PALM for the treatment of chemotherapy-induced peripheral neuropathy associated with cancer treatment

Abstract

The present disclosure provides a method for treating or preventing chemotherapy-induced peripheral neuropathy (CIPN) in a cancer patient who has been or will be treated with a chemotherapeutic agent that causes CIPN, the method comprising administering to the cancer patient a therapeutically effective amount of a composition containing peptide amphiphilic molecule lipid micelle (PALM) nanoparticles, the PALM nanoparticles comprising PALM containing the chemotherapeutic agent that causes the CIPN, the PALM comprising a peptide and a lipid component including sphingomyelin and one or more additional phospholipids.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This PCT application claims the benefit of U.S. Provisional Patent Application No. 62 / 886,282, filed August 13, 2019, the disclosure of which is incorporated herein by reference in its entirety. (Sequence Listing) This application incorporates by reference in its entirety the Sequence Listing entitled “236603_471132_SequenceListing_ST25.txt” (29 KB), which was created on August 11, 2020 and filed electronically herewith. The present invention relates to the treatment of cancer using peptide amphiphile lipid micelles (PALMs), where such use prevents, treats, ameliorates, or attenuates adverse effects, including chemotherapy-induced peripheral neuropathy (CIPN), caused by the administration of chemotherapeutic agents. More specifically, the present invention relates to a formulation technology that allows the incorporation of chemotherapeutic agents that induce CIPN into nanoparticles that can be easily parenterally administered for safe and effective delivery of the incorporated chemotherapeutic agents to their therapeutic targets, and attenuates adverse effects, including chemotherapy-induced peripheral neuropathy (CIPN), caused by the administration of chemotherapeutic agents. [Background technology]

[0002] A priority goal of the National Cancer Institute is to find a cure for chemotherapy-induced peripheral neuropathy (CIPN), an often debilitating and frequently treatment-compromising side effect of many established chemotherapies. Currently, there are no effective countermeasures beyond dose reduction, delay, or discontinuation. Exposure to reduced doses carries the risk of accelerated tumor growth, chemotherapy resistance, and treatment failure. Moreover, the discomfort of CIPN often persists for months or even years after treatment has ended, further reducing quality of life and impeding the ability to undergo significant follow-on chemotherapy (if required).

[0003] Finding a treatment for CIPN is particularly important for paclitaxel (PTX), which is one of the most widely used and effective chemotherapy agents, but also carries a particularly high risk of CIPN or, more specifically, PIPN. The prevalence of PIPN is greater than 60% among patients undergoing PTX infusions. Severe PIPN (grade 3 / 4), for which a change in treatment is indicated, occurs in at least 10% of patients with PIPN.

[0004] Symptoms of PIPN include tingling, numbness, burning, and pain in the extremities as well as loss of effective grip, fine dexterity, and balance. Patients' experiences range from bothersome to debilitating. The symptoms, their severity, and the amount of peripheral limb axis affected increase with increasing doses, frequency, and number of PTX administrations. Recovery from PIPN is slow and often interferes with activities of daily living for months to years after chemotherapy is completed.

[0005] Currently, dose reduction is the only effective treatment for the painful and debilitating sensory and motor effects of PIPN. Increasing the duration of infusion and the interval between treatments provides limited improvement. Potential neuroprotective and symptom-relieving drugs have been evaluated, but without great success.

[0006] Both currently approved PTX formulations, Taxol® and Abraxane®, cause PIPN to a similar extent and duration. This problem is not unique to paclitaxel. PIPN is also a major risk during clinical use of other taxanes, namely docetaxel (Taxotere®) and cabazitaxel (Jevtana®), and at lower doses.

[0007] The success of PTX-based chemotherapy would be greatly enhanced by a formulation that isolated PTX from nerves and instead targeted it to cancer cells. Cancer patients would experience improved treatment outcomes (i.e., better survival rates) without the discomfort or therapeutic risks of PIPN. Summary of the Invention

[0008] In a first aspect, the disclosure provides a method for the treatment of cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising a chemotherapeutic agent conjugated to a peptide amphiphilic molecule lipid micelle (PALM), wherein the subject experiences reduced chemotherapy-induced peripheral neuropathy when administered PALM compared to when treated with the chemotherapeutic agent in the absence of PALM treatment. PALM is formed in an aqueous suspension by a combination of amphiphilic peptides and phospholipids and optionally other hydrophobic molecules.

