2.5x dye-to-fluorescein ratio and >95% quenching at a 5x dye-to-fluorescein ratio (A). Other food dyes tested included Allura Red and Sunset Yellow. To test for in vivo quenching, we administered 50 mg / kg MW879.76 (approximately 1.5 μmol per 25 gm mouse) by direct intravenous injection to mice that had been injected with 150 nmol FAM-NP41 2 hours prior. This represents an approximately 10x dye-to-FAM-NP41 dose. Because some bladder fluorescence remained after imaging, additional dye (30 μl, 10 mM erythrosine extruder) was injected directly into the bladder. Images are shown of mouse bladders without dye quencher (B) and with the addition of erythrosine extruder (intravenously and intravesically) (C), in which bladder fluorescence was quenched to near background levels. If this method were used in human patients, dye would likely not be necessary, as bladder catheterization in the patient could be initiated once FAM-NP41 was administered and bladder fluorescence could be washed away.

[0190] [Figure 22] TAMRA-NP41 labels autonomic unmyelinated nerves in the rat prostate. Fluorescence image of periprostatic nerve bundles (white arrows) in a live male Sprague-Dawley rat imaged 15 minutes after intravenous injection of 500 nmol of NP41-TAMRA (A). Tissue was excised and cryofixed for verification of peptide fluorescent signal using confocal imaging (B) and immunohistochemistry with an antibody against TAMRA detected with horseradish peroxidase secondary and diaminobenzidine staining (C). Antibody staining against tyrosine hydroxylase was used to verify the presence of autonomic nerves (D). A non-primary negative control (E) was used.

[0191] [Figure 23] Screening of human nerve-binding peptides identified by phage display. Topical application of 100 μM human nerve-binding peptides FAM-HNP401 (A), FAM-HNP402 (B), and FAM-HNP403 (C) to serial sections of fresh, viable human sural nerve (top row) and human temporalis muscle (bottom row). For comparison, topical application of 100 μM carboxy-FAM (D) and peptides screened for binding to mouse nerve NP41-FAM (E). H&E staining of nerve and muscle (F). All fluorescent images were acquired with a Lumar microscope at 34x magnification and 2-second exposure and leveled equally for comparison.

[0192] [Figure 24] Screening of human nerve-binding peptides identified by phage display. Topical application of 100 μM of human nerve-binding peptides FAM-HNP401 (A), FAM-HNP402 (B), and FAM-HNP403 (C) to serial sections of fresh, viable human cervical trapezoid nerves (top row) and human greater auricular nerves (bottom row) from the necks of two different patients. For comparison, topical application of 100 μM of carboxy-FAM (D) and peptides screened for binding to mouse nerve NP41-FAM (E). All fluorescence images were acquired with a Lumar microscope at 34x magnification, 2-second exposure, and leveled equally for comparison.

[0193] [Figure 25]Differential binding of nerve-binding peptides to human and mouse tissues. Determination of the optimal dose-response by topical application of FAM-HNP401 to human pharyngeal nerve slices at final concentrations of 375 μM (A), 100 μM (B), 50 μM (C), 10 μM (D), and 1 μM (E). Images were imaged by confocal microscopy with identical parameters and leveled for comparison. **Images were enhanced 2x for visualization. Nerve-to-muscle contrast at the high concentration of 375 μM for FAM-NP41 (F and G) and FAM-HNP401 (H and I). Images were imaged by confocal microscopy and leveled for direct comparison. Mouse facial nerve (red arrow) with surrounding muscle treated with 375 μM (J) or 100 μM (K) FAM-NP41 or 375 μM (L) or 100 μM (M) FAM-HNP401. The lower image is equivalent and was acquired with a Lumar imaging scope using the same parameters. FAM-HNP401 shows high muscle binding in mouse tissue with lower contrast compared to FAMNP41. High-resolution confocal images of a low concentration of FAM-HNP401 (10 μM) on a human nerve show binding of the peptide to non-axonal structural components of the nerve (N).

[0194] [Figure 26] Autofluorescence in human nerve tissue. Topical application of 100 μM FAM-HNP401 (A) or buffer alone (B) onto a 10 μm section of unfixed human sural nerve, followed by imaging using a confocal microscope under identical acquisition parameters for direct comparison. Images were leveled evenly using Image J and subsequently brightened 16x compared to (B) for visualization.

[0195] [Figure 27] Mass spectrometry analysis of urine samples from mice injected with a neuronal-binding peptide. Fragmentation ion peaks from cysteine-FAM collected from the urine of mice injected with FAM-HNP401 indicate that the peptide is metabolized (A). Similar results were obtained in mice injected with FAM-NP41 (B). However, the peptide, made with d-amino acids, is detectable in the urine and not metabolized in mice injected with FAM-dNP41 (C).

[0196] [Figure 28A-B] Peptide stability in ex vivo human plasma and cerebrospinal fluid from rats. FAM-HNP401 peptide detected 5 min (A) and 2 h (B) after incubation at 37 °C in human plasma at a dose of 53.2 mg / kg or 2 μmol. An equal volume of 1:1 acetonitrile:water containing 2% acetic acid is added to precipitate the protein material, and the supernatant is extracted for analysis by LC-MS on a C18 reverse-phase column with a gradient of 9:1 HO + 0.05% TFA:acetonitrile + 0.05% TFA to 1:9 HO + 0.05% TFA:acetonitrile + 0.05% TFA in 20 min. The detector channel at 450 nm shows FAM-HNP401. The peptide remains intact 2 h after incubation with x% of the composition at 5 min after incubation with human plasma. [Fig. 28C-D] Peptide stability in ex vivo human plasma and cerebrospinal fluid from rats. The FAM-NP41 peptide was detected in human plasma at a dose of 53.2 mg / kg or 2 μmol after 5 minutes (C) and 2 hours (D) of incubation at 37°C, followed by LC-MS analysis using the method described above. Similar to our previous results, FAM-NP41 remains intact 2 hours after incubation with x% of the composition at 5 minutes after incubation with human plasma. [Figure 28E-F] Stability of peptides in ex vivo human plasma and cerebrospinal fluid from rats. FAM-HNP401(E) and FAM-NP41(F) were also tested in cerebrospinal fluid from rats at 2 hours after incubation to demonstrate the stability of the peptides in circulation.

[0197] [Figure 29]FAM-HNP401 binds to fresh, viable nerves obtained from the human prostate. Topical application of 100 μM FAM-HNP401 (A) or FAM-NP41 (B) to a 10 μm section of unfixed nerve from the prostate, followed by imaging using a confocal microscope. Immunofluorescence of the nerve using neurofilament antibody SMI312 (C) and corresponding H&E staining (D) on a fixed section of nerve from the prostate. These images are obtained from a different patient than the one shown in Figure 20.

[0198] [Figure 30] Table of peptide sequences and their abbreviations. DETAILED DESCRIPTION OF THE INVENTION

[0199] Detailed Description of the Invention I. Introduction Disclosed herein, in certain embodiments, is a targeting molecule comprising a peptide that specifically binds to human neurons, human nerves, or components of either. In some embodiments, the peptide is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 7), and Ac-QVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 8). -N-2; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C with a GGC linker; SEQ ID NO: 11), -2; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWE EPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4;SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-N-9 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVKKGG (HNP401-N-10 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYVVKKGG (HNP401-N-11 with a GG linker; SEQ ID NO: 123), SGQVPWEEPYYVVKKGG (HNP401-N-12 with a GG linker; SEQ ID NO: 124), SGQVPWEEPYYVVKKGG (HNP401-N-13 with a GG linker; SEQ ID NO: 125), SGQVPWEEPYYVVKKGG (HNP401-N-14 with a GG linker; SEQ ID NO: 126), SGQVPWEEPYYVVKKGG (HNP401-N-15 with a GG linker; SEQ ID NO: 127), SGQVPWEEPYYVVKKGG (HNP401-N-16 with a GG linker; SEQ ID NO: 128), SGQVPWEEPYYVVKKGG (HNP401-N- In some embodiments, the peptide is selected from the group consisting of SGQVPWEEPYYVVGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the peptide is not Ac-SHSNTQTLAKAPEHTGC (Ac-NP41; SEQ ID NO: 17). In some embodiments, the peptide is not SHSNTQTLAKAPEHTGC (NP41; SEQ ID NO: 18). In some embodiments, the peptide is not NTQTLAKAPEHT (NP41; SEQ ID NO: 19).

[0200] II. Definition In this description, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range and, where appropriate, fractions thereof (such as 1 / 10 and 1 / 100 of an integer), unless otherwise indicated. Also, any numerical range recited herein relating to any physical characteristic, such as polymer subunits, size, or thickness, should be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the term "about" means ±20% of the indicated range, value, or structure, unless otherwise indicated.

[0201] As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the listed components. The use of alternatives (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0202] In addition, it should be understood that each individual compound or group of compounds derived from the various combinations of structures and substituents described herein is disclosed by this application to the same extent as if each compound or group of compounds were individually described, and thus selection of a particular structure or particular substituents is within the scope of this disclosure.

[0203] As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0204] The central nervous system (CNS) consists of the brain and spinal cord and the retina.

[0205] The peripheral nervous system (PNS) extends outside the CNS. The PNS is divided into the somatic nervous system and the autonomic nervous system.

[0206] Neurons are electrically excitable cells that process and transmit information by electrical and chemical signaling.

[0207] A typical neuron has a cell body (often called the soma), dendrites, and an axon.

[0208] Nerves are enclosed cable-like bundles of nerve axons. Each nerve is a cord-like structure containing many axons. Each axon is surrounded by a layer of tissue called the endoneurium. Axons are organized into groups called fascicles, and each fascicle is surrounded by a layer of tissue called the perineurium. Neurons, or nerves, are surrounded by a layer of tissue called the epineurium.

[0209] As used herein, the term "targeting molecule" refers to any agent (e.g., a peptide, protein, nucleic acid polymer, aptamer, or small molecule) that specifically binds to a target of interest. In some embodiments, the targeting molecule comprises a peptide, also referred to herein as a "targeting peptide." The target of interest can be a tissue, a cell type, a cellular structure (e.g., an organelle), a protein, a peptide, a polysaccharide, or a nucleic acid polymer. In some embodiments, the targeting molecule is any agent that specifically binds to one or more neurons or nerves of a subject. In some embodiments, the targeting molecule further comprises a cargo (e.g., a drug, a fluorescent label, or a photosensitizer).

[0210] As used herein, the term "aptamer" refers to an oligonucleotide (e.g., DNA, RNA, or XNA) molecule selected from a random pool based on its ability to bind to other molecules with high affinity specificity based on non-Watson-Crick interactions with the target molecule (see, e.g., Cox and Ellington, Bioorg. Med. Chem. 9:2525-2531 (2001), Lee et al., Nuc. Acids Res. 32:D95-D100 (2004)). Alternatively, the term refers to a short peptide (e.g., 5-20 amino acids) embedded as a loop within a stable protein scaffold rather than as a free peptide. Aptamers can be selected to bind to nucleic acids, proteins, small organic compounds, vitamins, inorganic compounds, cells, and even whole organisms. In some embodiments, the targeting peptide can comprise an aptamer, or the targeting molecule peptide sequence can be in the form of a peptide aptamer.

[0211] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. These terms apply to naturally occurring amino acid polymers and amino acid polymers in which one or more amino acid residues are non-naturally occurring amino acids (e.g., amino acid analogs). These terms encompass amino acid chains of any length, including full-length proteins (i.e., antigens), in which the amino acid residues are linked by covalent peptide bonds. As used herein, the term "peptide" refers to a polymer of amino acid residues, typically ranging in length from 2 to about 50 residues. In certain embodiments, peptides range in length from about 2, 3, 4, 5, 7, 9, 10, or 11 residues to about 50, 45, 40, 45, 30, 25, 20, or 15 residues. In certain embodiments, peptides range in length from about 8, 9, 10, 11, or 12 residues to about 15, 20, or 25 residues. When amino acid sequences are provided herein, L-, D-, or beta-amino acid versions of the sequence are also contemplated, as are retro, inversion, and retro-inversion isoforms. Peptide also includes amino acid polymers and naturally occurring amino acid polymers, in which one or more amino acid residues are artificial chemical analogs of corresponding naturally occurring amino acids.In addition, the term also covers the amino acid that is linked by peptide bond or other modified bond (for example, when peptide bond is replaced by α-ester, β-ester, thioamide, phosphonamide, carbamate, hydroxylate, etc. (see, for example, Spatola, (1983) Chem. Biochem. Amino Acids and Proteins 7:267-357), when amide is replaced by saturated amine (see, for example, Skiles et al., U.S. Patent No. 4,496,542, and Kaltenbronn et al., (1990) Pp.969-970 in Proc. 11th American Peptide Symposium, ESCOM Science Publishers, The Netherlands, etc.), which are incorporated herein by reference).

[0212] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acids may be L- or D-amino acids. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids, i.e., carbons bonded to hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, and methionine sulfoxide. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics refer to chemical compounds that have a structure different from the general chemical structure of amino acids but function similarly to naturally occurring amino acids.

[0213] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUP AC-IUB Biochemical Nomenclature Commission. Similarly, nucleotides may be referred to by their commonly accepted one-letter codes.

[0214] Those skilled in the art will recognize that individual substitutions, deletions, or additions to peptide, polypeptide, or protein sequences that alter, add, or delete a single amino acid or a small percentage of amino acids in the encoded sequence are "conservatively modified variants," where the alteration results in the replacement of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to, and do not exclude, polymorphic variants, interspecies homologs, and alleles of the present invention.

[0215] The following eight groups contain amino acids that are conservative substitutions for each other: 1) alanine (A), glycine (G), 2) aspartic acid (D), glutamic acid (E), 3) asparagine (N), glutamine (Q), 4) arginine (R), lysine (K), 5) isoleucine (I), leucine (L), methionine (M), valine (V), 6) phenylalanine (F), tyrosine (Y), tryptophan (W), 7) serine (S), threonine (T), and 8) cysteine ​​(C), methionine (M) (see, e.g., Creighton, Proteins (1984)).

[0216] " sequence identity " as used herein refers to the percentage of amino acid residues in a single sequence that are identical to the amino acid residues in another reference polypeptide sequence, after aligning the sequence and introducing gaps as necessary to achieve the maximum sequence identity percentage, and does not take into account any conservative substitutions as part of sequence identity.Sequence identity percentage value can be determined by using the NCBI BLAST 2.0 software defined by Altschul et al. (1997), Nucl. Acids Res. 25:3389-3402, with parameters set to default.

[0217] As used herein, the term "label" refers to a molecule that facilitates visualization and / or detection of a targeting molecule disclosed herein. In some embodiments, the label is a fluorescent moiety.

[0218] The phrase "specifically bind" refers to the interaction between the targeting molecule disclosed herein and a target (e.g., purified protein, neuron or nervous tissue, neuron or nerve, brain neuron or nerve, central neuron or nerve, myelinated or unmyelinated neuron or nerve, or the connective tissue surrounding a neuron or nerve), and refers to the formation of a high affinity bond between the targeting molecule and the target.Furthermore, the term means that the targeting molecule has a low affinity for non-targets.

[0219] "Selective binding," "selectivity," and the like refer to the preference of an agent to interact with one molecule compared to another molecule. Preferably, the interaction between the targeting molecule disclosed herein and the target is specific and selective. Note that in some embodiments, the agent is designed to "specifically bind" and "selectively bind" two distinct but similar targets without binding to other undesired targets.

[0220] The terms "individual," "patient," or "subject" are used interchangeably. As used herein, they refer to any mammal (i.e., a species of any order, family, and genus within the taxonomic classification Animalia: Chordata: Vertebrates: Mammalia). In some embodiments, the mammal is a cow, horse, sheep, pig, cat, dog, goat, mouse, rat, rabbit, guinea pig, non-human primate, or human. None of these terms require, and are not limited to, a status under the care (e.g., permanent or temporary) of a health care professional (e.g., a physician, registered nurse, student nurse, physician assistant, ward assistant, or hospice worker).

[0221] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of an agent or composition to a desired site of biological action. These methods include, but are not limited to, parenteral injection (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intravitreal, infusion, or topical). Administration techniques optionally used with the agents and methods described herein include those discussed, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In some embodiments, administration is via systemic intravenous injection into a human patient.

[0222] As used herein, the term "pharmaceutically acceptable" refers to a material that does not abolish the biological activity or properties of the agents described herein and is relatively non-toxic (i.e., the toxicity of the material significantly outweighs the benefits of the material). In some cases, a pharmaceutically acceptable material can be administered to an individual without causing significant undesirable biological effects or interacting significantly adversely with any of the components of the composition in which it is contained.

[0223] The term "surgery" as used herein refers to any method that can be used to manipulate, alter, or cause an effect by physical intervention. These methods include, but are not limited to, open surgery, endoscopic surgery, laparoscopic surgery, minimally invasive surgery, robotic surgery, any procedure that can affect any neuron or nerve, such as placement of a retractor during spinal surgery, cardiac neuron or nerve ablation, epidural injection, intrathecal injection, neuron or nerve block, implantation of a device such as a neuron or nerve stimulator, and implantation of a pump. In some embodiments, the subject of surgery is a human subject or patient.

[0224] III. Target Disclosed herein, in identified embodiments, are human neuronal and / or neural targeting molecules that specifically bind to human neurons or neural targets.

[0225] In some embodiments, the target is a human neuron or nerve. The nerve can be any human nerve (e.g., motor nerve, sensory nerve, sympathetic and parasympathetic nerve, periprostatic neurovascular bundle, sciatic nerve, cranial nerve including the olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, hypoglossal nerve, spinal nerve, brachial plexus, or lumbosacral plexus). The neuron can be any neuron (e.g., sensory neuron (afferent neuron), motor neuron (efferent neuron), interneuron, unipolar neuron, bipolar neuron, multipolar neuron, basket cell, Betz cell, medium spiny neuron, Purkinje cell, pyramidal cell, Renshaw cell, granule cell, anterior horn cell). In some embodiments, the human neuron or nerve is myelinated. In some embodiments, the neuron or nerve is unmyelinated. In some embodiments, the human neuron or nerve is demyelinated. In some embodiments, the human neuron or nerve is undergoing demyelination.

[0226] In some embodiments, the neuron and / or neural target is a human neuron or neural component. The human neuron or neural component is any component of a neuron or nerve. In some embodiments, the target is tissue within or surrounding a neuron or nerve (e.g., epineurium, perineurium, or endoneurium). In some embodiments, the target is a component of myelin (e.g., myelin basic protein (MBP), myelin oligodendrocyte glycoprotein, or proteolipid protein). In some embodiments, the target is expressed by Schwann cells (e.g., MBP, glial fibrillary acidic protein, S-100, or myelin protein zero). In some embodiments, the target is a component of neuron or neural tissue (e.g., elastin, fibrillin, e-cadherin, cytokeratin, vimentin, collagen I, collagen III, collagen IV, or collagen V). In some embodiments, the target is a neurotrophic factor receptor expressed in neurons or nerves (e.g., tyrosine kinase receptors TrkA, TrkB, and TrkC, low-affinity neuronal or nerve growth receptors or p75 neurotrophin receptors, or GDNF family receptors alpha-1 or -2). In some embodiments, the target is a non-neurotrophic factor receptor expressed in neurons or neural tissue (e.g., epidermal growth factor receptor, transforming growth factor beta receptor, vascular endothelial growth factor receptor, endothelin A receptor, endothelin B receptor, and integrin receptors).

[0227] Determining whether a neuron and / or neural targeting molecule can bind to human neurons or nerves or their components can be achieved by any suitable method. In some embodiments, the method for determining whether a neuron and / or neural targeting molecule can bind to human neurons or nerves or their components comprises contacting a targeting molecule (e.g., peptide or aptamer) disclosed herein with a test agent for a sufficient time to allow the targeting molecule and the test agent to form a binding complex. The binding complex is detected using any suitable method. Suitable binding assays can be performed in vitro or in vivo, including but not limited to, phage display, two-hybrid screen, co-precipitation, cross-linking and expression cloning (see, for example, Bennett, JP and Yamamura, HI (1985) "Neurotransmitter, Hormone or Drug Receptor Binding Methods," in Neurotransmitter Receptor Binding (Yamamura, HL, et al., eds.), pp.61-89). Other binding assays involve the use of mass spectrometry or NMR techniques to identify molecules bound to a target of interest. The targeting molecules utilized in such assays can be naturally expressed, cloned, or synthetic.

[0228] In some embodiments, the targeting molecule is capable of crossing the blood-brain barrier to reach and bind to a human neuron or nerve of interest.