[0009] In a second aspect, the present disclosure provides a method for the treatment of chemotherapy-induced peripheral neuropathy (CIPN) in a subject in need of treatment for CIPN who is currently being treated and / or has previously been treated with a chemotherapeutic agent that causes CIPN, the method comprising administering a therapeutically effective amount of a composition comprising a chemotherapeutic agent conjugated to a peptide amphiphilic molecule lipid micelle (PALM), thereby forming a PALM nanoparticle, wherein the subject experiences reduced chemotherapy-induced peripheral neuropathy (e.g., paclitaxel-induced peripheral neuropathy) when administered the PALM nanoparticle compared to when treated with the chemotherapeutic agent in the absence of treatment with the PALM nanoparticle. In related embodiments, chemotherapy-induced peripheral neuropathy (CIPN) is caused by and / or associated with taxanes; epothilones (e.g., ixabepilone and sagopilone); vinca alkaloids, such as vinblastine, vincristine, vinorelbine, and etoposide (VP-16); thalidomide (Thalomid®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst®); proteasome inhibitors, such as bortezomib (Velcade®), carfilzomib (Kyprolis®), and ixazomib (Ninlaro); topoisomerase inhibitors, such as irinotecan or topotecan; and platinum analogs, including cisplatin, carboplatin, and oxaliplatin. In related embodiments, chemotherapy-induced peripheral neuropathy (CIPN) is caused by and / or associated with treatment of cancer with taxane chemotherapy, e.g., any one or more of paclitaxel (Taxol®), Abraxane®, docetaxel (Taxotere®), cabazitaxel (Jevtana®), larotaxel, mirataxel, ortataxel, BMS-275183, and tesetaxel.

[0010] In a third aspect, the disclosure provides a method for the treatment of paclitaxel-induced peripheral neuropathy (PIPN) in a cancer subject currently being treated and / or previously treated with paclitaxel, comprising administering a therapeutically effective amount of a composition comprising a PALM nanoparticle, the PALM nanoparticle comprising PALM conjugated to paclitaxel. In some related embodiments, the cancer subject experiences reduced PIPN when administered a PALM nanoparticle containing paclitaxel compared to being treated with paclitaxel alone in the absence of treatment with the PALM nanoparticle containing paclitaxel. [Brief description of the drawings]

[0011] [Figure 1] A shows an Edmundson wheel depiction of the peptide of SEQ ID NO:3, which exhibits an amphipathic structure. B shows an Edmundson wheel depiction of the peptide of SEQ ID NO:25, which exhibits an amphipathic structure. Figures 1A and 1B further show the axial position of the constituent amino acids (identified by their standard one-letter abbreviations) around the long axis of the alpha helix. The letter "B" represents 2-amino-isobutyric acid. The dashed lines indicate the approximate boundary between the hydrophilic amino acids (shaded) that form the polar face of the peptide and the hydrophobic amino acids that form the non-polar face. C shows a helical net depiction of the peptide of SEQ ID NO:3. D shows a helical net depiction of the peptide of SEQ ID NO:25.

[0012] [Diagram 2] Size-exclusion chromatograms of PALM containing miriplatin (solid line) compared to human HDL (dashed line) are shown. PALM was composed of peptide of SEQ ID NO:25 as well as POPC, SM, and miriplatin in a molar ratio of 2.5:3:7:0.75.

[0013] [Diagram 3] 1 shows a size-exclusion chromatograph of PALM containing XC and prepared with peptide of SEQ ID NO: 25 at a molar ratio of 1:4:0.4 peptide:phospholipid:XC. The elution positions of protein standards of various Stokes diameters are shown.