[0229] IV. Targeting Molecules Peptides and Aptamers The present disclosure provides peptides that can be bound to human motor / sensory and autonomic nerves and used in the human neuron or neuron targeting molecules of the present invention. In some embodiments, the targeting peptides have the amino acid sequence SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP 401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP 402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP 403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP 401 with a GGC linker; SEQ ID NO: 7), -N-2; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C with a GGC linker; SEQ ID NO: 11), -2; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWE EPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4;SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVKKGG (GG linker; SEQ ID NO: 122), SGQVPWEEPYYVVKKGG (HNP401-N-9 with a GG linker; SEQ ID NO: 123), SGQVPWEEPYYVVKKGG (HNP401-N-10 with a GG linker; SEQ ID NO: 124), SGQVPWEEPYYVVKKGG (HNP401-N-11 with a GG linker; SEQ ID NO: 125), SGQVPWEEPYYVVKKGG (HNP401-N-12 with a GG linker; SEQ ID NO: 126), SGQVPWEEPYYVVKKGG (HNP401-N-13 with a GG linker; SEQ ID NO: 127), SGQVPWEEPYYVVKKGG (HNP401-N-14 with a GG linker; SEQ ID NO: 128), SGQVPWEEPYYVVKKGG (HNP401-N-15 with a GG linker; SEQ ID NO: 129), SGQVPWEEPY SGQVPWEEPYYVVGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), or 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104);

[0230] In some embodiments, the human neuronal or neural targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac- PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWE EPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8;SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYV The peptide comprises a peptide sequence selected from the group consisting of VGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the peptide of the present invention comprises an amino acid sequence of about 8 to about 25 amino acids (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acids), about 10 to about 23 amino acids, or about 15 to about 21 amino acids containing the core binding domain of PYYVVKK (SEQ ID NO: 40). In some embodiments, peptides of the present invention comprise an amino acid sequence of about 13 to about 25 amino acids that includes the core binding domain of PYYVVKK (SEQ ID NO: 40) and the N-terminal sequence of QVPWEE (SEQ ID NO: 41). In some embodiments, peptides of the present invention comprise an amino acid core binding domain of PYY (SEQ ID NO: 116) or PYYVV (SEQ ID NO: 117) and the N-terminal sequence of QVPWEE (SEQ ID NO: 41). In some embodiments, peptides of the present invention comprise an amino acid core binding domain of PYY (SEQ ID NO: 116) and the N-terminal sequence of QVPWEE (SEQ ID NO: 41). In some embodiments, peptides of the present invention comprise an amino acid core binding domain of PYYVV (SEQ ID NO: 117) and the N-terminal sequence of QVPWEE (SEQ ID NO: 41).

[0231] One such embodiment is a peptide of QVPWEEPYYVVKK (SEQ ID NO: 42). In some embodiments, the targeting molecule comprises a peptide that is not Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker; SEQ ID NO: 17). In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the peptide is not NTQTLAKAPEHT (NP41; SEQ ID NO: 19).

[0232] In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3).

[0233] In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), and QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21).

[0234] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1).

[0235] In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2).

[0236] In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3).

[0237] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4).

[0238] In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5).

[0239] In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6).

[0240] In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7).

[0241] In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8).

[0242] In some embodiments, the targeting molecule comprises the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9).

[0243] In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10).

[0244] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11).

[0245] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12).

[0246] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13).

[0247] In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14).

[0248] In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16).

[0249] In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20).

[0250] In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21).

[0251] In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22).

[0252] In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23).

[0253] In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24).

[0254] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25).

[0255] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26).

[0256] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27).

[0257] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28).

[0258] In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118).

[0259] In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119).

[0260] In some embodiments, the targeting molecule comprises the peptide PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120).

[0261] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121).

[0262] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122).

[0263] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123).

[0264] In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124).

[0265] In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104).

[0266] In some embodiments, the targeting molecule comprises a peptide sequence that shares at least 80% homology with a peptide sequence disclosed herein. In some embodiments, the targeting molecule comprises a peptide sequence that shares at least 85% homology with a peptide sequence disclosed herein. In some embodiments, the targeting molecule comprises a peptide sequence that shares at least 90% homology with a peptide sequence disclosed herein. In some embodiments, the targeting molecule comprises a peptide sequence that shares at least 95% homology with a peptide sequence disclosed herein. In some embodiments, the targeting molecule comprises a peptide sequence that shares at least 99% homology with a peptide sequence disclosed herein.

[0267] In some embodiments, the targeting molecule is selected from the group consisting of the peptide sequences SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-P Ac-WEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC ( HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21); PWEE PYYVVKKSSGG (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8;SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-3 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 123), SGQVPWEEPYYVVGG (HNP401-C-5 with a GG linker; SEQ ID NO: 124), SGQVPWEEPYYVVGG (HNP401-C-6 with a GG linker; SEQ ID NO: 125), SGQVPWEEPYYVVGG (HNP401-C-7 with a GG linker; SEQ ID NO: 126), SGQVPWEEPYYVVGG (HNP401-C-8 with a GG linker; SEQ ID NO: 127), SGQVPWEEPYYVVGG (HNP401-C-9 with a GG linker; SEQ ID NO: 128), SGQVPWEEPYYVVGG (HNP401-C-10 with a GG linker; SEQ ID NO: 129), SGQVPWEEPYYVVGG (HNP401-C-11 with a GG linker; SEQ ID NO: 130), SGQVPWEEPYYVVGG NP401-C-4; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), or 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104);

[0268] In some embodiments, the targeting molecule comprises an aptamer.

[0269] The peptide and aptamer of the present invention can be synthesized by any suitable method.For example, the targeting peptide and aptamer of the present invention can be chemically synthesized by solid-phase peptide synthesis.In some embodiments, the peptide of the present invention is acetylated ("Ac" or "acetyl") at N-terminus, amidated ("CONH2" or "NH2") at C-terminus, or both. For example, the targeting peptides may be Ac-SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 43), Ac-WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 44), Ac-DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 45), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 46), Ac-QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 47), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with GGC linker; SEQ ID NO: 7), Ac-QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 48), Ac-PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 49), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSS (HNP401-N-5; SEQ ID NO: 9), 1-N-6; SEQ ID NO: 50), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSS (HNP401-N-8; SEQ ID NO: 51), Ac-PYYVVKKSSGGC (HNP401-N-8 with GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 52), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVV (HNP401-C-4;SEQ ID NO: 53), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 54), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEP (HNP401-C-8; SEQ ID NO: 55), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), SGQVPWEEPYYVVKKSS-CONH2 (HNP 401; SEQ ID NO: 56), WEYHYVDLNWTSQHPQ-CONH2 (HNP 402; SEQ ID NO: 57), DLPDIIWDFNWETA-CONH2 (HNP 403; SEQ ID NO: 58), SGQVPWEEPYYVVKKSSGGC-CONH2 (HNP401 with GGC linker; SEQ ID NO: 59), WEYHYVDLNWTSQHPQGGC-CONH2 (HNP402 with GGC linker; SEQ ID NO: 60), DLPDIIWDFNWETAGGC-CONH2 (HNP403 with GGC linker; SEQ ID NO: 61), DTHAHAKPRVPAFKSV-CONH2 (HNP 404; SEQ ID NO: 62), QVPWEEPYYVVKKSSGGC-CONH2 (HNP401-N-2 with a GGC linker; SEQ ID NO: 63), QVPWEEPYYVVKKSSGG-CONH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 64), PWEEPYYVVKKSSGGC-CONH2 (HNP401-N-4 with a GGC linker; SEQ ID NO: 65), EEPYYVVKKSSGGC-CONH2 (HNP401-N-6 with a GGC linker; SEQ ID NO: 66), PYYVVKKSSGGC -CONH2 (HNP401-N-8 with a GGC linker; SEQ ID NO: 67), SGQVPWEEPYYVVKKGGC-CONH2 (HNP401-C-2 with a GGC linker; SEQ ID NO: 68), SGQVPWEEPYYVVGGC-CONH2 (HNP401-C-4 with a GGC linker; SEQ ID NO: 69), SGQVPWEEPYYGGC-CONH2 (HNP401-C-6 with a GGC linker; SEQ ID NO: 70), SGQVPWEEPGGC-CONH2 (HNP401-C-8 with a GGC linker;SEQ ID NO: 71), QVPWEEPYYVVKKSS-CONH2 (HNP401-N-2; SEQ ID NO: 72), PWEEPYYVVKKSS-CONH2 (HNP401-N-4; SEQ ID NO: 73), EEPYYVVKKSS-CONH2 (HNP401-N-6; SEQ ID NO: 74), PYYVVKKSS-CONH2 (HNP401-N-8; SEQ ID NO: 75), SGQVPWEEPYYVVKK-CONH2 (HNP401-C-2; SEQ ID NO: 76), SGQVPWEEPYYVV-CONH2 (HNP401-C-4; SEQ ID NO: 77), SGQVPWEEPYY-CONH2 (HNP401-C-6; SEQ ID NO: 78) and SGQVPWEEP-CONH2 (HNP401-C-8; SEQ ID NO: 79), Ac-SGQVPWEEPYYVVKKSS-CONH2 (HNP401; SEQ ID NO: 80), Ac-WEYHYVDLNWTSQHPQ-CONH2 (HNP402; SEQ ID NO: 81), Ac-DLPDIIWDFNWETA-CONH2 (HNP403; SEQ ID NO: 82), Ac-SGQVPWEEPYYVVKKSSGGC-CONH2 (HNP401 with GGC linker; SEQ ID NO: 83), Ac-WEYHYVDLNWTSQHPQGGC-CONH2 (HNP402 with GGC linker; SEQ ID NO: 84), Ac-DLPDIIWDFNWETAGGC-CONH2 (HNP403 with GGC linker; SEQ ID NO: 85), Ac-DTHAHAKPRVPAFKSV-CONH2 (HNP 404; SEQ ID NO: 86), Ac-QVPWEEPYYVVKKSSGGC-CONH2 (HNP401-N-2 with a GGC linker; SEQ ID NO: 87), Ac-QVPWEEPYYVVKKSSGG-CONH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 88), Ac-PWEEPYYVVKKSSGGC-CONH2 (HNP401-N-4 with a GGC linker; SEQ ID NO: 89), Ac-EEPYYVVKKSSGGC-CONH2 (HNP401-N-6 with a GGC linker; SEQ ID NO: 90), Ac-PYYVVKKSSGGC-CONH2 (HNP401-N-8 with a GGC linker; SEQ ID NO: 91), Ac-SGQVPWEEPYYVVKKGGC-CONH2 (HNP401-C-2 with a GGC linker;SEQ ID NO: 92), Ac-SGQVPWEEPYYVVGGC-CONH2 (HNP401-C-4 with a GGC linker; SEQ ID NO: 93), Ac-SGQVPWEEPYYGGC-CONH2 (HNP401-C-6 with a GGC linker; SEQ ID NO: 94), Ac-SGQVPWEEPGGC-CONH2 (HNP401-C-8 with a GGC linker; SEQ ID NO: 95), Ac-QVPWEEPYYVVKKSS-CONH2 (HNP401-N-2; SEQ ID NO: 96), Ac-PWEEPYYVVKKSS-CONH2 (HNP401-N-4; SEQ ID NO: 97 ), Ac-EEPYYVVKKSS-CONH2 (HNP401-N-6; SEQ ID NO: 98), Ac-PYYVVKKSS-CONH2 (HNP401-N-8; SEQ ID NO: 99), Ac-SGQVPWEEPYYVVKK-CONH2 (HNP401-C-2; SEQ ID NO: 100), Ac-SGQVPWEEPYYVV-CONH2 (HNP401-C-4; SEQ ID NO: 101), Ac-SGQVPWEEPYY-CONH2 (HNP401-C-6; SEQ ID NO: 102), or Ac-SGQVPWEEP-CONH2 (HNP401-C-8; SEQ ID NO: 103). The technique of solid-phase synthesis is described, for example, by Barany and Merrifield (1963) Solid-Phase Peptide Synthesis; pp. 3-284 in The Peptides: Analysis, Synthesis, Biology. Vol. 2: Special Methods in Peptide Synthesis, Part A.; Merrifield et al. (1963) J. Am. Chem. Soc., 85:2149-2156; and Stewart et al. (1984) Solid Phase Peptide Synthesis, 2nd ed. Pierce Chem. Co., Rockford, IL.;

[0270] V. Cargo In some embodiments, the human neuron or neural targeting molecule further comprises a cargo. In some embodiments, the targeting peptide has the amino acid sequence SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 7), -N-2; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C with a GGC linker; SEQ ID NO: 11), -2; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWE EPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4;SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVKKGG (GG linker; SEQ ID NO: 122), SGQVPWEEPYYVVKKGG (HNP401-N-9 with a GG linker; SEQ ID NO: 123), SGQVPWEEPYYVVKKGG (HNP401-N-10 with a GG linker; SEQ ID NO: 124), SGQVPWEEPYYVVKKGG (HNP401-N-11 with a GG linker; SEQ ID NO: 125), SGQVPWEEPYYVVKKGG (HNP401-N-12 with a GG linker; SEQ ID NO: 126), SGQVPWEEPYYVVKKGG (HNP401-N-13 with a GG linker; SEQ ID NO: 127), SGQVPWEEPYYVVKKGG (HNP401-N-14 with a GG linker; SEQ ID NO: 128), SGQVPWEEPYYVVKKGG (HNP401-N-15 with a GG linker; SEQ ID NO: 129), SGQVPWEEPY SGQVPWEEPYYVVGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), or 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104);

[0271] In some embodiments, the human neuronal or neural targeting molecule further comprises a cargo. In some embodiments, the human neuronal or neural targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 7), -N-2; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C with a GGC linker; SEQ ID NO: 11), -2; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWE EPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22), EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4;SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-N-9 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVKKGG (HNP401-N-10 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYVVKKGG (HNP401-N-11 with a GG linker; SEQ ID NO: 123), SGQVPWEEPYYVVKKGG (HNP401-N-12 with a GG linker; SEQ ID NO: 124), SGQVPWEEPYYVVKKGG (HNP401-N-13 with a GG linker; SEQ ID NO: 125), SGQVPWEEPYYVVKKGG (HNP401-N-14 with a GG linker; SEQ ID NO: 126), SGQVPWEEPYYVVKKGG (HNP401-N-15 with a GG linker; SEQ ID NO: 127), SGQVPWEEPYYVVKKGG (HNP401-N-16 with a GG linker; SEQ ID NO: 128), SGQVPWEEPYYVVKKGG (HNP401-N- In some embodiments, the targeting molecule comprises a peptide sequence selected from the group consisting of SGQVPWEEPYYVVGG (HNP401-C-2; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker;In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of: SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1). In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2). In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4). In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5). In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7). In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22). In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8). In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23). In some embodiments, the targeting molecule is the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker;In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO:24). In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO:10). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO:25). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO:11). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO:26). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO:12). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the targeting molecule is Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker;In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the peptide is not NTQTLAKAPEHT (NP41; SEQ ID NO: 19).

[0272] In some embodiments, the peptide or aptamer is directly bound to the cargo. In some embodiments, the peptide or aptamer is indirectly bound to the cargo (e.g., via a linker). In some embodiments, the peptide or aptamer is bound to the cargo at its N-terminus, its C-terminus, or an internal position (e.g., an internal amino acid) of the peptide or aptamer. In some embodiments, two, three, four, or more peptides or aptamers are directly or indirectly bound to the cargo. In identification embodiments, the cargo is a drug, a fluorescent moiety, a photosensitizer, or a combination thereof. In some embodiments, the cargo is a drug. In some embodiments, the cargo is a fluorescent moiety or a fluorescent dye. In some embodiments, the cargo comprises a fluorescent moiety or a fluorescent dye. In some embodiments, the cargo is a photosensitizer. In some embodiments, the peptide or aptamer is bound to two or more cargo moieties. The two or more cargo moieties can be the same or different moieties, or can be from the same class of cargo moieties (e.g., two drugs) or different classes of cargo moieties (e.g., one drug and one fluorescent moiety).

[0273] Common classes of fluorescent dyes include, but are not limited to, xanthenes and their derivatives, such as rhodamine, rhodol, and fluorescein; bimanes; coumarins and their derivatives, such as umbelliferone and aminomethylcoumarin; aromatic amines, such as dansyl; squarate dyes; benzofurans; fluorescent cyanines; carbazoles; dicyanomethylenepyrans, polymethines, oxabenzanthrans, xanthenes, pyryliums, carbostils, perylenes, acridones, quinacridones, rubrenes, anthracenes, coronenes, phenanthracenes, pyrenes, butadienes, stilbenes, lanthanide metal chelate complexes, rare earth metal chelate complexes, and derivatives of such dyes. Fluorescent dyes are described, for example, in U.S. Patent Nos. 4,452,720, 5,227,487, and 5,543,295.

[0274] In some embodiments, the fluorescent moiety or dye is selected from the group consisting of xanthene, bimane, coumarin, aromatic amine, benzofuran, fluorescent cyanine, carbazole, dicyanomethylenepyran, polymethine, oxabenzanthrane, pyrylium, carbostyl, perylene, acridone, quinacridone, rubrene, anthracene, coronene, phenanthracene, pyrene, butadiene, stilbene, porphyrin, phthalocyanine, lanthanide metal chelate complexes, rare earth metal chelate complexes, FITC, Cy3, EGFP, cyan fluorescent protein (CFP), EGFP, 5-FAM, 6-FAM, FAM, fluorescein, IAEDANS, EDANS, and BODIPY FL, TRITC, Cy5, Cy3, YFP, 6-FAM, LC Red 640, Alexa Fluor 546, fluorescein, tetramethylrhodamine, Dabcyl, BODIPY FL, QSY7, QSY9, QSY21 and BBQ-650 dyes.

[0275] In some embodiments, the cargo comprises a fluorescein dye. Exemplary fluorescein dyes include, but are not limited to, 5-carboxyfluorescein, fluorescein-5-isothiocyanate, 5(6)-carboxyfluorescein, 5,6-dicarboxyfluorescein, 5-(and 6)-sulfofluorescein, sulfonefluorescein, succinylfluorescein, 5-(and 6)-carboxySNARF-1, carboxyfluorescein sulfonate, carboxyfluorescein zwitterion, carboxyfluorescein 1, carboxyfluorescein 2, carboxyfluorescein 3, carboxyfluorescein 4, carboxyfluorescein 5, carboxyfluorescein 6, carboxyfluorescein 7, carboxyfluorescein 8, carboxyfluorescein 9, carboxyfluorescein 10, carboxyfluorescein 11, carboxyfluorescein 12, carboxyfluorescein 13, carboxyfluorescein 14, carboxyfluorescein 15, carboxyfluorescein 16, carboxyfluorescein 17, carboxyfluorescein 18, carboxyfluorescein 19 ... Examples of other fluorescein dyes include quaternary ammonium, carboxyfluorescein phosphonate, carboxyfluorescein GABA, carboxyfluorescein-cys-Cy5, 5'(6')-carboxyfluorescein, fluorescein glutathione, and 6-carboxyfluorescein; examples of other fluorescein dyes can be found, for example, in U.S. Pat. No. 6,008,379, U.S. Pat. No. 5,750,409, U.S. Pat. No. 5,066,580, and U.S. Pat. No. 4,439,356. The cargo may include, for example, rhodamine dyes such as 5-(and 6)-carboxyrhodamine 110, tetramethylrhodamine-6-isothiocyanate, 5-carboxytetramethylrhodamine, 5-carboxyrhodol derivatives, tetramethyl and tetraethylrhodamine, diphenyldimethyl and diphenyldiethylrhodamine, dinaphthylrhodamine, rhodamine 101, sulfonyl chloride (sold under the trade name TEXAS RED®), and other rhodamine dyes. Other rhodamine dyes can be found, for example, in U.S. Pat. Nos. 6,080,852, 6,025,505, 5,936,087, and 5,750,409. In some embodiments, the cargo moiety includes, for example, a cyanine dye such as Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, or Cy7.

[0276] In some embodiments, the cargo moiety comprises a fluorophore. Fluorophores are commercially available, and any known and / or commercially available fluorophore can be used as the cargo. In some embodiments, the fluorophore exhibits a green fluorescent (e.g., 494 nm / 519 nm, etc.), orange fluorescent (e.g., 554 nm / 570 nm, etc.), red fluorescent (e.g., 590 nm / 617 nm, etc.), or far-red fluorescent (e.g., 651 nm / 672 nm, etc.) excitation / emission spectrum. In some embodiments, the fluorophore is a fluorophore having an excitation and emission spectrum in the range of about 350 nm to about 775 nm. In some embodiments, the excitation and emission spectra are about 346 nm / 446 nm, about 494 nm / 519 nm, about 554 nm / 570 nm, about 555 nm / 572 nm, about 590 nm / 617 nm, about 651 nm / 672 nm, about 679 nm / 702 nm, or about 749 nm / 775 nm. In some embodiments, the fluorophore is Alexa Fluor 3, Alexa Fluor 5, Alexa Fluor 350, Alexa Fluor 405, Alexa Fluor 430, Alexa Fluor 488, Alexa Fluor 500, Alexa Fluor 514, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 555, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 610, Alexa Fluor 633, Alexa Fluor 647, Alexa Fluor 660, Alexa Fluor 680, Alexa Fluor 700, and Alexa Fluor 750 (Life Technologies,In some embodiments, the fluorophores may include, but are not limited to, Cy dyes, including Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, and Cy7 (available from GE Life Sciences or Lumiprobes). In some embodiments, the fluorophores may include, but are not limited to, Cy3B 350, Cy3B 405, Cy3B 488, Cy3B 550, Cy3B 594, Cy3B 633, Cy3B 650, Cy3B 680, Cy3B 750, and Cy3B 800 (available from Thermo Scientific, USA). In some embodiments, the fluorophore is selected from the group consisting of, but not limited to, FluoProbes 390, FluoProbes 488, FluoProbes 532, FluoProbes 547H, FluoProbes 594, FluoProbes 647H, FluoProbes 682, FluoProbes 752, and FluoProbes 782, AMCA, DEAC (7-diethylaminocoumarin-3-carboxylic acid); 7-hydroxy-4-methylcoumarin-3; 7-hydroxycoumarin-3; MCA (7-methoxycoumarin-4-acetic acid); 7-methoxycoumarin-3; AMF (4'-(aminomethyl)fluorescein); 5-DTAF (5-(4,6-dichlorotriazinyl)aminofluorescein); 6-DTAF (6-(4,6-dichlorotriazinyl)aminofluorescein). ;FAM;6-FAM (6-carboxyfluorescein), 5(6)-FAM cadaverine;5-FAM cadaverine;5(6)-FAM ethylenediamine;5-FAM ethylenediamine;5-FITC (FITC isomer I; fluorescein-5-isothiocyanate);5-FITC cadaverine;fluorescein-5-maleimide;5-IAF (5-iodoacetamidofluorescein);6-JOE (6-carboxy-4',5'-dichloro-2',7'-Dimethoxyfluorescein; 5-CRl lO (5-carboxyrhodamine 110); 6-CRl lO (6-carboxyrhodamine 110); 5-CR6G (5-carboxyrhodamine 6G); 6-CR6G (6-carboxyrhodamine 6G); 5(6)-Carboxyrhodamine 6G cadaverine; 5(6)-Carboxyrhodamine 6G ethylenediamine; 5-ROX (5-carboxy-X-rhodamine); 6-ROX (6-carboxy-X-rhodamine); 5-TAMRA (5-carboxytetramethylrhodamine); 6-TAMRA (6-carboxytetramethylrhodamine); 5-TAMRA cadaverine; 6-TAMRA cadaverine; 5-TAMRA ethylenediamine; 6-TAMRA ethylenediamine; 5-TMR C6 maleimide; 6-TMR C6 maleimide; TR C2 maleimide; TR cadaverine; 5-TRITC; G isomer (tetramethylrhodamine-5-isothiocyanate); 6-TRITC; R isomer (tetramethylrhodamine-6-isothiocyanate); dansylcadaverine (5-dimethylaminonaphthalene-1-(N-(5-aminopentyl))sulfonamide); EDANS C2 maleimide; fluorescamine; NBD; and pyrromethene and their derivatives.

[0277] In some embodiments, the cargo comprises an environmentally sensitive fluorescent dye or fluorophore. Examples of environmentally sensitive fluorescent dyes or fluorophores include 5,6-carboxy-diethylrhodol (pH sensitive), merocyanine (membrane potential sensitive), and Nile red carboxylic acid (lipid sensitive).

[0278] In some embodiments, the cargo comprises a photosensitizer. A photosensitizer is any drug or compound useful in light-induced ablation therapy. When exposed to light of a specific wavelength, such drugs react with molecular oxygen to generate singlet oxygen, which is highly cytotoxic. Thus, targeting molecules of the present invention comprising a photosensitizer can be used to locally damage nerves. In certain embodiments, the photosensitizer is a porphyrin, a chlorin, or a dye. Examples of photosensitizers include porphyrin, protoporphyrin IX, purlitin, verteporfin, HPPH, temoporfin, methylene blue, photofrin, protofrin, hematoporphyrin, talaporfin, benzoporphyrin derivative monoacid, 5-aminolevulinic acid, lutetium texaphyrin, metallophthalocyanine, metallonaphthalocyanine sulfobenzo-porphyrazine, metallonaphthalocyanine, zinc tetrasulfophthalocyanine, bacteriochlorin, metallochlorin, chlorine derivative, tetra(m-hydroxyphenyl)chlorin (mTHPC), pheophorbide, dibromofluorescein (DBF), IR700DX, naphthalocyanine and porphyrin derivative. In some embodiments, the photosensitizer is conjugated to the C-terminal cysteine ​​residue of human neuron or neural targeting molecule via maleimide-mediated conjugation. Preferably, the photosensitizers of the present invention are activated by light having a wavelength between 400 nm and 700 nm. Even more preferably, the photosensitizers of the present invention are activated by light at 627 nm and 660 nm. An optimal light dose can be identified to maximize neuronal cell death while minimizing damage to adjacent tissue.

[0279] VI. Drugs In some embodiments, the human neuron or neural targeting molecule further comprises a drug. All drugs that act on neurons or nerves (or components thereof) are encompassed within the term "drug." The specific examples of drugs provided herein are exemplary and are not meant to limit the use of drugs with the targeting molecules disclosed herein. In some embodiments, the peptide or aptamer is directly attached to the drug. In some embodiments, the peptide or aptamer is indirectly attached to the drug (e.g., via a linker). In some embodiments, two or more peptides or aptamers are directly or indirectly attached to the drug. In some embodiments, the human neuron or neural targeting molecule further comprises a cargo. In some embodiments, the human neuron or neural targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKS SGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker;SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-3; SEQ ID NO: 22); NP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). Sequence number 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYV VGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), or 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401;SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1). In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2). In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4). In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5). In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker;In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22). In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8). In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23). In some embodiments, the targeting molecule comprises the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9). In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24). In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the targeting molecule is the peptide SGQVPWEEP (HNP401-C-8;In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104);

[0280] In some embodiments, the drug is selected from a drug that induces cell death (apoptosis or necrosis), a drug that inhibits cell death (apoptosis or necrosis), a drug that inhibits the transmission of neuronal or neural signals (i.e., electrochemical impulses), a drug that inhibits neurotransmitter release, a drug that agonizes GABA receptor activity, a drug that partially or completely inhibits neuronal repolarization, a drug that interferes with ion channel conduction, or a combination thereof.

[0281] In some embodiments, the drug is an antihistamine, a GABA receptor modulator, a neurotransmitter reuptake inhibitor, a local anesthetic, an anticholinergic, a sodium channel blocker, a calcium channel blocker, a thyrotropin-releasing hormone, a gamma-secretase inhibitor, an AMPA receptor agonist or antagonist, an NMDA receptor agonist or antagonist, an mGlu receptor agonist or antagonist, a growth factor, an antiemetic, a corticosteroid, a cytotoxic agent, an antioxidant, an iron chelator, a mitochondrial modulator, a sirtuin modulator, a nitric oxide (NO) and / or nitric oxide synthase (NOS) modulator, a potassium channel agonist or antagonist, a purinergic receptor agonist or antagonist, or a combination thereof.

[0282] In some embodiments, the drug is meclizine, diphenhydramine, dimenhydrinate, loratadine, quetiapine, mepyramine, piperoxane, antazoline, carbinoxamine, doxylamine, clemastine, pheniramine, chlorphenamine, chlorpheniramine, dexchlorpheniramine, brompheniramine, triprolidine, cyclizine, chlorcyclizine, hydroxyzine, promethazine, alimemazine, trimeprazine, cyproheptadine, azatadine, ketotifen, oxatomide, meclizine hydrochloride , promethazine hydrochloride, cinnarizine, hydroxyzine pamoate, betahistine dihydrochloride, alprazolam, bromazepam, brotizolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, estazolam, flunitrazepam, flurazepam, loprazolam, lorazepam, lormetazepam, idazolam, nimetazepam, nitrazepam, oxazepam, prazepam, temazepam, triazolam, clonazepam, diazepam, lorazepam, furosemide, bumetanide, ethacrynic acid, gabapentin, pregabalin, Cymol, baclofen, amitriptyline, nortriptyline, trimipramine, fluoxetine, paroxetine, sertraline, glycopyrrolate, homatropine, scopolamine, atropine, benzocaine, carticaine, cinchocaine, cyclomethicaine, lidocaine, prilocaine, propoxycaine, proparacaine, tetracaine, tocainide, trimecaine, carbamazepine, oxcarbazepine, phenytaine, valproic acid, sodium valproate, cinnarizine, flunarizine, nimodipine, thyrotropin The estrogen amifostine (also known as WR-2721 or ETHYOL®); carbamate compounds (e.g., 2-phenyl-1,2-ethaneethanediol monocarbamate and dicarbamate); LY450139 (hydroxyvaleryl monobenzocaprolactam); L685458 (1S-benzyl-4R[1-[1S-carbamoyl-2-phenethylcarbamoyl)-1S-3-methylbutylcarbamoyl]-2R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester);LY411575 (N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[bid]azepin-7yl]-L-alaninamide; MK-0752; Tarenflurvir; BMS-299897 (2-[(lR)-l-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)amino]ethyl]-5-fluorobenzenepropanol Panic acid;CNQX (6-cyano-7-nitroquinoxaline-2,3-dione);NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione);DNQX (6,7-dinitroquinoxaline-2,3-dione);Kynurenic acid;2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-[f]quinoxaline;1-aminoadamantane;Dextromethorphan;Dextrorphan;Ibogaine;Ke thamine; nitrous oxide; phencyclidine; riluzole; tiletamine; memantine; dizocilpine; aptiganel; remacimide; 7-chlorokynurenate; DCKA (5,7-dichlorokynurenic acid); kynurenic acid; 1-aminocyclopropanecarboxylic acid (ACPC); AP7 (2-amino-7-phosphonoheptanoic acid); APV (R-2-amino-5-phosphonopentanoate); CPPene (3-[(R)-2-carboxypiperazin-4-yl]-propionate) -2-enyl-l-phosphonic acid; (+)-(lS,2S)-l-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl-)-chroman-4; 7-diol; (IR; * ,2R *)-l-(4-Hydroxy-3-memylphenyl)-2-(4-(4-fluoro-phenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol-mesylate;LY389795((-)-2-Thia-4-aminobicyclo-hexane-4,6-dicarboxylate);LY379268((-)-2-Oxa-4-aminobicyclo-hexane-4,6-dicarboxylate);LY354740((+)-2-Aminobicyclo-hexane-2,6-dicarboxylate);DCG-IV((2S,2'R,3' R)-2-(2',31-dicarboxycyclopropyl)glycine; 2R,4R-APDC (2R,4R-4-aminopyrrolidine-2,4-dicarboxylate); (S)-3C4HPG ((S)-3-carboxy-4-hydroxyphenylglycine); (S)-4C3HPG ((S)-4-carboxy-3-hydroxyphenylglycine); L-CCG-I ((2S,1'S,2'S)-2-(carboxycyclopropyl)glycine); ACPT-I ((lS,3R,4S)-l-aminocyclopentane-l,3,4-trimethylolpropane) L-AP4 (L-(+)-2-amino-4-phosphonobutyric acid); (S)-3,4-DCPG ((S)-3,4-dicarboxyphenylglycine); (RS)-3,4-DCPG ((RS)-3,4-dicarboxyphenylglycine); (RS)-4-phosphonophenylglycine ((RS)PPG); AMN082 (,N'-bis(diphenylmethyl)-l,2-ethanediamine dihydrochloride); DCG-IV ((2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine); AMN082; brain-derived neurotrophic factor (BDNF); ciliary neurotrophic factor (CNTF); glial cell line-derived neurotrophic factor (GDNF); neurotrophin-3; neurotrophin-4; fibroblast growth factor (FGF) receptor; insulin-like growth factor (IGF); aminoglycoside antibiotics (e.g., gentamicin and amikacin); macrolide antibiotics (e.g., erythromycin); glycopeptide antibiotics (e.g., vancomycin); salicylic acid; nicotine; eburnamenine-14-carboxylic acid ethyl ester;Sipatridine (2-(4-methylpiperazin-l-yl)-5-(2,3,5-trichlorophenyl)-pyrimidin-4-amine); Amiloride (3,5-diamino-N-(aminoiminomethyl)-6-chloropyrazinecarboxamide hydrochloride); Carbamazepine (5H-dibenzo[b,f]azepine-5-carboxamide); TTX (octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano-10aH-[l,3]dioxocino[6,5-d]pyrimidine-4,7,10,ll,12-pentol); RS100642( l-(2,6-Dimethylphenoxy)-2-ethylaminopropane hydrochloride; Mexiletine ((l-(2,6-Dimethylphenoxy)-2-aminopropane hydrochloride)); QX-314 (N-(2,6-Dimethylphenylcarbamoylmethyl)triethylammonium bromide); Phenytoin (5,5-diphenylimidazolidine-2,4-dione); Lamotrigine (6-(2,3-dichlorophenyl)-l,2,4-triazine-3,5-diamine); 4030W92 (2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine) ;BW1003C87 (5-(2,3,5-trichlorophenyl)pyrimidine-2,4-1,1ethanesulfonate);QX-222 (2-[(2,6-dimethylphenyl)amino]-N,N,N-trimethyl-2-oxoethaniminium chloride);Ambroxol (trans-4-[[(2-amino-3,5-dibromophenyl)methyl]amino]cyclohexanol hydrochloride);R56865 (N-[1-(4-(4-fluorophenoxy)butyl]-4-piperidinyl-N-methyl-2-benzo-thiazolamine);Lubeluzole;Ajmaline ( (17R,21alpha)-Azimalan-17,21-diol); procainamide (4-amino-N-(2-diethylaminoethylbenzamide hydrochloride); flecainide; rilzolea; triamicinolone actenoid; dexamethasone; promethazine; prochlorperazine; trimethobenzamide; triethylperazine; dolasetron; granisetron; ondansetron; tropisetron; and palonosetron; droperidol; meclizine; perphenazine; thiethylperazine; domperidone; properidol; haloperidol; chlorpromazine;Promethazine; Prochlorperazine; Metoclopramide; Dronabinol; Nabilone; Sativex; Scopolamine; Dexamethasone; Trimethobenzamine; Emetrol; Propofol; Muscimol; Acridinecarboxamide; Actinomycin; 17-N-allylamino-17-demethoxygeldanamycin; Amsacrine; Aminopterin; Anthracyclines; Antineoplastic agents; Antineoplastons; 5-Azacytidine; Azathioprine; BL22; Bendamustine; Biricodar; Bleomycin; Bortezomib; Bryostatin; Busu Rufan; Calyculin; Camptothecin; Capecitabine; Carboplatin; Chlorambucil; Cisplatin; Cladribine; Clofarabine; Cytarabine; Dacarbazine; Dasatinib; Daunorubicin; Decitabine; Dichloroacetic acid; Discodermolide; Docetaxel; Doxorubicin; Epirubicin; Epothilon; Eribulin; Estramustine; Etoposide; Exatecan; Exisulind; Ferruginol; Floxuridine; Fludarabine; Fluorouracil; Fosfestrol; Fotemustine; Gemcitabine; Hydroxyurea; IT-101 ; Idarubicin; Ifosfamide; Imiquimod; Irinotecan; Irofulven; Ixabepilone; Laniquidar; Lapatinib; Lenalidomide; Lomustine; Lurtotecan; Mahosfamide; Masoprocol; Mechlorethamine; Melphalan; Mercaptopurine; Mitomycin; Mitotane; Mitoxantrone; Nelarabine; Nilotinib; Oblimersen; Oxaliplatin; PAC-I; Methotrexate (RHEUMATREX®, amethopterin); Cyclophosphamide (Cytoxan®), Thalidomide (THALIDOMID (registered trademark); paclitaxel; pemetrexed; pentostatin; pipobroman; pixantrone; plicamycin; procarbazine; proteasome inhibitors (e.g.; bortezomib); raltitrexed; rebeccamycin; rubitecan; SN-38; salinosporamide A; satraplatin; streptozotocin; swainsonine; tariquidar; taxanes; tegafur-uracil; temozolomide; testolactone; thiotepa; thioguanine; topotecan; trabectedin; tretinoin; triplatin tetranitrate; tris(2-chloroethyl)ammetha;Troxacitabine; uracil mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; zosuquidar; N-acetylcysteine; vitamin E; vitamin C; vitamin A; lutein; selenium; glutathione; melatonin; polyphenols; carotenoids; coenzyme Q10; ebselen (2-phenyl-l,2-benzisoselenazol-3(2H)-one (PZ51 or DR330) 5); L-Methionine; Azulenyl Nitrone; L-(+)-Ergothioneine; CAPE (Caffeic Acid Phenethyl Ester); Dimethylthiourea; Dimethyl Sulfoxide; Disfenton Sodium; Pentoxifylline; MCI-186; Ambroxol; U-83836E; MitoQ (Mitoquinone Mesylate); Idebenone (2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-cyclohexa-2,5-diene-l,4-dione); Desferrioxamine; Hydroxybenzylethylenediamine; Fullerenol-1, Pyrrolidine Dithiocarbamate; Acetylcarnitine; Lipoic Acid; Stilbenes; Chalcones; Flavones; Isoflavones; Flavanones; Anthocyanidins; Catechins; Isonicotinamide; Dipyridamole; ZM336372; Camptothecin; Coumestrol; Nordihydroguaiaretic Acid ;Esculetin;SRT-1720;SRT-1460;SRT-2183;Aminoguanidine;l-amino-2-hydroxyguanidine p-toluenesulfate;GED;Bromocriptine mesylate;Dexamethasone;SDMA;ADMA;L-NMMA;L-NMEA;D-MMA;L-NIL;L-NNA;L-NPA;L-NAME;L-VNIO;Diphenyleneiodonium chloride 2-ethyl-2-thiopseudourea; ;Haloperidol;L-NIO;MEG;SMT;SMTC;7-Ni;nNOS inhibitor;1,3-PBITU;L-thiocitrulline;TRIM;MTR-105;BBS-I;BBS-2;ONO-1714;GW273629;GW274150;PPA250;AR-R17477;AR-R18512;spiroquinazolone;1400W;S-NC;NTG;SNP;thapsigargin;VEGF;bradykinin;ATP;sphingosine-1-phosphate;estrogen;angiopoietin;acetylcholine;SIN-I;GEA3162 ;GEA;GEA5024;GEA5538;SNAP;Molsidomine;CNO-4;CNO-5;DEA / NO;IPA / NO;SPER / NO;SULFI / NO;OXI / NO;DETA / NO;Nicorandil;Minoxidil, levcromakalim;lemakalim;cromakalim;L-735,334;Retigabine;Flupirtine;BMS-204352;DMP-543;Linopirdine;XE991;4-AP;3,4-DAP;E-4031;DIDS;Way123,398;CGS-12066A;Dofetilide;Sotalol;Apamin; Amiodarone; Azimilide; Bretylium; Clofilium; Tedisamil; Ibutilide; Sematilide; Nifekalant; Tamulstoxin; ATP; ADP; UTP; UDP; UDP-glucose; Adenosine; 2-MESATP; 2-MESADP; ABMEATP; DATPAS; ATPrS; BZ-ATP; MRS2703; Denufosol tetrasodium; MRS2365; MRS2690; PSB0474; A-317491; RO-3 (Roche); Suramin; PPADS; PPNDS; DIDS; Pyridoxal-5-phosphate; 5-(3-Bromophenyl)-l,3-dihydro-2H-benzofuro-[3,2-e]-l,4-diazepin-2-one; Cibacron Blue; Basilene Blue; Ivermectin; A-438079; A-740003; NF023; NF449; NFIlO; NF157; MRS2179; NF279; MRS2211; MRS2279; MRS2500 tetrasodium salt; TNP-ATP; Tetramethylpyrazine; Ip5I; jγγ-carboxymethylene ATP; βγ-chlorophosphomethylene ATP; KN-62; Spinorphin; Minocycline;SB-203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-lH-imidazole); PD169316 (4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-lH-imidazole); SB202190 (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-lH-imidazole); RWJ67657 (4-[4-(4-fluorophenyl)-l-(3-phenylpropyl)-5-(4-pyridinyl) [L]-lH-imidazol-2-yl]-3-butyn-1-ol; SB220025 (5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(4-piperidinyl)imidazole); D-JNKI-I ((D)-hJIPi75-i57-DPro-DPro-(D)-HIV-TAT57-48); AM-111 (Auris); SP600125 (anthra[l,9-cd]pyrazol-6(2H)-one); JNK inhibitor I ((L)-HIV-TAT48-57-PP-JBD20); JNK Inhibitor III ((L)-HIV-TAT47-57-gaba-c-Junδ33-57); AS601245 (1,3-benzothiazol-2-yl(2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl)acetonitrile); JNK inhibitor VI (H2N-RPKRPTTLNLF-NH2) (SEQ ID NO: 125); JNK inhibitor VIII (N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)-2-(2,5-dimethoxyphenyl)acetamide); JNK inhibitor IX (N-(3-cyano-4,5, 6,7-tetrahydro-l-benzothien-2-yl)-l-naphthamide; dicoumarol (3,3'-methylenebis(4-hydroxycoumarin)); SC-236 (4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzene-sulfonamide); CEP-1347 (Cephalon); CEP-11004 (Cephalon); artificial proteins comprising at least a portion of a Bcl-2 polypeptide; recombinant FNK; V5 (also known as Bax inhibitor peptide V5);Bax channel blocker ((±)-l-(3,6-dibromocarbazol-9-yl)-3-piperazin-l-yl-propan-2-ol); Bax inhibitory peptide P5 (also known as Bax inhibitor peptide P5); Kp7-6; FAIM(S) (Fas apoptosis inhibitory molecule-short); FAIM(L) (Fas apoptosis inhibitory molecule-long); Fas:Fc; FAP-I; NOK2; F2051; F1926; F2928; ZB4; Fas M3m Ab; EGF; 740Y-P; SC3036 (KKHTDDGYMPMSPGVA) (SEQ ID NO: 126); PI3-kinase activator (Santa Cruz Biotechnology, Inc.); Pam3Cys((S)-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys4-OH, trihydrochloride); Actl (NF-kB activator 1); anti-DcB antibody; acetyl-11-keto-b-boswellic acid; andrographolide; caffeic acid phenethyl ester (CAPE); gliotoxin; isohelenin; NEMO binding domain binding peptide (DRQIKIWFQNRRMKWKKTALDWSWLQTE) (SEQ ID NO: 127); NF-kB activation inhibitor (6-amino-4-(4-phenoxyphenylethylamino)quinazoline); NF-kB activation inhibitor II (4-methyl-Nl-(3-phenylpropyl)benzene-l, 2-diamine; NF-kB activation inhibitor III (3-chloro-4-nitro-N-(5-nitro-2-thiazolyl)-benzamide); NF-kB activation inhibitor IV ((E)-2-fluoro-4'-methoxystilbene); NF-kB activation inhibitor V (5-hydroxy-(2,6-diisopropylphenyl)-IH-isoindole-1,3-dione); NF-kBSN50 (AAVALLPAVLLALLAPVQRKRQKLMP) (SEQ ID NO: 128); oridonin; parthenolide; PPM-18 (2-benzoylamino-1,4-naphthoquinone); Rol06-9920; sulfasalazine; TIRAP inhibitor peptide (RQIKiWFNRRMKWKKLQLRDAAPGGAIVS) (SEQ ID NO: 129); withaferin A; wogonin;BAY11-7082 ((E)3-[(4-methylphenyl)sulfonyl]-2-propenenitrile); BAY11-7085 ((E)3-[(4-t-butylphenyl)sulfonyl]-2-propenenitrile); (E)-capsaicin; gold thiomalate (ATM or Au™); evodiamine; hypoestoxide; IKK inhibitor III (BMS-345541); IKK inhibitor VII; IKK inhibitor X; IKK inhibitor II; IKK-2 inhibitor IV; IKK-2 inhibitor V; IKK-2 inhibitor VI; IKK-2 inhibitor (SC-514); IkB kinase inhibitor peptide; IKK-3 inhibitor IX; ARRY-797 (Array BioPharma; SB-220025 (5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(4-piperidinyl)imidazole); SB-239063 (trans-4-[4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-lH-imidazol-l-yl]cyclohexanol); SB-202190 (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)lH-imidazole); JX-401 (-[2-methoxy-4-(methylthio)benzoyl]-4-(phenylmethyl)piperidine); PD-169316 (4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-lH-imidazole); S KF-86002 (6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo[2,1b]thiazole dihydrochloride); SB-200646 (N-(1-methyl-1H-indol-5-yl)-N'-3-pyridinylurea); CMPD-1 (2'-fluoro-N-(4-hydroxyphenyl)-[1,1'-biphenyl]-4-butanamide); EO-1428 ((2-methylphenyl)-[4-[(2-amino-4-bromophenyl)amino]-2-chlorophenyl]methanone); SB-253080 (4-[5-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine); SD-169 (1H-indole-5-carboxamide);SB-203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)lH-imidazole); TZP-101 (Tranzyme Pharma); TZP-102 (Tranzyme Pharma); GHRP-6 (growth hormone-releasing peptide-6); GHRP-2 (growth hormone-releasing peptide-2); EX-1314 (Elixir Pharmaceuticals; MK-677 (Merck); L-692,429 (butanamide, 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-l-((2'-(lH-tetrazol-5-yl)(l,l'-biphenyl)-4-yl)methyl)-lH-l-benzazepin-3-yl)-, (R)-); EP1572 (Aib-DTrp-DgTrp-CHO); diltiazem; metabolite of diltiazem; BR E (protein expressed in the brain and reproductive organs); verapamil; nimodipine; diltiazem; omega-conotoxin; GVIA; amlodipine; felodipine; lacidipine; mibefradil; NPPB (5-nitro-2-(3-phenylpropylamino)benzoic acid); flunarizine; erythropoietin; piperine; hemin; brazilin; z-VAD-FMK (benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone); z-LEH D-FMK (benzyloxycarbonyl-Leu-Glu(OMe)-His-Asp(OMe)-fluoromethylketone); BD-FMK (boc-aspartyl(Ome)-fluoromethylketone); Ac-LEHD-CHO (N-acetyl-Leu-Glu-His-Asp-CHO); Ac-IETD-CHO (N-acetyl-Ile-Glu-Thr-Asp-CHO); z-IETD-FMK (benzyloxycarbonyl-Ile-Glu( (OMe)-Thr-Asp(OMe)-fluoromethylketone; FAM-LEHD-FMK (benzyloxycarbonylLeu-Glu-His-Asp-fluoromethylketone); FAM-LETD-FMK (benzyloxycarbonylLeu-Glu-Thr-Asp-fluoromethylketone); Q-VD-OPH (quinoline-Val-ASp-CH2-O-Ph); XIAP; cIAP-1; cIAP-2; ML-IAP; ILP-2; NAIP;Survivin; Bruce; IAPL-3; Fortilin; Leupeptin; PD-150606 (3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid); MDL-28170 (Z-Val-Phe-CHO); Calpeptin; Acetyl-calpastatin; MG132 (N-[(phenylmethoxy)carbonyl]-L-leucyl-N-[(lS)-l-formyl-3-methylbutyl]-L-leucinamide); MYODUR; BN82270 (Ipsen); BN2204 (Ipsen); AHLi-11 (Quark Pharmaceuticals), anmdm2 protein, pifithrin-α (l-(4-methylphenyl)-2-(4,5,6,7-tetrahydro-2-imino-3(2H)-benzothiazolyl)ethanone); trans-stilbene; cis-stilbene; resveratrol; piciatannol; rhapontin; deoxyrhapontin; butein; chalcone; isoliquirtigen; butein; 4,2',4'-trihydroxychalcone; 3,4,2',4',6'-pentahydroxychalcone; flavone; morin; fisetin; luteolin; quercetin; kaempferol; apigenin; gossypetin; myricetin; 6-hydroxyapigenin; 5-hydroxyflavone; 5,7,3',4',5'-pentahydroxyflavone; 3,7,3',4',5'-pentahydroxyflavone; 3,6,3',4'-tetrahydroxy Flavone; 7,3',4',5'-tetrahydroxyflavone; 3,6,2',4'-tetrahydroxyflavone; 7,4'-dihydroxyflavone; 7,8,3',4'-tetrahydroxyflavone; 3,6,2',3'-tetrahydroxyflavone; 4'-hydroxyflavone; 5-hydroxyflavone; 5,4'-dihydroxyflavone; 5,7-dihydroxyflavone; daidzein; genistein; narin Genin; Flavanone; 3,5,7,3',4'-Pentahydroxyflavanone; Pelargonidin chloride; Cyanidin chloride; Delphinidin chloride; (-)-Epicatechin (Hydroxyl sites: 3,5,7,3',4); (-)-Catechin (Hydroxyl sites: 3,5,7,3',40); (-)-Gallocatechin (Hydroxyl sites: 3,5,7,3',4',5O(+)-Catechin (Hydroxyl sites: 3,5,7,3',4^;(+)-Epicatechin (hydroxy moiety: 3,5,7,3',41J); Hinokitiol (b-thujaplicin; 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one); L-(+)-Ergothioneine ((S)-a-carboxy-2,3-dihydro-N,N,N-trimethyl-2-thioxo-lH-imidazole 4-ethanaminium inner salt); Caffeic acid phenyl ester; MCI-186 (3-methyl HBED (N,N'-di-(2-hydroxybenzylethylenediamine-HN'-diacetic acid·H2O); ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)cyclohexane-HCl); and U-83836E ((-)-2-((4-(2,6-di-l-pyrrolidinyl-4-pyrimidinyl)-l-piperazinyl)methyl)-3,4-dihydro- 2,5,7,8-Tetramethyl-2H-l-benzopyran-6-ol *2HCl); / 5-1-5-Methyl-nicotinamide-2'-deoxyribose; / SD-I'-5-Methyl-nicotinamide-2'-deoxyribofuranoside; / 3-1'-4,5-Dimethyl-nicotinamide-2'-deoxyribose; / 3-D-I'-4,5-Dimethyl-nicotinamide-2'-deoxyribofuranoside;1-Naphthyl PP1 (1-(1,1-dimethylethyl)-3-(1-naphthalenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine);Lavenderstin A (5-[[(2,5-dihydroxyphenyl)methyl][(2-hydroxyphenyl)methyl]amino]-2-hydroxybenzoic acid);MNS (3,4-methylenedioxy-b-nitrostyrene);PP1 (1-(1,1-dimethylethyl)-1-(4-methylphenyl )-1H-pyrazolo[3,4-d]pyrimidin-4-amine; PP2 (3-(4-chlorophenyl)l-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); KX1-004 (Kinex); KX1-005 (Kinex); KX1-136 (Kinex); KX1-174 (Kinex); KX1-141 (Kinex); KX2-328 ( Kinex; KX1-306 (Kinex); KX1-329 (Kinex); KX2-391 (Kinex); KX2-377 (Kinex); ZD4190 (AstraZeneca; N-(4-bromo-2-fluorophenyl)-6-methoxy-7-(2-(lH-l,2,3-triazol-l-yl)ethoxy)quinazolin-4-amine); AP22408 (Ariad Pharmaceuticals); AP23236 (Ariad Pharmaceuticals); AP23451 (Ariad Pharmaceuticals); AP23464 (Ariad Pharmaceuticals); AZD0530 (AstraZeneca); AZM475271 (M475271; AstraZeneca); dasatinib (N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-l-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide); GN963 (trans-4-(6,7-dimethoxyquinoxalin-2ylamino)cyclohexanol sulfate);Bosutinib (4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methyl-l-piperazinyl)propoxy)-3-quinolinecarbonitrile); or a combination thereof.