[0014] [Figure 4] A comparison of size-exclusion chromatograms of PALM containing XTT and prepared with peptide of SEQ ID NO:25 (dashed line) or R4F peptide (solid line) are shown. Both compositions had a molar equivalent ratio of peptide:POPC:SM:XTT of 1:2.8:1.2:0.4.

[0015] [Diagram 5] 1 shows a size-exclusion chromatogram of PALM containing fenretinide prepared with the peptide of SEQ ID NO: 25. The PALM composition had a molar equivalent ratio of peptide:POPC:SM:fenretinide of 2.5:3:7:2.

[0016] [Figure 6] 1 shows inhibition of PC3 prostate cancer cell proliferation by PALM (MP) compared to inhibition by cisplatin.

[0017] [Figure 7] 1 shows the effect of SR-BI antibodies in inhibiting PC3 prostate cancer cell proliferation by PALM (MP). The line represents the fitting of the data to a logistic equation.

[0018] [Figure 8] 1 shows inhibition of SKOV3 ovarian cancer cell proliferation by PALM / (XC) (squares, dotted line) or PALM(XTT) (diamonds, solid line) compared to inhibition by paclitaxel (circles, dashed line). Lines represent fitting of data to a logistic equation.

[0019] [Figure 9]PALMs prepared with the various peptides indicated and containing DiI were incubated with BHK (SR-BI) cells stably transfected with the mifepristone-inducible human SR-BI gene. Incubations were performed with non-induced (control) or induced cells. Human HDL labeled with DiI was tested for comparison. The amount of DiI taken up by the cells over a 4-hour incubation was detected by fluorescence.

[0020] [Figure 10] BHK (SR-BI) cells carrying the mifepristone-inducible human SR-BI gene, either induced (SR-BI+) or not induced (control), were incubated with the indicated concentrations of PTX or PALM (XTT) for 12 hours. The cells were further incubated for another 36 hours in the absence of the test agent, after which the % proliferation was detected by MTT assay.

[0021] [Figure 11] It is shown that SR-BI antibody inhibited the uptake of XTT from PALM(XTT) (arrow).

[0022] [Figure 12] 1 shows a bar graph depicting cytokine IL-6 secretion by SKOV-3 cells incubated for 24 hours with no addition (control), with lipopolysaccharide (10 μg / ml LPS), with paclitaxel (PTX), or with PALM (XTT).

[0023] [Figure 13] Line graphs showing the growth of human ovarian tumors (SKOV-3) in athymic mice administered cremophor / ethanol vehicle (A), paclitaxel (10 mg / kg) (B), PALM(XTT) (8 mg / kg paclitaxel equivalent) (C), or (D) PALM(XTT) (24 mg / kg paclitaxel equivalent).

[0024] [Figure 14] Line graphs showing mechanical allodynia in rats administered cremophor / ethanol vehicle (A), 1 mg / kg paclitaxel (B), saline (PALM vehicle) (C), 1 mg / kg equivalent dose of PALM(XTT) (D), and 2.7 mg / kg equivalent dose of PALM(XTT) (E).

[0025] [Figure 15] 1 shows line graphs depicting the growth of human ovarian tumors (SKOV-3) in athymic mice administered cremophor / ethanol vehicle (A), paclitaxel (10 mg / kg) (B), or PALM without XTT (C). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] definition

[0027] "Nanoparticle" means a particle having no dimension greater than 200 nm.

[0028] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0029] It should be noted that in this disclosure, terms such as "comprises," "comprised," "comprising," "contains," "containing," and the like have their meaning under U.S. patent law, which are inclusive or open ended and do not exclude additional elements or method steps not recited. Terms such as "consisting essentially of" and "consists essentially of" have their meaning under U.S. patent law, which allow for the inclusion of additional elements or steps that do not materially affect the basic and novel characteristics of the claimed invention. The terms "consist of" and "consisting of" have their meaning under U.S. patent law, i.e., these terms are closed ended.

[0030] The use of "about" in front indicates that the value is approximate. For example, the range "about 1 mg to about 50 mg" indicates that the value is approximate. The range "about 1 mg to about 50 mg" includes the approximate value as well as the specific value. For example, the range includes about 1 mg, 1 mg, about 50 mg, and 50 mg.

[0031] When a range is listed, the range includes both the endpoints of the range and all values ​​therebetween. For example, "between 1 mg and 10 mg" includes 1 mg, 10 mg, and all amounts between 1 mg and 10 mg. Similarly, "1 mg and 10 mg" includes 1 mg, 10 mg, and all amounts between 1 mg and 10 mg.

[0032] As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group containing 7 to 21 carbon atoms. As used herein, the term (C1-Cn)alkyl refers to an alkyl group containing 1 to n carbon atoms. For example, (C8-C 12 ) Alkyl refers to an alkyl group containing 8, 9, 10, 11, or 12 carbon atoms. The alkyl group can be branched or unbranched.

[0033] As used herein, "alkenyl" refers to an aliphatic carbon group containing 7-21 carbon atoms and at least one double bond. As used herein, the term (C1-Cn)alkenyl refers to an alkenyl containing 1-n carbon atoms. Alkenyl groups can be branched or unbranched.

[0034] When used to describe a lipid component, "consisting essentially of" means that the lipid component contains less than 0.1 mol % of any additional lipid other than those specified.

[0035] "XC" is an abbreviation for paclitaxel 2'-cholesteryl carbonate.

[0036] "XT3" or "XTT" is an abbreviation for paclitaxel 2'-δ-tocotrienyl carbonate.

[0037] "MP" is an abbreviation for miriplatin.

[0038] "PTX" is an abbreviation for paclitaxel.

[0039] "POPC" is an abbreviation for 1-palmitoyl-2-oleoylphosphatidylcholine.

[0040] "SM" is an abbreviation for sphingomyelin.

[0041] "TBA" is an abbreviation for tert-butyl alcohol.

[0042] "DMSO" is an abbreviation for dimethyl sulfoxide

[0043] "HDL" is an abbreviation for high density lipoprotein.

[0044] "SR-BI" is an abbreviation for scavenger receptor class B type 1.

[0045] "BHK" is an abbreviation for Baby Hamster Kidneys.

[0046] "DiI" is an abbreviation for 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine.

[0047] "IL-6" is an abbreviation for interleukin-6.

[0048] "CIPN" is an abbreviation for chemotherapy-induced peripheral neuropathy.

[0049] "PIPN" is an abbreviation for paclitaxel-induced peripheral neuropathy.

[0050] "PALM" is an acronym used to identify peptide amphiphile lipid micelles formed by the combination of amphipathic peptides with phospholipids and optionally other hydrophobic molecules in aqueous suspension.

[0051] "Amphiphilic" refers to a molecule or polymer (e.g., a peptide) that has an affinity for both lipid and aqueous phases due to a conformation in which the hydrophilic (wetting) and hydrophobic (water-repelling) substituents of the molecule or polymer are structurally separate from one another.

[0052] "Lipophilic" refers to a substance that partitions preferentially into the lipid domains of lipid-rich particles in aqueous suspension. Lipid-rich particles include lipid micelles, liposomes, lipoproteins, cell membranes, and lipid emulsions.

[0053] A "peptide" is a polymer made from alpha amino acid monomers linked together by amide bonds formed between the carboxylic acid group of one amino acid and the alpha amine group of the next amino acid in the polymer. A "peptide" also includes polymers of amino acid monomers linked together. Both the L-optical isomer and the D-optical isomer of amino acids may be used. The amino acids that make up the polymer may be either those found in nature (i.e., natural amino acids) or unnatural amino acids. The term "residue" or "amino acid residue" includes reference to an amino acid that is incorporated into a peptide, polypeptide, or protein.

[0054] By convention, and as used herein, peptide sequences are written from N-terminus to C-terminus, left to right.

[0055] "Micelles" are multimolecular structures organized by non-covalent interactions in the aqueous phase. Micelles are composed of amphiphilic and hydrophobic molecules that aggregate such that the hydrophobic domains of the molecules are protected from the water and the hydrophilic components are located at the micelle-water interface.