[0283] VII. Fluorescent Moieties In some embodiments, the human neuronal or neural targeting molecule further comprises a fluorescent moiety (e.g., a fluorescent protein, peptide, or fluorescent dye molecule). All fluorescent moieties are encompassed within the term "fluorescent moiety." The specific examples of fluorescent moieties provided herein are exemplary and are not meant to limit the use of the fluorescent moiety with the targeting molecules disclosed herein. In some embodiments, the human neuronal or neural targeting molecule further comprises a cargo. In some embodiments, the human neuronal or neural targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4;SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with GG linker; SEQ ID NO: 119), PYYVVKKS The peptide comprises a peptide sequence selected from the group consisting of SGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker;In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1). In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2). In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4). In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5). In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7). In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22). In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8). In some embodiments, the targeting molecule is the peptide EEPYYVVKKSS (HNP401-N-6;In some embodiments, the targeting molecule comprises the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9). In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24). In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the targeting molecule is the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker;In some embodiments, the targeting molecule comprises a peptide that is not Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker; SEQ ID NO: 17). In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the peptide is not NTQTLAKAPEHT (NP41; SEQ ID NO: 19).

[0284] In some embodiments, the peptide or aptamer is directly bound to the fluorescent moiety. In some embodiments, the peptide or aptamer is indirectly bound to the fluorescent moiety (e.g., via a linker). In some embodiments, the peptide or aptamer is bound to the fluorescent moiety at its N-terminus, its C-terminus, or an internal position (e.g., an internal amino acid) of the peptide or aptamer. In some embodiments, two or more peptides or aptamers are directly or indirectly bound to a single fluorescent moiety.

[0285] Examples of fluorescent dyes include, but are not limited to, xanthenes (e.g., rhodamine, rhodol, and fluorescein and their derivatives), bimanes, coumarins and their derivatives (e.g., umbelliferone and aminomethylcoumarin), aromatic amines (e.g., dansyl, squarate dyes), benzofurans, fluorescent cyanines, carbazoles, dicyanomethylenepyrans, polymethines, oxabenzanthrans, xanthenes, pyryliums, carbostyls, perylenes, acridones, quinacridones, rubrenes, anthracenes, coronenes, phenanthracenes, pyrenes, butadienes, stilbenes, porphyrins, phthalocyanines, lanthanide metal chelate complexes, rare earth metal chelate complexes, and derivatives of such dyes.

[0286] In some embodiments, the fluorescent moiety is a fluorescein dye. Examples of fluorescein dyes include, but are not limited to, 5-carboxyfluorescein, fluorescein-5-isothiocyanate and 6-carboxyfluorescein, 5,6-dicarboxyfluorescein, 5-(and 6)-sulfofluorescein, sulfonefluorescein, succinylfluorescein, 5-(and 6)-carboxySNARF-1, carboxyfluorescein sulfonate, carboxyfluorescein zwitterion, carboxyfluorescein quaternary ammonium, carboxyfluorescein phosphonate, carboxyfluorescein GABA, 5'(6')-carboxyfluorescein, carboxyfluorescein-cys-Cy5, and fluorescein glutathione.

[0287] In some embodiments, the fluorescent moiety is a rhodamine dye. Examples of rhodamine dyes include, but are not limited to, tetramethylrhodamine-6-isothiocyanate, 5-carboxytetramethylrhodamine, 5-carboxyrhodol derivatives, carboxyrhodamine 110, tetramethyl and tetraethylrhodamine, diphenyldimethyl and diphenyldiethylrhodamine, dinaphthylrhodamine, and rhodamine 101 sulfonyl chloride (sold under the trade name TEXAS RED®).

[0288] In some embodiments, the fluorescent moiety is a cyanine dye. Examples of cyanine dyes include, but are not limited to, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, and Cy7.

[0289] In some embodiments, the fluorescent moiety is a peptide. In some embodiments, the fluorescent moiety is green fluorescent protein (GFP). In some embodiments, the fluorescent moiety is a derivative of GFP (e.g., EBFP, EBFP2, Azurite, mKalamal, ECFP, Cerulean, CyPet, YFP, Citrine, Venus, YPet).

[0290] Fluorescent labels are detected by any suitable method, for example, by exciting the fluorochrome with the appropriate wavelength of light and detecting the resulting fluorescence, e.g., by microscope, visual inspection, via photographic film, by the use of electronic detectors such as charge-coupled devices (CCDs), photomultipliers, etc.

[0291] In some embodiments, the fluorescent moiety is conjugated to a high molecular weight molecule such as a water-soluble polymer, including, but not limited to, dextran, PEG, serum albumin, or poly(amidoamine) dendrimers.

[0292] Exemplary targeting molecules according to the present invention include 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104), Ac-SGQVPWEEPYYVVKKSSGGC-5FAM (HNP401 with a GGC linker; SEQ ID NO: 105), Ac-WEYHYVDLNWTSQHPQGGC-5FAM (HNP402 with a GGC linker; SEQ ID NO: 106), Ac-DLPDIIWDFNWETAGGC-5FAM (HNP403 with a GGC linker; SEQ ID NO: 107), Ac-QVPWEEPYYVVKKSSGGC-5FAM (HNP401-N-2 with a GGC linker; SEQ ID NO: 108), Ac-PWEEPYYVVKKSSGGC-5FAM (HNP401- Ac-EEPYYVVKKSSGGC-5FAM (HNP401-N-6 with a GGC linker; SEQ ID NO: 110), Ac-PYYVVKKSSGGC-5FAM (HNP401-N-8 with a GGC linker; SEQ ID NO: 111), Ac-SGQVPWEEPYYVVKKGGC-5FAM (HNP401-C-2 with a GGC linker; SEQ ID NO: 112), Ac-SGQVPWEEPYYVVGGC-5FAM (HNP401-C-4 with a GGC linker; SEQ ID NO: 113), Ac-SGQVPWEEPYYGGC-5FAM (HNP401-C-6 with a GGC linker; SEQ ID NO: 114), and Ac-SGQVPWEEPGGC-5FAM (HNP401-C-8 with a GGC linker; SEQ ID NO: 115).

[0293] VIII. Linkers In some embodiments, the cargo (e.g., a fluorescent moiety, photosensitizer, or drug) is directly attached to the human neuronal or neural targeting molecule, for example, at the end of the targeting peptide. Alternatively, in some embodiments, the cargo (e.g., a fluorescent moiety or drug) is indirectly attached to the targeting molecule disclosed herein (e.g., via a linker). In some embodiments, the human neuronal or neural targeting molecule further comprises a cargo. In some embodiments, the human neuronal or neural targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP40 with GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with GGC linker; SEQ ID NO: 9), Ac-PYYV VKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker;SEQ ID NO:21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO:22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO:23), PYYVVKKSS (HNP401-N-8; SEQ ID NO:24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO:25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO:26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO:27), SGQVPWEEP (HNP401-C-8; SEQ ID NO:28), PWEEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO:118), EEPYYVVKKSSGG (HNP401-N-6 with GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), and Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker;In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of: SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1). In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2). In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4). In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5). In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7). In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22). In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8). In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23). In some embodiments, the targeting molecule is the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker;In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO:24). In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO:10). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO:25). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO:11). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO:26). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO:12). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule is Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker;In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the targeting molecule comprises a peptide that is not NTQTLAKAPEHT (SEQ ID NO: 19).

[0294] As used herein, a "linker" refers to any molecule that can be (e.g., covalently) linked to a targeting molecule disclosed herein. Linkers include, but are not limited to, straight-chain or branched-chain carbon linkers, heterocyclic carbon linkers, amino acid linkers (e.g., D- or L-amino acids), lipophilic residues, peptide linkers, peptide nucleic acid linkers, hydrazone linkers, SPDB disulfide, sulfo-SPDB, maleimidomethylcyclohexane-1-carboxylate (MCC), aminohexanoic acid linkers, and polyether linkers (e.g., PEG). For example, poly(ethylene glycol) linkers are available from Quanta Biodesign, Powell, OH. These linkers optionally have an amide bond, a sulfhydryl bond, or a heterofunctional bond.

[0295] In some embodiments, the linker is attached to a targeting molecule disclosed herein by a covalent bond, which in some embodiments comprises an ether bond, a thioether bond, an amine bond, an amide bond, a carbon-carbon bond, a carbon-nitrogen bond, a carbon-oxygen bond, or a carbon-sulfur bond.

[0296] In some embodiments, the linker is flexible. In some embodiments, the linker is rigid.

[0297] In some embodiments, the linker comprises a linear structure. In some embodiments, the linker comprises a non-linear structure. In some embodiments, the linker comprises a branched structure. In some embodiments, the linker comprises a cyclic structure.

[0298] In some embodiments, the linker is alkyl. In some embodiments, the linker is heteroalkyl.