[0056] A "cargo molecule" is a hydrophobic or amphipathic chemotherapeutic molecule having anti-cancer therapeutic or diagnostic properties that is stably incorporated into the PALM and does not interfere with the stability of the PALM.

[0057] "siRNA" is a small interfering ribonucleic acid engineered to control cellular gene expression as part of an RNA-induced gene silencing complex.

[0058] "Aib" is the three letter code for the amino acid alpha-aminoisobutyric acid.

[0059] "Aba" is the three-letter code for the amino acid alpha-aminobutyric acid.

[0060] "Amv" is the three letter code for the unnatural amino acid α-methylvaline.

[0061] "Orn" is the three letter code for the amino acid ornithine.

[0062] "SEC" is size exclusion chromatography.

[0063] "DLS" is dynamic light scattering.

[0064] As used herein, a "subject" is defined to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In a preferred embodiment, the subject is a human. The subject may include a cancer patient or patients.

[0065] As used herein, a "chemotherapeutic agent" or "chemotherapeutic agent" or "anti-tumor agent" refers to an agent that reduces, prevents, and / or delays the growth or metastasis of a neoplasm in a subject with a neoplastic disease, or that, in a pharmacologic effective amount, directly kills neoplastic cells by necrosis or apoptosis, thereby reducing, preventing, and / or delaying the growth or metastasis of a neoplasm.

[0066] "Chemotherapy" refers to treatment with chemotherapeutic drugs, agents, or anti-tumor agents.

[0067] With respect to a composition containing PALM conjugated to a chemotherapeutic drug, an "effective amount" or "pharmacologically effective amount" refers to an amount of the composition sufficient to induce a desired biological, pharmacological, or therapeutic result in a subject.

[0068] "Chemotherapy-induced peripheral neuropathy" is a toxic neuritis resulting from direct damage to the peripheral nervous system by a chemotherapy drug(s). CIPN can be acute or chronic. CIPN can be sensory, motor, autonomic, or mixed of any of the three types.

[0069] "Neurotoxic effect" and "neurotoxicity" refer to a toxic substance that alters the normal activity of the nervous system.

[0070] "Neuropathic pain" is intractable pain caused by dysfunction in the peripheral or central nervous system.

[0071] Without being bound by any theory, paclitaxel (PTX) is believed to interfere with nerve function by several mechanisms. The most prominent is perineural inflammation due to the ability of PTX to activate Toll-like receptor 4 (TLR4) on resident macrophages (microglia) adjacent to nerves. Binding of PTX to TLR4 prompts the production and release of inflammatory cytokines by microglia. The cytokines then begin to activate pain channels in adjacent nerves. PIPN also results from PTX entering nerves and interfering with tubulin-dependent neurotransmitter transport in axons due to its tubulin targeting ability. Furthermore, there is evidence that PTX causes neuronal atrophy and nerve loss.

[0072] Paclitaxel is also at the root of another neurological disorder that afflicts chemotherapy patients: cognitive impairment. Paclitaxel-induced cognitive impairment is due to paclitaxel's ability to penetrate the hippocampus, cause inflammation, and interfere with neuronal function there -- the same processes that cause PIPN.

[0073] The multiple mechanisms by which PTX affects nerves suggest that a single symptom-alleviating drug to combat PIPN is unlikely to be successful. A better approach would be to develop a formulation that completely sequesters PTX from TLR4 and nerves while maintaining its exposure to the tumor.

[0074] There is an additional benefit to the technique of inhibiting PTX from interacting with TLR4. PTX interaction with TLR4 has been linked to gastroenteritis and chemotherapy resistance. Activation has also been linked to the induction of cancer cell metastasis and proliferation. Furthermore, the inflammatory cascade triggered by TLR4 activation leads to immunosuppression within tumors. It has been shown in mouse models that inflammation induced by PTX leads to reduced immunosuppression of tumor growth. These examples of the impact of TLR4 on tumor progression are supported by the finding that tumors with low TLR4 are associated with significantly higher patient survival rates.

[0075] The present disclosure addresses this need by providing novel PALM nanoparticle formulations of lipids and peptides, and methods of forming them that allow for the incorporation of chemotherapeutic molecules, e.g., drugs, where the nanoparticles are stable in infusion or injection solutions. The formulations of the present invention provide one or more improvements, including, but not limited to, improved pharmacokinetic parameters, increased half-life, targeted delivery, reduced toxicity, or improved therapeutic index, of parenterally administered anticancer agents, particularly chemotherapeutic agents that cause or are associated with CIPN and particularly PIPN.

[0076] The present disclosure provides an amphipathic alpha-helical peptide comprising the amino acid sequence of SEQ ID NO:1, SEQ ID NO:24, SEQ ID NO:37, or SEQ ID NO:59.

[0077] Additionally, the present disclosure provides peptide amphiphilic molecule lipid micelles (PALMs) comprising a peptide comprising an amino acid sequence of the present disclosure, a sphingomyelin, and one or more additional phospholipids. The PALMs of the present disclosure optionally include one or more cargo molecules, such as imaging agents and drugs.

[0078] The present disclosure also provides processes for preparing PALM compositions formulated with a PALM and a cargo molecule.

[0079] In addition, the disclosure provides compound conjugates suitable for use with PALM, and methods of preparing the compound conjugates.

[0080] The disclosure further provides methods of treating or preventing CIPN (eg, PIPN) adverse events by administering a PALM-chemotherapeutic drug conjugate.

[0081] The present invention provides a method for treating CIPN in a subject, comprising administering to the subject a therapeutically effective amount of a composition containing PALM nanoparticles containing a CIPN-causing chemotherapeutic drug as exemplified herein.

[0082] In another aspect, the present invention provides a method for the preventive treatment of CIPN in a subject, comprising administering to the subject an effective amount of a composition containing PALM nanoparticles containing a CIPN-causing chemotherapeutic drug as exemplified herein.

[0083] In another aspect, the present invention provides a method for reducing the neurotoxic effects of a chemotherapeutic agent that causes and / or is associated with CIPN, comprising administering to a subject an effective amount of a composition comprising PALM nanoparticles containing a chemotherapeutic agent that causes CIPN, as exemplified herein.

[0084] In yet another aspect, the present invention provides a method for treating chemotherapy-induced neuropathic pain in a subject, comprising administering to the subject an effective amount of a composition containing a PALM moiety conjugated to a CIPN-causing chemotherapeutic drug as exemplified herein.

[0085] In some embodiments of the present disclosure, the PALM moiety contains or comprises one or more "amphipathic peptides." Amphipathic peptides can adopt an alpha-helical conformation in which the helix has opposite polar and non-polar faces oriented along the long axis of the helix. Techniques for synthesizing peptides are well known in the art. The peptides of the present disclosure can be synthesized by any technique known in the art.

[0086] Table 1 shows the charge distribution of certain amphipathic peptides of the present disclosure compared to several prior art sequences. The charge distribution of the peptides of the present invention is novel in view of the prior art shown below. [Table 1]

[0087] One embodiment of the first aspect of the disclosure is a peptide having the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 wherein X1 is an amino acid D, and X2 and X 20 are amino acids V and Aib, respectively, and X3, X6, and X 10 , and X 13 are each an amino acid independently selected from the group consisting of L and F; X, X 12 , and X 19 are amino acids Q, X5 is amino acid A or Aib, X7, X 16 , and X 18 are the amino acid K, and X and X 15 are the amino acid E, and X and X 14 are each an amino acid independently selected from the group consisting of A, L, F, and Aib; 11is an amino acid selected from the group consisting of A, Aib, and N; X 17 is an amino acid selected from the group consisting of W, F, and L (SEQ ID NO: 1), and the peptide is 20 to 24 amino acids in length.