[0299] In some embodiments, the linker is an alkylene. In some embodiments, the linker is an alkenylene. In some embodiments, the linker is an alkynylene. In some embodiments, the linker is a heteroalkylene.

[0300] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl portion can be a saturated or unsaturated alkyl. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).

[0301] An "alkyl" moiety may have 1 to 10 carbon atoms (wherever it appears herein, a numerical range such as "1 to 10" refers to each integer in the specified range; for example, "1 to 10 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also covers "alkyl" without a specified numerical range). An alkyl group can also be a "lower alkyl" having 1 to 6 carbon atoms. The alkyl group of the compounds described herein may be designated as "C1-C4 alkyl" or similar terminology. By way of example, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, and the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.

[0302] In some embodiments, the linker comprises a ring structure (e.g., aryl). As used herein, the term "ring" refers to a structure optionally closed by a covalent bond. Rings include, for example, carbocycles (e.g., aryl and cycloalkyl), heterocycles (e.g., heteroaryl and non-aromatic heterocycles), aromatic rings (e.g., aryl and heteroaryl), and non-aromatic rings (e.g., cycloalkyl and non-aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic.

[0303] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. The aryl ring can be formed by 5, 6, 7, 8, 9, or more than 9 carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, the aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0304] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls can be saturated or partially unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms. Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0305] In some embodiments, the ring is a cycloalkane. In some embodiments, the ring is a cycloalkene.

[0306] In some embodiments, the ring is an aromatic ring. The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. An aromatic ring can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. An aromatic can be optionally substituted. The term "aromatic" includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0307] In some embodiments, the ring is a heterocycle. The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups containing 1 to 4 heteroatoms selected from O, S, and N, respectively, where each heterocyclic group has 4 to 10 atoms in its ring system, provided that the ring of the group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, while aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyran ... These include lysinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, and quinolizinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and fallopyridinyl. The aforementioned groups can be C-bonded or N-bonded where possible. For example, a group derived from pyrrole can be pyrrol-1-yl (N-bonded) or pyrrol-3-yl (C-bonded). Furthermore, groups derived from imidazole can be imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo groups (=0), such as pyrrolidin-2-one. Depending on the structure, heterocyclic groups can be monovalent or divalent (i.e., heterocyclene groups).

[0308] In some embodiments, the rings are fused. The term "fused" refers to a structure in which two or more rings share one or more bonds; in some embodiments, the rings are dimers. In some embodiments, the rings are trimers. In some embodiments, the rings are substituted.

[0309] The term "carbocyclic" or "carbocycle" refers to a ring in which each of the atoms forming the ring is a carbon atom. Carbocycles include aryls and cycloalkyls. Thus, the term distinguishes between carbocycles and heterocycles ("heterocyclic") in which the ring backbone contains at least one atom other than carbon (i.e., a heteroatom). Heterocycles include heteroaryls and heterocycloalkyls. Carbocycles and heterocycles can be optionally substituted.

[0310] In some embodiments, the linker is substituted. The term "optionally substituted" or "substituted" means that the recited groups can be individually and independently substituted with one or more additional groups selected from C-Ce alkyl, C-Cg cycloalkyl, aryl, heteroaryl, C-C heteroalicyclic, hydroxy, C-C alkoxy, aryloxy, C-C alkylthio, arylthio, C-C alkylsulfoxide, arylsulfoxide, C-C alkylsulfone, arylsulfone, cyano, halo, C-C acyl, C-C acyloxy, nitro, C-C haloalkyl, C-C fluoroalkyl, and amino, including C-C alkylamino, and protected derivatives thereof. By way of example, the optional substituents may be L or R, where each L is independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(O)2NH-, -NHS(O)2-, -OC(O)NH-, -NHC(O)O-, -(CpC6 alkyl)-, or -(C2-C6 alkenyl)-, and each R is independently selected from H, (C1-C4 alkyl), (C3-C8 cycloalkyl), heteroaryl, aryl, and C1-C6 heteroalkyl. Optionally substituted non-aromatic groups may be substituted with one or more oxo (=O). Protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art.

[0311] In some embodiments, a bifunctional linker is used to form the desired conjugate, with one functional group reactive with a group on one molecule (e.g., a targeting molecule) and another reactive group on the other molecule (e.g., a fluorescent moiety or a drug). Alternatively, in some embodiments, derivatization is performed to provide the functional groups. Thus, for example, procedures for generating free sulfhydryl groups on peptides are also known (see U.S. Pat. No. 4,659,839). Alternatively, the linker may include a heterobifunctional crosslinker containing two or more different reactive groups that form a heterocycle that can interact with the targeting molecule. For example, a heterobifunctional crosslinker such as cysteine ​​may contain an amine-reactive group, and a thiol-reactive group can interact with an aldehyde on a derivatized targeting molecule. Additional combinations of reactive groups suitable for heterobifunctional crosslinkers include, for example, amine and sulfhydryl reactive groups, carbonyl and sulfhydryl reactive groups, amine and photoreactive groups, sulfhydryl and photoreactive groups, carbonyl and photoreactive groups, carboxylate and photoreactive groups, and arginine and photoreactive groups. Examples of heterobifunctional crosslinkers include N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) and maleimidomethylcyclohexane-1-carboxylate (MCC).

[0312] In some embodiments, a peptide linker consisting of one or more amino acids is used to connect the targeting molecule and the fluorescent moiety or drug. Generally, peptide linkers have no specific biological activity other than connecting molecules or maintaining a minimum distance or other spatial relationship between molecules. However, the constituent amino acids of the linker can be selected to affect certain properties of the molecule, such as folding, net charge, or hydrophobicity. In some embodiments, the peptide linker is relatively short, typically less than about 10 amino acids, preferably less than about 8 amino acids, and more preferably less than 5 amino acids. Non-limiting illustrative examples include glycine and glycine-serine linkers, which can be added to the C-terminus of the targeting peptide. In some embodiments, the peptide linker is a glycine-glycine-glycine-cysteine ​​(GGGC) linker, a glycine-glycine-cysteine ​​(GGC) linker, a glycine-glycine (GG) linker, or a cysteine ​​(C) linker. In some embodiments, a GGGC, GGC, GG, or C linker is added to the C-terminus of the targeting peptide.

[0313] IX. FURTHER MODIFICATIONS In some embodiments, the human neuron or neural targeting molecule of the present invention is optionally conjugated to a high molecular weight molecule that increases the multivalency and avidity of the label. In some embodiments, the high molecular weight molecule is a water-soluble polymer. Examples of suitable water-soluble polymers include, but are not limited to, peptides, saccharides, poly(vinyl), poly(ether), poly(amine), poly(carboxylic acid), etc. In some embodiments, the water-soluble polymer is dextran, polyethylene glycol (PEG), polyoxyalkylene, polysialic acid, starch, or hydroxyethyl starch. Any suitable method can be used to conjugate the peptide to the water-soluble polymer (see Hermanson G., Bioconjugate Techniques 2nd Ed., Academic Press, Inc. 2008). In some embodiments, the human neuron or neural targeting molecule further comprises a cargo. In some embodiments, the human neuronal or neural targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N with a GGC linker; SEQ ID NO: 7), -2; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker;SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (GG linker HNP401-N-2; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22), EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), 7), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), In some embodiments, the targeting molecule comprises a peptide sequence selected from the group consisting of SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide sequence selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403;SEQ ID NO: 3) and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), Ac-QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20) and Ac-QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1). In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2). In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4). In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5). In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker;In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO:7). In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO:22). In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO:8). In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO:23). In some embodiments, the targeting molecule comprises the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO:9). In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO:24). In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the targeting molecule is the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker;In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide that is not Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker; SEQ ID NO: 17). In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the targeting molecule comprises a peptide that is not NTQTLAKAPEHT (SEQ ID NO: 19);

[0314] In some embodiments, the targeting molecules of the present invention are conjugated to factors with neurotrophic properties (e.g., neurotrophic proteins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), and small non-protein molecules with neurotrophic properties).

[0315] In some embodiments, the targeting molecules of the present invention are modified to increase solubility. Peptide modifications that increase solubility include the addition of hydrophilic amino acids, PEG moieties, or both. In some embodiments, the PEG moiety is 8-amino-3,6-dioxaoctanoic acid (AEEA), 12-amino-4,7,10-trioxadodecanoic acid, or 15-amino-4,7,10,13-tetraoxapentadecanoic acid. In some embodiments, to increase solubility, approximately 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) hydrophilic amino acids can be added to the N-terminus, C-terminus, internal positions, or any combination thereof of the targeting molecule. Hydrophilic amino acids include D, E, H, K, N, Q, R, S, T, and G. In some embodiments, the targeting molecule contains K, KK, G, or GG at the N-terminus or C-terminus.

[0316] X. Multidomain targeting molecules In certain embodiments, the human neuronal or neural targeting molecules provided herein are multi-domain neuronal or neural targeting molecules comprising two or more neuronal or neural targeting peptides, wherein a first peptide is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP404 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (GGC Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2;SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQV In some embodiments, the first peptide comprises PWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), or 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the first peptide comprises SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), or DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the first peptide comprises SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21), or 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the first peptide is SGQVPWEEPYYVVKKSS(HNP 401;In some embodiments, the first peptide comprises Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO:4). In some embodiments, the first peptide comprises Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO:5). In some embodiments, the first peptide comprises Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO:6). In some embodiments, the first peptide comprises QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO:20). In some embodiments, the first peptide comprises QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the first peptide comprises Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7). In some embodiments, the first peptide comprises PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22). In some embodiments, the first peptide comprises Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8). In some embodiments, the first peptide comprises EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23). In some embodiments, the first peptide comprises Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9). In some embodiments, the first peptide comprises PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24). In some embodiments, the first peptide comprises Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10). In some embodiments, the first peptide comprises SGQVPWEEPYYVVKK (HNP401-C-2;In some embodiments, the first peptide comprises Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11). In some embodiments, the first peptide comprises SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26). In some embodiments, the first peptide comprises Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12). In some embodiments, the first peptide comprises SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the first peptide comprises Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the first peptide comprises SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the first peptide comprises Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the first peptide comprises DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the first peptide comprises 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104).

[0317] The two or more neuronal or neural targeting peptides within a multidomain targeting molecule can be the same neuronal or neural targeting peptide or preferably are different neuronal or neural targeting peptides. In some embodiments, the multidomain targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEE PYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), No. 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24);SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO: 119), 01-N-6; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWE EPGG (HNP401-C-8 with GG linker; SEQ ID NO: 124), 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with GG linker; SEQ ID NO: 104), SHSSEFPRSWDMETN (HNP301; SEQ ID NO: 29); SHSMLPSVLD (HNP303; SEQ ID NO: 30); SHSTMKTLSL (HNP305; SEQ ID NO: 31); VAPTKAPLHSPS (NP121; SEQ ID NO: 32), N a second peptide comprising NLKTGTSAPTG (NP122; SEQ ID NO: 33), HKTAQWPFIAFR (NP123; SEQ ID NO: 34), RLTNAPAYQAPA (NP124; SEQ ID NO: 35), MQNPLNGKPGR (NP125; SEQ ID NO: 36), THYSRSLTDGTR (NP126; SEQ ID NO: 37), YPSPNRPPNLTN (NP127; SEQ ID NO: 38), or NTQTLAKAPEHTG (NP117; SEQ ID NO: 39);

[0318] In some embodiments, the first neuronal or neural targeting peptide is selected from the group consisting of QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO:20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO:21), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO:25), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO:104). In some embodiments, the second peptide is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO:1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO:2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO:3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKS SGGC (HNP401-N-8 with GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21);PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEE PYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQV PWEEPYYGG (HNP401-C-6 with GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with GG linker; SEQ ID NO: 124), 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with GG linker; SEQ ID NO: 104), SHSSEFPRSWDMETN (HNP301; SEQ ID NO: 29); SHSMLPSVLD (HNP303; SEQ ID NO: 30); SHSTMKTLSL (HNP305; SEQ ID NO: 31); VAPT KAPLHSPS (NP121; SEQ ID NO: 32), NNLKTGTSAPTG (NP122; SEQ ID NO: 33), HKTAQWPFIAFR (NP123; SEQ ID NO: 34), RLTNAPAYQAPA (NP124; SEQ ID NO: 35), MQNPLNGKPGR (NP125; SEQ ID NO: 36), THYSRSLTDGTR (NP126; SEQ ID NO: 37), YPSPNRPPNLTN (NP127; SEQ ID NO: 38) or NTQTLAKAPEHTG (NP117; SEQ ID NO: 39);

[0319] In some embodiments, the first neuronal or neural targeting peptide comprises QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the first neuronal or neural targeting peptide is QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the second peptide is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 1 0), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23);PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27) and SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWE EPYYGG (HNP401-C-6 with GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with GG linker; SEQ ID NO: 124), SHSSEFPRSWDMETN (HNP301; SEQ ID NO: 29); SHSMLPSVLD (HNP303; SEQ ID NO: 30); SHSTMKTLSL (HNP305; SEQ ID NO: 31); VAPTKAPLHSPS (NP121; SEQ ID NO: 32), NNLKTGT SAPTG (NP122; SEQ ID NO: 33), HKTAQWPFIAFR (NP123; SEQ ID NO: 34), RLTNAPAYQAPA (NP124; SEQ ID NO: 35), MQNPLNGKPGR (NP125; SEQ ID NO: 36), THYSRSLTDGTR (NP126; SEQ ID NO: 37), YPSPNRPPNLTN (NP127; SEQ ID NO: 38) or NTQTLAKAPEHTG (NP117; SEQ ID NO: 39);

[0320] In some embodiments, the first neuronal or neural targeting peptide comprises QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the first neuronal or neural targeting peptide is QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the second peptide is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), row number 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6;SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO: 118), PYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-5 with a GG linker; SEQ ID NO: 123), -6; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with GG linker; SEQ ID NO: 124), 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with GG linker; SEQ ID NO: 104), SHSSEFPRSWDMETN (HNP301; SEQ ID NO: 29); SHSMLPSVLD (HNP303; SEQ ID NO: 30); SHSTMKTLSL (HNP305; SEQ ID NO: 31); VAPTKAPLHSPS (HNP121 ; SEQ ID NO: 32), NNLKTGTSAPTG (NP122; SEQ ID NO: 33), HKTAQWPFIAFR (NP123; SEQ ID NO: 34), RLTNAPAYQAPA (NP124; SEQ ID NO: 35), MQNPLNGKPGR (NP125; SEQ ID NO: 36), THYSRSLTDGTR (NP126; SEQ ID NO: 37), YPSPNRPPNLTN (NP127; SEQ ID NO: 38) or NTQTLAKAPEHTG (NP117; SEQ ID NO: 39);

[0321] In some embodiments, the first neuronal or neural targeting peptide comprises SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25). In some embodiments, the first neuronal or neural targeting peptide is SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25). In some embodiments, the second peptide is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 1 0), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23);PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO: 118), EEPYYV VKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), and SGQVPWEEPYYGG (HNP401-C-7 with a GG linker; SEQ ID NO: 124). SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with GG linker; SEQ ID NO: 124), 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with GG linker; SEQ ID NO: 104), SHSSEFPRSWDMETN (HNP301; SEQ ID NO: 29); SHSMLPSVLD (HNP303; SEQ ID NO: 30); SHSTMKTLSL (HNP305; SEQ ID NO: 31); VAPTKAPLHSPS (HNP121; SEQ ID NO: 32); sequence number 32), NNLKTGTSAPTG (NP122; SEQ ID NO: 33), HKTAQWPFIAFR (NP123; SEQ ID NO: 34), RLTNAPAYQAPA (NP124; SEQ ID NO: 35), MQNPLNGKPGR (NP125; SEQ ID NO: 36), THYSRSLTDGTR (NP126; SEQ ID NO: 37), YPSPNRPPNLTN (NP127; SEQ ID NO: 38) or NTQTLAKAPEHTG (NP117; SEQ ID NO: 39);

[0322] In some embodiments, the first neuronal or neural targeting peptide comprises 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the first neuronal or neural targeting peptide is 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the second peptide is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 10), HNP401-N-8; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22);PYYVVKKSS (HNP401-N-6; SEQ ID NO: 23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP with GG linker) 401-N-4; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-5 with a GG linker; SEQ ID NO: 123), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 124), SGQVPWEEPYYGG (HNP401-C-7 with a GG linker; SEQ ID NO: 125), SGQVPWEEPYYGG (HNP401-C-8 with a GG linker; SEQ ID NO: 126), SGQVPWEEPYYGG (HNP401-C-9 with a GG linker; SEQ ID NO: 127), SGQVPWEEPYYGG (HNP401-C-10 with a GG linker; SEQ ID NO: 128), SGQVPWEEPYYGG (HNP401-C-11 with a GG linker; SEQ ID NO: 129), SGQVPWEEPYYGG (HNP401-C-12 with a GG linker; SEQ ID NO: 130), SGQVPWEEPYYGG (HNP401-C-13 with a GG linker; SEQ ID NO: 131), SGQVPWEEPYYGG (HNP401- HNP401-C-6 with GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with GG linker; SEQ ID NO: 124), 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with GG linker; SEQ ID NO: 104), SHSSEFPRSWDMETN (HNP301; SEQ ID NO: 29); SHSMLPSVLD (HNP303; SEQ ID NO: 30); SHSTMKTLSL (HNP305; SEQ ID NO: 31); VAPTKAPLHSPS (NP121; SEQ ID NO: 32), NNLKTGTSAPTG (NP122; SEQ ID NO: 33), HKTAQWPFIAFR (NP123; SEQ ID NO: 34), RLTNAPAYQAPA (NP124; SEQ ID NO: 35), MQNPLNGKPGR (NP125; SEQ ID NO: 36), THYSRSLTDGTR (NP126; SEQ ID NO: 37), YPSPNRPPNLTN (NP127; SEQ ID NO: 38) or NTQTLAKAPEHTG (NP117; SEQ ID NO: 39);

[0323] In some embodiments, the neuronal or neural targeting peptides in the multidomain targeting molecule are directly linked to each other. In some embodiments, the neuronal or neural targeting peptides in the multidomain targeting molecule are indirectly linked to each other, for example, via a linker or cargo. In some embodiments, the targeting peptides are arranged linearly. In some embodiments, the targeting peptides of the multidomain targeting molecule are arranged in a branched structure. In some embodiments, the multidomain targeting molecule comprises two, three, four, five or more neuronal or neural targeting peptides.

[0324] XI. Labeling Methods Disclosed herein, in an identification embodiment, is a method for labeling a neuron or nerve (or any component) by contacting the neuron or nerve with a human neuron or nerve targeting molecule described herein. In some embodiments, the human neuron or nerve targeting molecule further comprises a cargo. In some embodiments, the human neuron or nerve targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), row number 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22), EEPYYVVKKSS (HNP401-N-6;SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 121), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 122), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 123), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 124), SGQVPWEEPYYVVKK (HNP401-N-8 with a GG linker; SEQ ID NO: 125), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 126), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 127), PYYV 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), and QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker;In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of: SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1). In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2). In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4). In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5). In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7). In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22). In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8). In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23). In some embodiments, the targeting molecule is the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker;In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO:24). In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO:10). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO:25). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO:11). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO:26). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO:12). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the targeting molecule is Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker;In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the targeting molecule comprises a peptide that is not NTQTLAKAPEHT (SEQ ID NO: 19).

[0325] In some embodiments, a first human neuron or neural targeting molecule is administered in combination (simultaneously, concomitantly, or sequentially) with a second human neuron or neural targeting molecule. In further embodiments, the first targeting molecule, the second targeting molecule, or both, comprise a cargo. In yet further embodiments, the cargo of the first targeting molecule, the cargo of the second targeting molecule, or both, are fluorescent moieties, which may be the same or different fluorescent moieties.

[0326] In some embodiments, the human neuron or neural targeting molecule is administered in combination (simultaneously, concomitantly, or sequentially) with a fluorescent moiety (e.g., a "free" fluorescent moiety that is not conjugated to a targeting molecule). In some embodiments, the fluorescent moiety is fluorescein, e.g., carboxyfluorescein.

[0327] In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro.

[0328] In some embodiments, neurons or nerves (or components thereof) are labeled for identification during surgery. In some embodiments, the surgery is cancer surgery. In some embodiments, the cancer is selected from the group consisting of prostate cancer, liver cancer (HCC), colorectal cancer, ovarian cancer, endometrial cancer, breast cancer, pancreatic cancer, gastric cancer, cervical cancer, head and neck cancer, thyroid cancer, testicular cancer, urothelial cancer, lung cancer, melanoma, testicular germ cell tumor, mesothelioma, and esophageal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the method comprises administering a targeting molecule disclosed herein to a subject who will undergo surgery. In some embodiments, the method comprises administering a targeting molecule disclosed herein to a subject undergoing surgery. In some embodiments, the targeting molecule disclosed herein is administered systemically to a patient. In some embodiments, the targeting molecule disclosed herein is administered locally to a patient.