[0088] Another embodiment of the first aspect is a peptide having the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 wherein X1 is an amino acid D, X2 and X3 are each independently an amino acid selected from the group consisting of: 20 are amino acids V and Aib, respectively, and X3, X6, and X 10 , and X 13 are each an amino acid independently selected from the group consisting of L and F; X, X 12 , and X 19 are amino acids Q, X5 is amino acid A or Aib, X7, X 16 , and X 18 are the amino acid K, and X and X 15 are the amino acid E, and X and X 14 are each an amino acid independently selected from the group consisting of A, L, F, and Aib; 11 is an amino acid selected from the group consisting of A, Aib, and N; X 17 is an amino acid selected from the group consisting of W, F, and L (SEQ ID NO: 1), and the peptide is 20 to 24 amino acids in length.

[0089] Yet another embodiment of the first aspect is a peptide having the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X15 -X 16 -X 17 -X 18 -X 19 -X 20 wherein X1 is an amino acid D, and X2 and X 20 are amino acids V and Aib, respectively, and X3, X6, and X 10 , and X 13 are each an amino acid independently selected from the group consisting of L and F; X, X 12 , and X 19 are amino acids Q, X5 is amino acid A or Aib, X7, X 16 , and X 18 are the amino acid K, and X and X 15 are the amino acid E, and X and X 14 are each an amino acid independently selected from the group consisting of A, L, F, and Aib; 11 is an amino acid selected from the group consisting of A, Aib, and N; X 17 is an amino acid selected from the group consisting of W, F, and L (SEQ ID NO:1).

[0090] Yet another embodiment of the first aspect is a peptide having the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 wherein X1, X8, and X 15 are independently selected from the group consisting of amino acids D and E; X2 and X 20 are V, I , Aib, and L; X 3 and X 13 are each an amino acid independently selected from the group consisting of L, I, V, W, Y, Amv, Aib, and F; X6 and X10 teeth , each, L, I, V, W, Y, Aib, Amv, From the group consisting of Independently The amino acid of choice is X4 、X 12 , and X 19 are each an amino acid independently selected from the group consisting of Q and N; X, X 16 , and X 18 are each an amino acid independently selected from the group consisting of K, R, H, and Orn; X 7 is an amino acid selected from A, G, S, Aib, and Aib; X 9 Reach B 14 are A, G.S. X is an amino acid independently selected from the group consisting of V, Amv, and Aib; 11 is an amino acid selected from the group consisting of A, G, S, Aib, Amv, V, and N; X 17 is an amino acid selected from the group consisting of W, F, Y, I, V, and L (SEQ ID NO: 24), and the peptide is 20 to 24 amino acids in length.

[0091] Another embodiment of the first aspect is a peptide having the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 wherein X1 is an amino acid selected from the group consisting of D and E, and X2 and X3 are selected from the group consisting of 20 are each an amino acid independently selected from the group consisting of V, I, Aib, and L; X3, X6, X 10 , X 13 are L, I, V, W, Y, respectively. Aib, Amv, and F; X, X 12 , and X 19are each an amino acid independently selected from the group consisting of Q and N; X, X 16 , and X 18 are each an amino acid independently selected from the group consisting of K, R, H, and Orn; X7 is selected from the group consisting of A, G, S, V, Aib, and Amv; X8 and X 15 are independently selected from the group consisting of amino acids E and D; 14 is an amino acid independently selected from the group consisting of A, G, S, L, F, V, Amv, and Aib; X 11 is an amino acid selected from the group consisting of A, G, S, Aib, Amv, V, and N; X 17 is an amino acid selected from the group consisting of W, F, Y, I, V, and L (SEQ ID NO: 24), and the peptide is 20 to 24 amino acids in length.

[0092] Yet another embodiment of the first aspect is a peptide having the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 wherein X1 is an amino acid selected from the group consisting of D and E, and X2 and X3 are 20 are each an amino acid independently selected from the group consisting of V, I, Aib, and L; X3, X6, X 10 , X 13 are L, I, V, W, Y, respectively. Aib, Amv, and F; X, X 12 , and X 19 are each an amino acid independently selected from the group consisting of Q and N; X, X 16 and X 18are each an amino acid independently selected from the group consisting of K, R, H, and Orn; X7 is selected from the group consisting of A, G, S, V, Aib, and Amv; X8 and X 15 are independently selected from the group consisting of amino acids E and D; 14 is an amino acid independently selected from the group consisting of A, G, S, L, F, V, Amv, and Aib; X 11 is an amino acid selected from the group consisting of A, G, S, Aib, Amv, V, and N; X 17 is an amino acid selected from the group consisting of W, F, Y, I, V, and L (SEQ ID NO:24).