[0329] XII. Drug Delivery Disclosed herein are methods of targeted drug delivery in identified embodiments. In some embodiments, the human neuronal or neural targeting molecules disclosed herein deliver drugs to identified targets. In some embodiments, the targeting molecules disclosed herein deliver drugs to neurons or nerves. In some embodiments, the human neuronal or neural targeting molecules further comprise a cargo. In some embodiments, the human neuronal or neural targeting molecules are selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYV VKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker;SEQ ID NO:21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO:22), EEPYYVVKKSS (HNP401-N-6; SEQ ID NO:23), PYYVVKKSS (HNP401-N-8; SEQ ID NO:24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO:25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO:26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO:27), SGQVPWEEP (HNP401-C-8; SEQ ID NO:28), PWEEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO:118), EEPYYVVKKSSGG (HNP401-N-6 with GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2;In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO:21). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO:1). In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO:2). In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO:3). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO:4). In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO:5). In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7). In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22). In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8). In some embodiments, the targeting molecule is the peptide EEPYYVVKKSS (HNP401-N-6;In some embodiments, the targeting molecule comprises the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9). In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24). In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the targeting molecule is the peptide DTHAHAKPRVPAFKSV (HNP 404;In some embodiments, the targeting molecule comprises a peptide that is not Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker; SEQ ID NO: 17). In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the targeting molecule comprises a peptide that is not NTQTLAKAPEHT (SEQ ID NO: 19).

[0330] In some embodiments, the drug is an agent that reduces pain (either the perception of pain or the activity of a painful stimulant). In some embodiments, the drug is an anesthetic. In some embodiments, the drug is benzocaine, carticaine, cinchocaine, cyclomethycaine, lidocaine, prilocaine, propoxycaine, proparacaine, tetracaine, tocainide, and trimecaine, or a combination thereof.

[0331] In some embodiments, the drug is an agent that modulates neuronal or neural cell death (e.g., via apoptosis or necrosis). In some embodiments, the drug is a cytotoxic agent. In some embodiments, the drug is a cytotoxic agent, such as methotrexate (RHEUMATREX®, amethopterin); cyclophosphamide (CYTOXAN®); thalidomide (THALIDOMID®); paclitaxel; pemetrexed; pentostatin; pipobroman; pixantrone; plicamycin; procarbazine; proteasome inhibitors (e.g., bortezomib); raltitrexed; rebeccamycin; rubitecan; SN-38; salinospora In some embodiments, the drug is a pro-apoptotic agent. In some embodiments, the drug is an anti-apoptotic agent. In some embodiments, the drug is minocycline; SB-203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)lH-imidazole); PD 169316 (4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-lH-imidazole); SB 202190 (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)lH-imidazole); RWJ 67657 (4-[4-(4-fluorophenyl)-l-(3-phenylpropyl)-5-(4-pyridinyl)-lH-imidazol-2-yl]-3-butyn-l-ol); SB 220025 (5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole);D-JNKI- 1 ((D)-hJIP 175_i 57-DPrO-DPrO-(D)-HIV-TAT57-48); AM-111 (Auris); SP600125 (anthra[l,9-cd]pyrazol-6(2H)-one); JNK inhibitor I ((L)-HIV-T AT48-57-PP- JBD20; JNK inhibitor III ((L)-HIV-TAT47-57-gaba-c-Junδ33-57); AS601245 (l,3-benzothiazol-2-yl(2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl)acetonitrile); JNK inhibitor VI (H2N-RPKRPTTLNLF-NH2); JNK inhibitor VIII (N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)-2-(2,5-dimethoxyphenyl)acetamide); JNK inhibitor IX (N-(3-cyano-4,5,6,7-tetrahydro-l-benzothien-2-yl)-l-naphthamide); dicoumarol (3,3'-methylenebis(4-hydroxycoumarin)); SC-236 (4-[5-(4-chlorobenzoyl)ethyl]amino]-4-pyrimidinyl)acetonitrile)

[00100] (1,1-dibromophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzene-sulfonamide; CEP-1347 (Cephalon); CEP-11004 (Cephalon); artificial proteins comprising at least a portion of a Bcl-2 polypeptide; recombinant FNK; V5 (also known as Bax inhibitor peptide V5); Bax channel blocker ((±)-l-(3,6-dibromocarbazol-9-yl)-3-piperazin-l-yl-propan-2-ol); Bax inhibitor peptide P5 (also known as Bax inhibitor peptide P5); Kp7-6; FAIM(S) (Fas apoptosis inhibitory molecule-short); FAIM(L) (Fas apoptosis inhibitory molecule-long); Fas:Fc; FAP- 1; NOK2; F2051; Fl 926; F2928; ZB4; Fas M3 mAb; EGF; 740 YP; SC 3036 (KKHTDDGYMPMSPGVA) (SEQ ID NO: 126); PI 3-kinase activator (Santa Cruz Biotechnology, Inc.);Pam3Cys((S)-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys4-OH, trihydrochloride); Actl (NF-kB activator 1); anti-DcB antibody; acetyl-11-keto-b-boswellic acid; andrographolide; caffeic acid phenethyl ester (CAPE); gliotoxin; isohelenin; NEMO binding domain binding peptide (DRQIKIWFQNRRMKWKKTALDWSWLQTE) (SEQ ID NO: 127); NF-kB NF-kB activation inhibitor (6-amino-4-(4-phenoxyphenylethylamino)quinazoline); NF-kB activation inhibitor II (4-methyl-Nl-(3-phenylpropyl)benzene-l,2-diamine); NF-kB activation inhibitor III (3-chloro-4-nitro-N-(5-nitro-2-thiazolyl)-benzamide); NF-kB activation inhibitor IV ((E)-2-fluoro-4'-methoxystilbene); NF-kB activation inhibitor V (5-hydroxy-(2,6-diisopropylphenyl)-lH-isoindole-l,3-dione); NF-kB SN50 (AA VALLP A VLLALLAP VQRKRQKLMP) (SEQ ID NO: 128); oridonin; parthenolide; PPM-18 (2-benzoylamino-1,4-naphthoquinone); Rol06-9920; sulfasalazine; TIRAP inhibitor peptide (RQIKIWFNRRMKWKKLQLRD AAPGG AIVS) (SEQ ID NO: 129); withaferin A; wogonin; BAY11-7082 ((E)3-[(4-methylphenyl)sulfonyl]-2-propenenitrile); BAY11-7085 ((E)3-[(4-t-butylphenyl)sulfonyl]-2-propenenitrile); (E)-capsaicin; gold thiomalate (ATM or Au™); evodiamine; hypoestoxide; IKK inhibitor III (BMS-345541); IKK inhibitor VII; IKK inhibitor X; IKK inhibitor II; IKK-2 inhibitor IV; IKK-2 inhibitor V; IKK-2 inhibitor VI; IKK-2 inhibitor (SC-514); IkB kinase inhibitor peptide; IKK-3 inhibitor LX; ARRY-797 (Array BioPharma);SB-220025 (5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole); SB-239063 (trans-4-[4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-1H-imidazol-1-yl]cyclohexanol); SB-202190 (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)- Nyl)-5-(4-pyridyl)-1H-imidazole; JX-401 (-[2-methoxy-4-(methylthio)benzoyl]-4-(phenylmethyl)piperidine); PD-169316 (4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole); SKF-86002 (6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazole) Dazo[2,1b]thiazole dihydrochloride; SB-200646 (N-(1-methyl-1H-indol-5-yl)-N'-3-pyridinylurea); CMPD-I (2'-fluoro-N-(4-hydroxyphenyl)-[1,1'-biphenyl]-4-butanamide); EO-1428 ((2-methylphenyl)-[4-[(2-amino-4-bromophenyl)amino]-2-chlorophenyl]methyl) Tanone; SB-253080 (4-[5-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine); SD-169 (1H-indole-5-carboxamide); SB-203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole); TZP-101 (Tranzyme Pharma); TZP-102 (Tranzyme Pharma); GHRP-6 (growth hormone-releasing peptide-6); GHRP-2 (growth hormone-releasing peptide-2); EX-1314 (Elixir Pharmaceuticals); MK-677 (Merck); L-692,429 (butanamide, 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-l-((2'-(lH-tetrazol-5-yl)(l,l'-biphenyl)-4-yl)methyl)-lH-l-benzazepin-3-yl)-, (R)-);EP1572 (Aib-DTrp-DgTφ-CHO); diltiazem; metabolites of diltiazem; BRE (protein expressed in brain and reproductive organs); verapamil; nimodipine; diltiazem; omega-conotoxin; GVIA; amlodipine; felodipine; lacidipine; mibefradil; NPPB (5-nitro-2-(3-phenylpropylamino)benzoic acid); flunarizine; erythropoietin; piperine; hemin; brazilin; zV AD-FMK (benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone); z-LEHD-FMK (benzyloxycarbonyl-Leu-Glu(OMe)-His-Asp(OMe)-fluoromethyl ketone); BD-FMK (boc-aspartyl(Ome)-fluoromethyl ketone); Ac-LEHD-CHO (N-acetyl-Leu-Glu-His-Asp-CHO); Ac-IETD-CHO (N-acetyl-Ile-Glu-Thr-Asp-CHO); z-IETD-FMK (benzyloxycarbonyl-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethyl ketone); FAM-LEHD-FMK (benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethyl ketone); FAM-LETD-F MK (benzyloxycarbonyl Leu-Glu-Thr-Asp-fluoromethylketone); Q-VD-OPH (quinoline-Val-ASp-CH2-O-Ph); XIAP; cIAP-1; cIAP-2; ML-IAP; ILP-2; NAIP; survivin; brace; IAPL-3; fortilin; leupeptin; PD-150606 (3-(4-iodophenyl)-2-mercapto- (Z)-2-Propenoic acid; MDL-28170 (Z-Val-Phe-CHO); calpeptin; acetyl-calpastatin; MG132 (N-[(phenylmethoxy)carbonyl]-L-leucyl-N-[(lS)-l-formyl-3-methylbutyl]-L-leucinamide); MYODUR; BN82270 (Ipsen); BN2204 (Ipsen); AHLi-11 (Quark Pharmaceuticals), mdm2 protein, pifithrin-α (l-(4-methylphenyl)-2-(4,5,6,7-tetrahydro-2-imino-3(2H)-benzothiazolyl)ethanone);trans-Stilbene; cis-Stilbene; Resveratrol; Piciatannol; Rhapontin; Deoxyrhapontin; Butein; Chalcone; Isoliquirtigen; Butein; 4,2',4'-Trihydroxychalcone; 3,4,2',4',6'-Pentahydroxychalcone; Flavone; Morin; Fisetin; Luteolin; Quercetin; Kaempferol; Apigenin; Gossypetin; Myricetin; 6-Hydroxyapigenin; 5-Hydroxyflavone; 5,7,3',4',5'-Pentahydroxyflavone Lavone;3,7,3',4',5'-Pentahydroxyflavone;3,6,3',4'-Tetrahydroxyflavone;7,3',4',5'-Tetrahydroxyflavone;3,6,2',4'-Tetrahydroxyflavone;7,4'-Dihydroxyflavone;7,8,3',4'-Tetrahydroxyflavone;3,6,2',3'-Tetrahydroxyflavone;4'-Hydroxyflavone;5-Hydroxyflavone;5,4'-Dihydroxyflavone;5,7-Dihydroxyflavone;Daizein;Geni Stains; Naringenin; Flavanone; 3,5,7,3',4'-Pentahydroxyflavanone; Pelargonidin chloride; Cyanidin chloride; Delphinidin chloride; (-)-Epicatechin (Hydroxyl sites: 3,5,7,3',4^); (-)-Catechin (Hydroxyl sites: 3,5,7,3',4); (-)-Gallocatechin (Hydroxyl sites: 3,5,7,3',4',5); (+)-Catechin (Hydroxyl sites: 3,5,7,3',4^); (+)-Epicatechin (Hydroxyl sites: 3,5,7,3',40; Heptahydroxyflavanone Nokitiol (b-thujaplicin; 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-l-one); L-(+)-ergothioneine ((S)-a-carboxy-2,3-dihydro-N,N,N-trimethyl-2-thioxo-lH-imidazole 4-ethanaminium inner salt); caffeic acid phenyl ester; MCI-186 (3-methyl-l-phenyl-2-pyrazolin-5-one); HBED (N,N'-di-(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid); *H2O; ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)cyclohexane-HCl; and U-83836E ((-)-2-((4-(2,6-di-l-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl)methyl)-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol·2HCl); β-1-5-methyl-nicotinamide-2'-deoxyribose; / 3-D-1'-5-methyl-nicotinamide-2'-deoxyribofuranoside; / 3-1'-4,5-dimethyl-nicotinamide-2'-deoxyribose; / 3-D-l'-4,5-dimethyl-nicotinamide -2'-Deoxyribofuranoside; 1-Naphthyl PPl (1-(1,1-dimethylethyl)-3-(l-naphthalenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine); Lavendustin A (5-[[(2,5-dihydroxyphenyl)methyl][(2-hydroxyphenyl)methyl]amino]-2-hydroxybenzoic acid); MNS (3,4-methylenedioxy-b-nitrostyrene); PPl (l-(l,l-dimethylethyl)-l-(4-methylphenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine); PP2 (3-(4-chlorophenyl)l-(l,l-dimethylethyl)-lH-pi Lazolo[3,4-d]pyrimidin-4-amine; KX1-004 (Kinex); KX1-005 (Kinex); KX1-136 (Kinex); KX1-174 (Kinex); KX1-141 (Kinex); KX2-328 (Kinex); KX1-306 (Kinex); KX1-329 (Kinex); KX2-391 (Kinex); KX2-377 (Kinex); ZD4190 (AstraZeneca; N-(4-bromo-2-fluorophenyl)-6-methoxy-7-(2-(lH-l,2,3-triazol-l-yl)ethoxy)quinazolin-4-amine); AP22408 (Ariad Pharmaceuticals); AP23236 (Ariad Pharmaceuticals); AP23451 (Ariad Pharmaceuticals); AP23464 (Ariad Pharmaceuticals); AZD0530 (AstraZeneca); AZM475271 (M475271; AstraZeneca); dasatinib (N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-l-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide); GN963 (trans-4-(6,7-dimethoxyquinoxalin-2ylamino)cyclohexanol sulfate); bosutinib (4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methyl-l-piperazinyl)propoxy)-3-quinolinecarbonitrile); or combinations thereof.

[0332] In some embodiments, the drug is an agent that reduces unwanted neuronal or nerve impulses. In some embodiments, the drug reduces one or more symptoms of dyskinesia or syncope. In some embodiments, the drug is carbamazepine, oxcarbazepine, phenytaine, valproic acid, sodium valproate, cinnarizine, flunarizine, or nimodipine, or a combination thereof.

[0333] In some embodiments, the drug is an agent that promotes the regeneration of neurons or nervous tissue. In some embodiments, the drug is a growth factor. In some embodiments, the drug is selected from brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3, neurotrophin-4, fibroblast growth factor (FGF) receptor, insulin-like growth factor (IGF), or a combination thereof.

[0334] XIII. Methods for Light-Induced Nerve Ablation The present disclosure provides a method for delivering a photosensitizer to a human neuron or nerve, comprising contacting the human neuron or nerve with a human neuron or nerve targeting molecule comprising (a) a peptide that specifically binds to the neuron or nerve or a component thereof and (b) a photosensitizer. In some embodiments, the method further comprises exposing the human neuron or nerve to a light source that activates the photosensitizer, where the activated photosensitizer induces ablation or cell death of the human neuron or nerve. Upon exposure to light of a distinguishing wavelength, the photosensitizer reacts with molecular oxygen to produce singlet oxygen, which is cytotoxic. In a distinguishing embodiment, the photosensitizer is a porphyrin, chlorin, or dye. Examples of photosensitizers include porphyrin, protoporphyrin IX, purlitin, verteporfin, HPPH, temoporfin, methylene blue, photofrin, protofrin, hematoporphyrin, talaporfin, benzoporphyrin derivatives monoacid, 5-aminolevulinic acid, lutetium texaphyrin, metallophthalocyanines, metallonaphthalocyanines sulfobenzo-porphyrazines, metallonaphthalocyanines, zinc tetrasulfophthalocyanines, bacteriochlorins, metallochlorins, chlorine derivatives, tetra(m-hydroxyphenyl)chlorin (mTHPC), pheophorbide, dibromofluorescein (DBF), IR700DX, naphthalocyanines, and porphyrin derivatives. In some embodiments, the human neuronal or neural targeting molecule is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker;SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-3 with a GGC linker; SEQ ID NO: 12), 1-C-4; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22), EEPYYVVKKSS (HNP 401-N-6; SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-8 with GG linker; SEQ ID NO: 119), SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker;In some embodiments, the peptide comprises a peptide sequence comprising SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), or DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the peptide comprises SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), or QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the peptide comprises SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1). In some embodiments, the peptide comprises WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2). In some embodiments, the peptide comprises DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the peptide comprises Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4). In some embodiments, the peptide comprises Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5). In some embodiments, the peptide comprises Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6). In some embodiments, the peptide comprises QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the peptide comprises QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker;In some embodiments, the peptide comprises Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO:7). In some embodiments, the peptide comprises PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO:22). In some embodiments, the peptide comprises Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO:8). In some embodiments, the peptide comprises EEPYYVVKKSS (HNP401-N-6; SEQ ID NO:23). In some embodiments, the peptide comprises Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO:9). In some embodiments, the peptide comprises PYYVVKKSS (HNP401-N-8; SEQ ID NO:24). In some embodiments, the peptide comprises Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10). In some embodiments, the peptide comprises SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25). In some embodiments, the peptide comprises Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11). In some embodiments, the peptide comprises SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26). In some embodiments, the peptide comprises Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12). In some embodiments, the peptide comprises SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the peptide comprises Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the peptide comprises SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the peptide comprises 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker;In some embodiments, the peptide comprises Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the peptide comprises DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the targeting molecule comprises a peptide that is not Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker; SEQ ID NO: 17). In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the targeting molecule comprises a peptide that is not NTQTLAKAPEHT (SEQ ID NO: 19).

[0335] The human neuron or neural targeting molecules comprising the photosensitizers disclosed herein can be used in methods for localized nerve killing in a subject. In some embodiments, the human neuron or neural targeting molecules comprising the photosensitizers are used to treat chronic pain (e.g., back, neck, or joint pain) in a subject. In some embodiments, the human neuron or neural targeting molecules comprising the photosensitizers are used to treat prostate cancer in a subject. Autonomic innervation may contribute to prostate cancer growth and metastasis through light-induced ablation of local autonomic nerves. Thus, local autonomic nerves may be a viable target for prostate cancer therapy. In some embodiments, the human neuron or neural targeting molecules comprising the photosensitizers are used to treat renovascular hypertension in a subject through light-induced ablation of sympathetic nerves in the renal blood vessels. In some embodiments, the human neuron or neural targeting molecules comprising the photosensitizers are used to treat hyperhidrosis. In some embodiments, the human neuron or neural targeting molecules comprising the photosensitizers are used to treat arrhythmias. In some embodiments, human neuronal or neural targeting molecules comprising photosensitizers are used to treat pathological muscle spasms (eg, Meige syndrome, hemifacial spasm, torticollis).

[0336] XIV. Methods of Nerve Labeling and Mapping, Image- or Map-Guided Surgery and Nerve Ablation, and Therapeutic Delivery to Nerves In the embodiment of identification, disclosed herein are uses and methods of neural labeling and mapping.Human neurons or neural targeting molecules disclosed herein are used to label nerves.Devices such as robotic navigation systems or catheters can be used to irradiate, image, map, or any combination of these, the labeled nerves in the identified body region, organ, or tissue.The images or maps can then be used to identify neural sites for irradiation and / or ablation of the nerves imaged or mapped by such systems during surgery or during the operation of the irradiation and / or ablation system.

[0337] In some aspects, the present disclosure provides a method for labeling pulmonary neurons or nerves (or any component) in a human subject by contacting the pulmonary neurons or nerves with a human neuron or nerve targeting molecule described herein. In some embodiments, the human neuron or nerve targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQV PWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-7 with a GGC linker; SEQ ID NO: 14), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 15), Ac-SGQVPWEEPGGC (HNP401-C-9 with a GGC linker; SEQ ID NO: 16), Ac-SGQVPWEEPGGC (HNP401-C-10 with a GGC linker; SEQ ID NO: 17), Ac-SGQVPWEEPGGC (HNP401-C-11 with a GGC linker; SEQ ID NO: 18), Ac-SGQVPWEEPGGC (HNP401-C-12 with a GGC linker; SEQ ID NO: 19), Ac-SGQVPWEEPGGC (HNP401-C-13 with a GGC linker; SEQ ID NO: 20), Ac-SGQVPWEEPGGC (HNP401-C-14 with a GGC linker; SEQ ID NO: 21), Ac-SGQVPWEEPGGC (HNP401-C-15 with a GGC linker; SEQ ID NO: 22), Ac-SGQVPWEEPGGC (HNP401-C-16 with a GGC linker; SEQ ID NO: 23), Ac-SGQVPWEEPGGC (HNP401-C-17 with a GGC linker; SEQ ID NO: 24), Ac-SGQVPWEEP -8; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22), EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8;SEQ ID NO: 24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 1 20), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124), and 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), and QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker;In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of: SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1). In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2). In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4). In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5). In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7). In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22). In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8). In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23). In some embodiments, the targeting molecule is the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker;In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO:24). In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO:10). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO:25). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO:11). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO:26). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO:12). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the targeting molecule is Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker;In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the targeting molecule comprises a peptide that is not NTQTLAKAPEHT (SEQ ID NO: 19).

[0338] The human neuron targeting or human neural targeting molecules described herein may further comprise a cargo. In some embodiments, the cargo comprises a fluorescent moiety, a drug, a photosensitizer, or a combination thereof. In some embodiments, the fluorescent moiety comprises a fluorophore, a fluorescent dye, a fluorescent protein, a fluorescent peptide, or any combination thereof.

[0339] In certain embodiments, the cargo comprises a fluorescent moiety, such as a fluorophore, fluorescent dye, fluorescent protein, fluorescent peptide, or any combination thereof. In such embodiments, the human neuron-targeting or human neural targeting molecule described herein can be administered to a human patient (e.g., by systemic intravenous injection) along with the cargo. After administration, or after a sufficient time for the human neuron-targeting or human neural targeting molecule described herein to bind to pulmonary nerves, the cargo is illuminated through the bronchial wall in the lung. In certain embodiments, a bronchoscope, catheter, or other device can be inserted into one or both bronchi of the patient's lung. The bronchoscope, catheter, or other device can include a light source that generates light inside the lung and / or a light source that generates light outside the lung and an optical fiber for delivering the light generated in the lung. Such a configuration can be activated to illuminate the inner walls of the bronchi through part or all of the patient's lung. Such illumination causes the cargo bound to the pulmonary nerves to fluoresce, such as behind and / or through the bronchial wall. The bronchoscope may also include a photoreceptive or photosensitive device that receives light emitted by cargo within the lung, such as through and / or from the wall of the bronchus, or an optical fiber that delivers such light outside the lung, and a photoreceptive or photosensitive device for receiving light outside the lung.

[0340] In a further embodiment, the light generated by the cargo and received by the bronchoscope arrangement can be used to map, such as computer-aided imaging or digital mapping, the location of one or both bronchi of a patient's lungs, and particularly the nerves surrounding the bronchi. Such images or maps can then be used to identify pulmonary nerves during lung surgery or operation of an irradiation and / or ablation system and during irradiation and / or ablation of nerves mapped by such a system. Such irradiation and ablation can be performed using non-ionizing radiation, such as electromagnetic radiation, radiofrequency ablation (RFA), cryoablation, photodynamic therapy (e.g., photosensitizers), and microwave ablation, or any other suitable technique described herein.

[0341] Robotic systems are commercially available to assist in the performance of such irradiation, imaging, mapping, and image- or map-guided procedures. As an example, Medtronic and / or Covidien offer systems available under the SUPERDIMENSION trade name, details of which are available as of October 9, 2019, at the following URL: https: / / www.medtronic.com / covidien / en-us / products / interventional-lung-solutions / superdimension-navigation-system.html. The information provided on this webpage describes the SUPERDIMENSION system as "a navigation system that uses fluoroscopic navigation technology," explains that "electromagnetic navigation bronchoscopy (ENB) is a minimally invasive approach to access hard-to-reach areas of the lung," and states that "SUPERDIMENSION TM The navigation system "displays an image of the tracheobronchial tree that helps the physician guide endoscopic tools or catheters in the respiratory tract and allows for the placement of markers in the soft tissue of the lungs."

[0342] In other embodiments, the cargo comprises a photosensitizer. When exposed to light of a distinguishing wavelength, such agents react with molecular oxygen to produce highly cytotoxic singlet oxygen. In such embodiments, the human neuron-targeting or human neural targeting molecules described herein can be administered to a patient (e.g., by systemic intravenous injection) along with the cargo. After administration, or after a sufficient time for the human neuron-targeting or human neural targeting molecules described herein to bind to pulmonary nerves, a bronchoscope, catheter, or other device can be inserted into one or both bronchi of the patient's lungs. The bronchoscope can include a light source that generates light inside the lungs and / or a light source that generates light outside the lungs and an optical fiber for delivering the light generated in the lungs. Such a configuration can be activated to illuminate the inner walls of the bronchi through part or all of the patient's lungs.

[0343] Such illumination travels through the bronchial walls and activates cargo bound to pulmonary nerves via human neuron-targeting or human neural targeting molecules, which react with molecular oxygen to produce highly cytotoxic singlet oxygen, thereby localizing nerve injury or ablation. Therefore, such photosensitizers may be referred to as "ablation agents." An optimal light dose can be identified to maximize nerve killing while minimizing damage to adjacent tissue. Such techniques may be referred to as "photo-induced ablation therapy." The commercially available robotic lung navigation systems described herein, available from Medtronic and / or Covidien, may assist in the implementation of such techniques.

[0344] Using the techniques described herein with respect to Section XIV, nerves within a patient's body can be labeled, mapped, and ablated. Such nerves surround the patient's lungs and can be accessed throughout the patient's lungs via the bronchi, as in the treatment of chronic obstructive pulmonary disease (COPD). Cholinergic parasympathetic nerves innervate both large and small airway nerves and provide the predominant innervation of the human lung. Pulmonary parasympathetic activity is enhanced in COPD. Therefore, blocking parasympathetic activity in the lungs can have a therapeutic effect in the treatment of COPD.

[0345] As another example, the human neuron-targeting or human neural targeting molecules described herein, optionally further comprising a cargo, are used to label renal nerves. The human neuron-targeting or human neural targeting molecules described herein, together with the cargo, can be administered to a human patient (e.g., by systemic intravenous injection). After administration, or after a sufficient time for the human neuron-targeting or human neural targeting molecules described herein to bind to renal nerves, the cargo is illuminated through the wall of the renal artery within the kidney. In a specific embodiment, a catheter or other device can be inserted into the renal vasculature (e.g., the renal artery). The catheter or other device can include a light source that generates light within the renal artery and / or a light source that generates light outside the kidney and an optical fiber for delivering the light generated outside the kidney. Such a configuration can be activated to illuminate the inner wall of the renal artery. Such illumination causes cargo bound to sympathetic nerves within the renal artery to fluoresce, such as behind and / or through the wall of the renal artery. The catheter may include a photoreceptive or photosensitive device for receiving light generated by cargo within the kidney through and / or from the wall of the renal artery or an optical fiber for delivering such light to the kidney and a photoreceptive or photosensitive device for receiving light outside the kidney.

[0346] In a further embodiment, light emitted by the cargo and received by the catheter configuration can be used to image or generate maps, such as computer-assisted digital maps, of the location of the patient's kidneys, particularly the sympathetic nerves around the renal arteries. Such images or maps can then be used to mark and identify renal nerves during renal surgery or operation of an irradiation and / or ablation system and irradiation and / or ablation of the nerves mapped by such a system. Such irradiation and ablation can be performed using non-ionizing radiation, such as electromagnetic radiation, radiofrequency ablation (RFA), cryoablation, photodynamic therapy (e.g., photosensitizers), and microwave ablation, or any other suitable technique described herein. Catheter systems for renal ablation are commercially available, for example, the Symplicity Spyral catheter available from Medtronic, Inc. TM Renal Denervation Catheter; EnligHTN from St. Jude Medical TM Renal Denervation System, One-Shot from Covidien TM Renal denervation system; and Vessix from Boston Scientific TM There is a renal denervation system.

[0347] XV. Pharmaceutical Compositions In a specific embodiment, the present disclosure provides pharmaceutical compositions comprising the human neuron or neural targeting molecules disclosed herein.The pharmaceutical compositions herein are formulated using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of active agents into pharmaceutical preparations.Appropriate formulations depend on the selected route of administration.Summaries of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L,., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins, 1999). In some embodiments, the human neuronal or neural targeting molecule is SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker;SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22), EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27), SGQVPW EEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401-C-2 with a GG linker; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123), SGQVPWEEPGG (HNP401-C-8 with a GG linker;In some embodiments, the targeting molecule comprises a peptide sequence selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises a peptide selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20), and QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO: 21). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1). In some embodiments, the targeting molecule comprises the peptide WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2). In some embodiments, the targeting molecule comprises the peptide DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4). In some embodiments, the targeting molecule comprises the peptide Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5). In some embodiments, the targeting molecule comprises the peptide Ac-DLPDIIWDFNWETAGGC (HNP403 with a GGC linker;In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO:20). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HNP401-N-2 with a GG linker; SEQ ID NO:21). In some embodiments, the targeting molecule comprises the peptide Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO:7). In some embodiments, the targeting molecule comprises the peptide PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO:22). In some embodiments, the targeting molecule comprises the peptide Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO:8). In some embodiments, the targeting molecule comprises the peptide EEPYYVVKKSS (HNP401-N-6; SEQ ID NO:23). In some embodiments, the targeting molecule comprises the peptide Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9). In some embodiments, the targeting molecule comprises the peptide PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24). In some embodiments, the targeting molecule comprises the peptide Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26). In some embodiments, the targeting molecule is the peptide Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with a GGC linker;In some embodiments, the targeting molecule comprises the peptide SGQVPWEEPYY (HNP401-C-6; SEQ ID NO: 27). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13). In some embodiments, the targeting molecule comprises the peptide SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28). In some embodiments, the targeting molecule comprises the peptide 5FAM-QVPWEEPYYVVKKSSGG-NH2 (HNP401-N-2 with a GG linker; SEQ ID NO: 104). In some embodiments, the targeting molecule comprises the peptide Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14). In some embodiments, the targeting molecule comprises the peptide DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16). In some embodiments, the targeting molecule comprises a peptide that is not Ac-SHSNTQTLAKAPEHTGC (NP41 with an Ac-GC linker; SEQ ID NO: 17). In some embodiments, the targeting molecule comprises a peptide that is not SHSNTQTLAKAPEHTGC (NP41 with a GC linker; SEQ ID NO: 18). In some embodiments, the targeting molecule comprises a peptide that is not NTQTLAKAPEHT (SEQ ID NO: 19).

[0348] In certain embodiments, the pharmaceutical compositions disclosed herein further comprise a pharmaceutically acceptable diluent, excipient, or carrier. In some embodiments, the pharmaceutical compositions comprise other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents, or emulsifiers, solution propellants, salts for adjusting osmotic pressure, and / or buffers. In addition, the pharmaceutical compositions may also contain other therapeutically valuable substances.

[0349] In certain embodiments, the human neuron or neural targeting molecules disclosed herein are delivered to a subject via a drug delivery vehicle or carrier. In some embodiments, the delivery vehicle is made of natural or synthetic materials, or both. In some embodiments, the delivery vehicle is a nanoparticle, a microparticle, a polymeric micelle, a nanocapsule, a dendrimer, a large PEG, a nanogel, a liposome, a fullerene, a nanostructured lipid carrier, a nanoshell, a quantum dot, a protein-based nanocarrier (e.g., albumin, elastin, gliadin, legumin, zein, soy protein, milk protein, whey-based nanocarrier), an organic nanocarrier (e.g., gelatin, dextran, guar gum, chitosan, collagen), a polysaccharide-based carrier (e.g., dextran, chitosan, pectin), a lipid emulsion, or a combination thereof.

[0350] In certain embodiments, the pharmaceutical compositions disclosed herein are administered to a subject by any suitable route of administration, including, but not limited to, parenteral (intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intravitreal, infusion, or topical) administration.

[0351] Preparations suitable for intramuscular, subcutaneous or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (olive oil, etc.) and injectable organic esters such as ethyl oleate.Appropriate fluidity is maintained, for example, by using a coating such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.Preparations suitable for subcutaneous injection also contain optional additives such as preservatives, wetting agents, emulsifiers and dispensing agents.

[0352] For intravenous injections, the active agents are optionally formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.

[0353] Parenteral injections optionally include bolus injections or continuous infusions.Injectable preparations are optionally provided in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives.In some embodiments, the pharmaceutical compositions described herein are in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents.Pharmaceutical preparations for parenteral administration include aqueous solutions of active agents in water-soluble form.In addition, suspensions are optionally prepared as suitable oily injection suspensions.

[0354] In some embodiments, the pharmaceutical compositions described herein are in unit dosage form suitable for single administration of a precise dosage. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of the active agent disclosed herein. In some embodiments, the unit dosage is in the form of a package containing individual amounts of the formulation. Non-limiting examples include packaged tablets or capsules and powders in vials or ampoules. In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection are provided in unit dosage form or in multi-dose containers with added preservatives, including, but not limited to, ampoules.

[0355] In some embodiments, the human neuronal or neural targeting molecule is administered to the human subject by systemic intravenous injection. [Example]

[0356] Example 1: Peptides for targeting human nerves and their use in image-guided surgery, diagnostics, and therapeutic delivery overview A phage display screen was used to identify peptides that bind to human nerves and may therefore be useful for whole-body in vivo labeling of nerves during fluorescence-assisted surgery. Specifically, an m13 phage library (Creative Biolabs) expressing a 16-amino acid sequence randomly located at the N-terminus of gIII was processed by selection for binding to freshly excised or frozen human nerves. In parallel, a newly designed NP41 X12+4 library was screened. Each library was processed through up to six binding and washing cycles. Selected phages were further counterselected for high-affinity binding to tissues by pre-absorb- ing the library to muscle and adipose tissues, which have low affinity, prior to positive selection for nerve binding. Sequencing of individual phages yielded unique sequences that were highly enriched and therefore had higher affinity than the pool of clones: SGQVPWEEPYYVVKKSS (HNP401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP403; SEQ ID NO: 3) from the X16 library, and DTHAHAKPRVPAFKSV (HNP404; SEQ ID NO: 16) from the NP41-X12+4 library. Amino acid sequences derived from the sequences of selected phages were chemically synthesized as peptides by solid-phase synthesis and labeled with fluorescein (FAM) or Cy5 at the C-terminus via a GGC linker for in vitro binding to human nerves and in vivo labeling of rodent nerves. Strong labeling of human nerves and fresh sections of in vivo labeled mouse sciatic nerves was demonstrated. Useful labeling occurred 2-6 h after intravenous administration and could be visualized using a customized fluorescent dissecting microscope, a Maestro imager from CRI or a Zeiss Lumar.

[0357] Preservation of peripheral nerves is one of the most important goals of any surgical procedure, as accidental severing of peripheral nerves during surgical procedures results in significant morbidity for patients. Furthermore, nerves grow back more slowly and incompletely after severing than almost all other tissues. Typically, peripheral nerves are identified by their relatively constant relationship to nearby structures and their typical appearance as elongated, whitish, shiny structures. However, in many cases, identifying peripheral nerves using these criteria can be difficult, for example, in cases of tumor involvement, inflammation / infection, a previously operated surgical field, or when the nerve is encased in bone.

[0358] Current methods for nerve labeling primarily rely on retrograde or anterograde tracing of individually identified axonal tracts through the use of fluorescent dyes. The fluorescent dye is either applied to an innervation target and travels retrogradely to label the innervating nerve fibers, or it is applied directly to an identified nerve, labeling nerve fibers both anterogradely and retrogradely. This technique has the drawback of only being able to label one nerve fiber tract at a time, which depends on the location of the dye injection. A second drawback is that retrograde axonal tracers typically accumulate in the neuronal cell body, limiting axonal labeling by these fluorescent dyes, resulting in limited accumulation of the fluorescent dye along the axonal tract. A third disadvantage of this technique is that retrograde transport is relatively slow (on the order of several millimeters per day), thus requiring a long time to label human nerves that are often longer than one meter (as in the case of the sciatic nerve and its dendritic branches). Furthermore, application of fluorescent dye to innervation targets, such as direct intramuscular injection to label motor nerves, is typically contaminated with variable amounts of tracer dye remaining at the injection site. Because nerve dissection depends on accurate visualization of adjacent structures before encountering them, a surgical site that is contaminated with fluorescent dye is undesirable. Finally, direct injection of the fluorescent dye itself may damage the target organ or nerve of interest, either through mechanical injury or through very high local concentrations of dye and vehicle at the injection site.

[0359] The method of systemic injection of fluorescently labeled peptides to label nerves described herein addresses all of the disadvantages of fluorescent tracers mentioned above. First, because the peptides are delivered systemically, all peripheral nerves in the body can potentially be labeled. This contrasts with current methods, which label only one nerve at a time. Second, because the peptides described herein are selected for their ability to bind to nerves, nerve fibers are clearly visualized relative to adjacent non-neuronal structures. This contrasts with the preferential accumulation in neuronal cell bodies rather than axons that occurs with most current fluorescent dyes. Third, binding of the peptides described herein to nerves is very rapid, and visualization of peripheral nerves using this technique can be achieved within a few hours. This contrasts with the relatively slow rate of labeling with anterograde or retrograde tracers. Finally, because the peptides are applied systemically via intravenous injection, damage to nerves at the injection site is not an issue.

[0360] Neurohoming peptide sequences derived using mouse peripheral nerves for laboratory studies have been previously described (U.S. Patent No. 8,685,372, April 1, 2014). However, because the intended ultimate clinical application of neuronal labeling is in human patients, the identification of unique peptide sequences that bind to human nerves was sought. The peptide sequences described in this application were identified by their ability to bind to human nerves. These peptide sequences were identified by their ability to bind to human nerves after systemic intravenous injection into human patients, and therefore, these peptides are more likely to bind to human nerves compared to sequences selected for rodent nerves.

[0361] Current methods for labeling neurons include the application of fluorescent tracer dyes (Fast Blue, Rhodamine-isothiocyanate, Fluoro-Ruby, Fluoro-Emerald), carbocyanine dyes (DiI, DiAsp, DiO, DiA), Fluoro-Gold, fluorescently labeled latex beads, fluorescently labeled plant lectins and bacterial toxins (wheat germ agglutinin, peanut agglutinin, concanavalin A, Phaseolus vulgaris leukoagglutinin (PHA-L), soybean agglutinin, gorse agglutinin, castor bean agglutinin (I and II), tetanus toxin fragment C, cholera toxin B, and fluorescently labeled dextran conjugates.

[0362] method: Experimental Details: To identify peptides that bind to human neural tissue, we used an m13 phage library (Creative Biolabs) expressing random 16-amino acid sequences at the N-terminus of gIII or an in-house generated library expressing derivatives of NP41.

[0363] Peptide selection Human peripheral nerves were obtained from patients undergoing neurectomy and homogenized. The phage library mixture was incubated with the nerve homogenate bound to a high-protein-binding 6-well plate. After incubation, the mixture was centrifuged and the pellet was either washed with PBS or the plate was washed with PBS. The pellet was either rehomogenized and plated for titering and reamplification or released from the plate with a low pH buffer. Bound phage were sequenced at each round, and repeats were recorded. No repeats were identified until round 4 of selection. SGQVPWEEPYYVVKKSS (HNP401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP403; SEQ ID NO: 3) and DTHAHAKPRVPAFKSV (SEQ ID NO: 16) from the X16 library were identified after round 5. Table 1. [Table 1]

[0364] In vivo testing of peptides Mice were intravenously injected with either 150 nmol or 450 nmol of fluorescein-labeled synthetic peptide. After a 2-hour wait period to allow for washout of nonspecific binding, mice were anesthetized, and a skin incision was made over the dorsal hind limb to expose the sciatic nerve. Brightfield and fluorescent images were obtained under a dissecting microscope using Metamorph software (Figure 1). Quantification of fluorescence in nerves and adjacent non-neural tissues was performed with Image J (Figure 2). Peptides were also applied topically to human nerve sections. Nerves were fresh-frozen at 0°C before sectioning. Peptides were applied topically at a concentration of 300 μM, and images of HNP401, HNP402, HNP404, and the previously reported nerve-binding peptide NP41 are shown (Figure 3). Images of variants HNP301 (SEFPRSWDMETN) (SEQ ID NO: 130) and NP124 are also shown. NP713 was also tested, but has not been reported in publications. NP713 is a derivative of NP41 with the sequence NTHPHTTSRVPSQIAR (SEQ ID NO: 131), which was enriched after seven rounds of selection on mouse tissues and was also found after four rounds of selection on human tissues. NP713 phage binding demonstrated a 4.8-fold higher nerve:muscle ratio compared to wild-type phage. FAM-NP713 demonstrated similar nerve:muscle contrast to NP41 (data not shown). All D-amino acid controls of NP-41 and NP713, as well as carboxyfluorescein not conjugated to a peptide, are also shown. HNP401 demonstrated the highest nerve-specific contrast, with the majority of labeling occurring in the perineurium. To further demonstrate the selective binding of HNP401, HNP401, NP41, and HNP404 were tested at a lower concentration of 100 μM (Figure 4). HNP401 was then tested in vivo for labeling of rat sciatic nerve and rat prostate cavernous nerve. Figure 5 shows in vivo labeling of the rat sciatic nerve. Figures 6 and 7 show in vivo labeling of the rat prostatic cavernous nerve compared to white light visualization.

[0365] Neurohoming peptide sequences identified for laboratory studies by their ability to bind to mouse nerves have been previously described. Because the peptide sequences described herein are identified by their ability to bind to human nerves after systemic intravenous injection into human patients, these peptides are even more likely to bind to human nerves compared to sequences selected for rodent nerves.

[0366] Fluorescently labeled human nerve-binding peptides are applied systemically via intravenous injection. After a short waiting period for washout of nonspecific binding, peripheral nerves can be visualized within the surgical field with appropriate excitation and emission filters.

[0367] Human nerve-binding peptides can also be conjugated to factors that may have neurotrophic or neuroprotective properties. After systemic application by intravenous injection, peptide-trophic / neuroprotective factor conjugates can promote repair / regeneration of injured nerves both peripherally and in the spinal cord.

[0368] Human nerve-binding peptides conjugated to neuroprotective / neurotrophic factors may also be conjugated to damage-homing peptides to further improve the local delivery of these factors to injured nerves and potentially promote injury resistance / repair / regeneration.

[0369] Uses and applications: Fluorescently labeled nerve-binding peptides can be used to assist surgeons in visualizing nerves during surgical procedures before physically encountering and potentially damaging them. This is particularly important during prostate surgery, because the cavernous nerves that control erections in men run very close to the prostate but are usually virtually invisible.

[0370] Nerve-binding peptide-neurotrophic / neuroprotective factor conjugates can be used to promote repair / regeneration of damaged nerves.

[0371] Nerve-binding peptides can be conjugated to photosensitizing dyes for potential use in light-induced nerve killing as a treatment for local pain. References 1. Whitney M, Crisp J, Nguyen L, Friedman B, Gross L, Steinbach P, Tsien R, Nguyen Q. Fluorescent peptides highlight peripheral nerves during surgery in mice. Nature Biotechnology. 2011;29:352-356. 2. Wu AP, Whitney MA, Crisp J LJL, Friedman B, Tsien RY, Nguyen Q.TQT. Improved facial nerve identification with novel fluorescently labeled probe. The Laryngoscope. 2011;121:805-810. 3. Kobbert C,., Apps, R., Bechmann, I., Laciego, JL, Mey, J., Thanos, S. Currents concepts in neuroanatomical tracing. Progress in Neurobiology 62 (2000) 327-351. 4. Richmond, FJR, Gladdy R., Creasy, JL, Ktamura S., Smits, E., Thomson DB Efficacy of seven retrograde tracers, compared in multiple-labelling studies of feline motoneurones. Journal of Neuroscience Methods 53 (1994) 35-46.2..2 5. Marangos, N., Illing R., Kruger J., Laszig R. In vivo visualization of the cochlear nerve and nuclei with fluorescent axonal tracers. Hearing Research 162 (2001) 48-52 6. O'Malley, M, Wittkopf, J., Cutler J., Labadie, R, Hackett, T, Haynes, D. Fluorescent retrograde axonal tracing of the facial nerve. The Laryngoscope 116 (2006) 1792-1797.

[0372] Example 2: Optimized peptides for targeting human nerves and their use in image-guided surgery, diagnostics, and therapeutic delivery overview A phage display screen was used to identify peptides that bind to human nerves and may therefore be useful for whole-body in vivo labeling of nerves during fluorescence-assisted surgery. Specifically, an m13 phage library (Creative Biolabs) expressing a 16-amino acid sequence at the N-terminus of gIII was subjected to selection for binding to freshly excised or frozen human nerves. The library was subjected to up to six binding and washing cycles. Selected phages were further counterselected for high-affinity binding to tissues by pre-absorb- ing the library with low-affinity muscle and adipose tissues prior to positive selection for nerve binding. Sequencing of individual phages yielded these unique sequences, which were highly enriched and therefore had higher affinity compared to the pool of clones: SGQVPWEEPYYVVKKSS (HNP401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP402; SEQ ID NO: 2), and DLPDIIWDFNWETA (HNP403; SEQ ID NO: 3). The amino acid sequences derived from the selected phage sequences were chemically synthesized as peptides by solid-phase synthesis and labeled with fluorescein or Cy5 for in vitro binding to human nerves and in vivo labeling of rodent nerves. We demonstrated strong labeling of fresh sections of human peripheral nerves (motor, sensory, and autonomic) and in vivo labeled mouse and rat sciatic nerves. Useful labeling occurred 2–6 h after intravenous administration and could be visualized using a customized fluorescent dissecting microscope, a Maestro imager from CRI, or a Zeiss Lumar dissecting microscope.

[0373] result Nerve identification and preservation is essential in head and neck surgery. Identification of peripheral nerves is important for their preservation during surgery, as accidental cutting or injury can result in significant patient morbidity, including chronic pain, numbness, or permanent paralysis. 1 Nerve identification is particularly important during head and neck surgery. For example, facial nerve dysfunction has been reported to be 40% during the acute postoperative period and 30% one month after parotidectomy. 2、3Similarly, facial nerve dysfunction has been reported to reach 30% one year after vestibular schwannoma surgery. 4 Temporary and permanent vocal cord immobility is a major surgical complication of thyroid surgery, anterior cervical approach to the spine, esophagectomy, and carotid endarterectomy. 5 Although the course of the facial nerve typically follows defined anatomical landmarks, extensive interpatient variability has been documented for each branch of the extratemporal facial nerve, including variability in the total number of divisions, the origin of individual divisions, and the connections between divisions. 6-9 Even within the same patient, the left and right facial nerves may show differences in course and division. 10 Similar variability has been documented for the recurrent laryngeal nerve. 11、12 In the case of tumor invasion, inflammation, trauma, or reoperation, nerve identification can become even more difficult. Finally, the identification of degenerating nerves, which is crucial during reconstructive surgery, is even more difficult than their functioning counterparts because they become smaller and thinner with time. Consequently, any means of improving the visual determination between neural and non-neural tissue represents a significant advance in surgical technique.

[0374] Nerve identification and preservation is essential during other surgeries, including prostate cancer surgery. Prostate cancer is the most common solid organ malignancy in American men. For men with localized prostate cancer, surgery provides excellent cancer control. Often, this cancer treatment comes at the expense of erectile function, urinary control, and overall quality of life. Preservation of the autonomic neurovascular bundle during radical prostatectomy is a critical aspect of surgery. For nearly 20 years, the importance of preserving the autonomic nerves that run along the posterolateral aspect of the prostate to preserve erectile function has been recognized. However, the autonomic nerve fibers themselves are rarely visualized. Instead, surgeons preserve the vascular complex or neurovascular bundle, which has been shown to have the highest density of autonomic nerves. Erectile dysfunction and urinary incontinence are common, even among the most experienced surgeons. 14 As such, the exact location and distribution of these autonomic nerves varies. 13-18Improved sexual function outcomes are associated with increased surgeon experience and avoidance of crush or traction injuries to these nerves. Significant anatomical variability and differences in surgeon experience and volume create opportunities for improving surgical quality while minimizing adverse outcomes. In cases of tumor infiltration, inflammation, trauma, or reoperation, nerve identification and preservation represent additional challenges. Finally, tactile feedback 19 The increasing use of robotic-assisted surgery, with its inherent lack of visual information, further increases the surgeon's reliance on visual information. Consequently, any means of improving visual decision-making between neural and non-neural tissue represents a significant advancement.

[0375] Small nerves are difficult to identify intraoperatively. Thin or buried nerves are particularly difficult to distinguish and are therefore most likely to be damaged during surgical procedures. Identification of motor nerves before direct exposure is currently achieved through electromyography (EMG) monitoring, in which stimulating electrodes are inserted and distal muscle contractions are monitored. 20-22 EMG is not an imaging technique, so even if a nerve is identified at one location, there is no visual guide as to how far and in what direction it lies from the stimulation site. Furthermore, EMG only identifies motor pathways, not sensory fibers such as the first two divisions of the trigeminal or cochleovestibular nerves, nor sympathetic pathways such as the neurovascular bundles around the prostate. 23-25 Nerve damage after radical prostatectomy leads to significant urinary incontinence and erectile dysfunction 26 Electrode insertion itself can damage nerves. Finally, EMG fails when axonal or neuromuscular transmission is temporarily blocked at a location distant from the recording site by nerve compression, trauma, tumor infiltration, local anesthetics, or neuromuscular blocking agents. Optical coherence tomography 27 or laser confocal microscopy 28There are several potential techniques for in vivo nerve visualization without exogenous probe molecules, such as MRI, MRI, and MRI. However, nerves have very little intrinsic contrast to distinguish them from other tissues, and these techniques do not easily generate real-time live images across the field of view necessary to guide surgery. Degenerated nerves, which are important to identify during reconstructive surgery after cancer resection, traumatic, or therapeutic amputation, also lack myelin and therefore do not benefit from these agents.

[0376] Competing strategies for improving intraoperative nerve visualization. For these reasons, there is great interest in developing labeling reagents that improve intraoperative neurovisualization. 29-32 or the B subunit of cholera toxin (CTb488) 33 Nerve labeling, which relies on retrograde or anterograde tracing of individual axon tracts through the use of fluorescent dyes, has gained considerable attention. Fluorescent dyes are applied to innervation targets and travel in a retrograde manner to label innervating nerve fibers, or they are applied directly to identified nerves, labeling nerve fibers both anterogradely and retrogradely. Local injections have the disadvantage of only being able to label a single nerve fiber tract at a time. Anterograde and retrograde transport are relatively slow and can take days to travel several millimeters, leaving most of the tracer at the injection site. Because nerve dissection relies on accurate visualization of adjacent structures, a surgical site heavily contaminated with excess fluorescent dye is undesirable. Finally, direct injection of fluorescent dyes can damage the target organ or nerve of interest, either through mechanical injury or very high local concentrations of dye and vehicle at the injection site.

[0377] More recently, there has been interest in labeling the vascular supply of nerves (i.e., the vasa nervorum) using vascular dyes such as indocyanine green (ICG). 34、35 One limitation of this technique is that small nerves (such as the cavernous nerves important for prostate surgery) have proportionally fewer neurovasculature, limiting contrast and intensity compared to adjacent tissue.

[0378] Distyrylbenzene (DSB) derivatives 36, coumarin derivatives and anti-ganglioside antibodies 37 Myelin-targeting agents have also been attracting attention, including DSB and coumarin derivatives, which are small molecules with inherent fluorescence, and anti-ganglioside antibodies, which can be conjugated to fluorescent dyes for imaging. 36-43 While these molecules are potentially promising for peripheral nerve imaging, unmyelinated nerves (autonomic and minimally myelinated), such as cavernous nerves, have little binding, which may limit their usefulness in these important procedures. Degenerating nerves have limited myelin present and therefore are not labeled by these agents.

[0379] The method of systemic injection of fluorescently labeled peptides to label nerves described herein addresses all of the disadvantages of other nerve targeting techniques mentioned above. First, because the peptides are delivered systemically, all peripheral nerves in the body can potentially be labeled. This is in contrast to current methods, which label only one nerve at a time. Second, because the peptides described herein were selected for their ability to bind to nerves, nerve fibers are clearly visualized compared to adjacent non-neuronal structures. This contrasts with the preferential accumulation in neuronal cell bodies rather than axonal processes with most current fluorescent dyes. Third, the peptides described herein bind to nerves very rapidly, and visualization of peripheral nerves using this technique can be achieved within a few hours. This contrasts with the relatively slow rate of labeling with anterograde or retrograde tracers. Finally, because the peptides are applied systemically via intravenous injection, damage to nerves at the injection site is not an issue.

[0380] Nerve-homing peptide sequences derived using mouse peripheral nerves for laboratory studies have been previously described (U.S. Patent No. 8,685,372, April 1, 2014; Peptides and aptamers for targeting of neurons or nerves, US2012 / 0148499 and WO2010 / 121023A2). However, because the ultimate clinical application of neuronal labeling is intended for human patients, the identification of unique peptide sequences that bind to human nerves was sought. The peptide sequences described in this application were identified by their ability to bind to human nerves. These peptide sequences were identified by their ability to bind to human nerves after systemic intravenous injection into human patients, and as such, are more likely to bind to human nerves than peptide sequences selected for rodent nerves.

[0381] Current methods for labeling neurons include the application of fluorescent tracer dyes (Fast Blue, Rhodamine-isothiocyanate, Fluoro-Ruby, Fluoro-Emerald), carbocyanine dyes (DiI, DiAsp, DiO, DiA), Fluoro-Gold, fluorescently labeled latex beads, fluorescently labeled plant lectins and bacterial toxins (wheat germ agglutinin, peanut agglutinin, concanavalin A, Phaseolus vulgaris leukoagglutinin (PHA-L), soybean agglutinin, gorse agglutinin, castor bean agglutinin (I and II), tetanus toxin fragment C, cholera toxin B, and fluorescently labeled dextran conjugates.

[0382] Fluorescent dyes can be applied to innervation targets and travel in a retrograde manner to label innervating nerve fibers, or they can be applied directly to identified nerves, labeling nerve fibers both anterogradely and retrogradely. As noted above, local injections have the disadvantage of only being able to label one nerve fiber tract at a time. Anterograde and retrograde transport are relatively slow and can take days to travel several millimeters, leaving most of the tracer at the injection site. Because nerve dissection relies on accurate visualization of adjacent structures, a surgical site heavily contaminated with excess fluorescent dye is undesirable. Finally, direct injection of fluorescent dye can damage the intended target organ or nerve, either through mechanical injury or very high local concentrations of dye and vehicle at the injection site.

[0383] More recently, there has been interest in labeling the vascular supply of nerves (i.e., the vasa nervorum) using vascular dyes such as indocyanine green (ICG). 34、35 One limitation of this technique is that small nerves (such as the cavernous nerves important for prostate surgery) have proportionally fewer neurovasculature, limiting contrast and intensity compared to adjacent tissue.

[0384] Distyrylbenzene (DSB) derivatives 36 , coumarin derivatives and anti-ganglioside antibodies 37 Myelin-targeting agents have also been attracting attention, including DSB and coumarin derivatives, which are small molecules with inherent fluorescence, and anti-ganglioside antibodies, which can be conjugated to fluorescent dyes for imaging. 36-43 While these molecules are potentially promising for peripheral nerve imaging, unmyelinated nerves (autonomic and minimally myelinated), such as cavernous nerves, have little binding, which may limit their usefulness in these important procedures. Degenerating nerves have limited myelin present and therefore are not labeled by these agents.

[0385] Neurohoming peptide sequences identified for laboratory studies by their ability to bind to mouse nerves have been previously described. Because the peptide sequences described herein are identified by their ability to bind to human nerves after systemic intravenous injection into human patients, these peptides are even more likely to bind to human nerves compared to sequen...

Claims

1. 1. A method for labeling and mapping pulmonary nerves in a human subject, comprising: (a) contacting a pulmonary nerve with a human neuron or neuronal targeting molecule, wherein the human neuron or neuronal targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-P WEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWE EPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-3 with a GG linker; SEQ ID NO: 21) 401-N-2; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6;SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401- a peptide selected from the group consisting of SGQVPWEEPYYVVGG (HNP401-C-2; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123) and SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124); and a cargo comprising a fluorescent moiety, thereby labeling pulmonary nerves; and (b) directing the cargo through the bronchi into the lung; receiving fluorescence from the cargo; and using the received fluorescence to generate a map of the lung. A method comprising:

2. 10. The method of claim 1, wherein the fluorescent moiety comprises a fluorophore, a fluorescent dye, a fluorescent protein, a fluorescent peptide, or any combination thereof.

3. 3. The method of claim 1 or 2, further comprising using the bronchial map to identify pulmonary nerves and perform irradiation or ablation of the pulmonary nerves.

4. The method of any one of claims 1 to 3, wherein the bronchial map is generated using a robotic pulmonary navigation system.

5. 4. The method of claim 3, wherein the pulmonary nerves are ablated by radiofrequency ablation, cryoablation, photodynamic therapy, or microwave ablation.

6. The method of claim 1 , wherein cargo irradiation comprises use of a robotic pulmonary navigation system.

7. 1. A method for labeling and mapping renal nerves in a human subject, comprising: (a) contacting a renal nerve with a human neuron or neuronal targeting molecule, wherein the human neuron or neuronal targeting molecule is selected from the group consisting of SGQVPWEEPYYVVKKSS (HNP 401; SEQ ID NO: 1), WEYHYVDLNWTSQHPQ (HNP 402; SEQ ID NO: 2), DLPDIIWDFNWETA (HNP 403; SEQ ID NO: 3), DTHAHAKPRVPAFKSV (HNP 404; SEQ ID NO: 16), Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with a GGC linker; SEQ ID NO: 4), Ac-WEYHYVDLNWTSQHPQGGC (HNP402 with a GGC linker; SEQ ID NO: 5), Ac-DLPDIIWDFNWETAGGC (HNP403; SEQ ID NO: 6), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with a GGC linker; SEQ ID NO: 7), Ac-P WEEPYYVVKKSSGGC (HNP401-N-4 with a GGC linker; SEQ ID NO: 8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with a GGC linker; SEQ ID NO: 9), Ac-PYYVVKKSSGGC (HNP401-N-8 with a GGC linker; SEQ ID NO: 10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with a GGC linker; SEQ ID NO: 11), Ac-SGQVPWE EPYYVVGGC (HNP401-C-4 with a GGC linker; SEQ ID NO: 12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with a GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with a GGC linker; SEQ ID NO: 14), QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO: 20); QVPWEEPYYVVKKSSGG (HNP401-N-3 with a GG linker; SEQ ID NO: 21) 401-N-2; SEQ ID NO: 21), PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO: 22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO: 23), PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24), SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO: 25), SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO: 26), SGQVPWEEPYY (HNP401-C-6;SEQ ID NO: 27), SGQVPWEEP (HNP401-C-8; SEQ ID NO: 28), PWEEPYYVVKKSSGG (HNP401-N-4 with a GG linker; SEQ ID NO: 118), EEPYYVVKKSSGG (HNP401-N-6 with a GG linker; SEQ ID NO: 119), PYYVVKKSSGG (HNP401-N-8 with a GG linker; SEQ ID NO: 120), SGQVPWEEPYYVVKKGG (HNP401- a peptide selected from the group consisting of SGQVPWEEPYYVVGG (HNP401-C-2; SEQ ID NO: 121), SGQVPWEEPYYVVGG (HNP401-C-4 with a GG linker; SEQ ID NO: 122), SGQVPWEEPYYGG (HNP401-C-6 with a GG linker; SEQ ID NO: 123) and SGQVPWEEPGG (HNP401-C-8 with a GG linker; SEQ ID NO: 124); and a cargo comprising a fluorescent moiety, thereby labeling renal neurons; and (b) irradiating the cargo through the wall of the renal artery in the kidney; receiving fluorescence from the cargo; and using the received fluorescence to generate a map of the kidney. A method comprising:

8. 8. The method of claim 7, wherein the fluorescent moiety comprises a fluorophore, a fluorescent dye, a fluorescent protein, a fluorescent peptide, or any combination thereof.

9. 8. The method of claim 7, further comprising using a map of the kidney to identify and ablate renal nerves.

10. 10. The method of claim 9, wherein the renal nerves are ablated by radiofrequency ablation, cryoablation, photodynamic therapy, or microwave ablation.

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