[0093] Any of the disclosed embodiments of a peptide according to the first aspect is contemplated to be optionally acylated at the alpha amine of the N-terminal amino acid of the peptide, optionally amidated at the terminal carboxyl group of the peptide, or optionally acylated at the alpha amine of the N-terminal amino acid of the peptide and amidated at the terminal carboxyl group. The peptides may be acylated or amidated by methods known in the art.

[0094] Specific peptides of the invention are listed in Table 2 below. [Table 2-1] [Table 2-2]

[0095] One embodiment of the first aspect of the present disclosure is a peptide comprising any of the amino acid sequences of SEQ ID NOs: 1-23, wherein the peptide is 20-24 amino acids in length. Yet another embodiment is a peptide consisting essentially of any of the amino acid sequences of SEQ ID NOs: 1-23, wherein the peptide is 20-24 amino acids in length. Yet another embodiment is a peptide consisting of any of the amino acid sequences of SEQ ID NOs: 1-23. In any of the above embodiments of the peptide of the present disclosure, optionally, the alpha amine of the N-terminal amino acid of the peptide is acylated, the terminal carboxyl group is amidated, or the alpha amine of the N-terminal amino acid of the peptide is acylated and the terminal carboxyl group is amidated.

[0096] One embodiment of the first aspect of the present disclosure is a peptide comprising any of the amino acid sequences of SEQ ID NOs: 25-36, wherein the peptide is 20-24 amino acids in length. Yet another embodiment is a peptide consisting essentially of any of the amino acid sequences of SEQ ID NOs: 25-36, wherein the peptide is 20-24 amino acids in length. Another embodiment is a peptide consisting of any of the amino acid sequences of SEQ ID NOs: 25-36. Optionally, in any of the above embodiments of the peptide of the present invention, the alpha amine of the N-terminal amino acid of the peptide is acylated, the terminal carboxyl group is amidated, or the alpha amine of the N-terminal amino acid of the peptide is acylated and the terminal carboxyl group is amidated.

[0097] Embodiments of the present disclosure further include peptides having the reverse sequences of the peptides generally defined by SEQ ID NOs:1 and 24.

[0098] One embodiment of the first aspect of the disclosure provides a peptide that is the reverse of SEQ ID NO:1, the peptide having the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17-X 18 -X 19 -X 20 wherein X1 and X 19 are the amino acids V and Aib, respectively, and X2, X9, and X 17 are the amino acid Q, and X, X, and X 14 X is an amino acid selected from the group consisting of W, F, and L; X and X 13 are the amino acid E, and X7 and X 12 are each an amino acid independently selected from the group consisting of A, L, F, and Aib; X, X 11 , X 15 , and X 18 are each an amino acid independently selected from the group consisting of L and F; 10 is an amino acid selected from the group consisting of A, Aib, and N; X 16 is an amino acid selected from the group consisting of A and Aib, and X 20 is the amino acid D (SEQ ID NO: 37), and the peptide is 20 to 24 amino acids in length.

[0099] Another embodiment of the first aspect of the disclosure provides a peptide that is the reverse of SEQ ID NO:24, the reverse peptide having the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 wherein X1 and X 19 are each an amino acid independently selected from the group consisting of V, Aib, I, and L; X2, X9, and X 17 are each an amino acid independently selected from the group consisting of Q and N; X, X, and X 16are each an amino acid independently selected from the group consisting of K, R, H, and Orn, X4 is an amino acid selected from the group consisting of W, F, Y, I, V, and L, X6, X 13 , and X 20 are amino acids independently selected from the group consisting of E and D; X and X 12 are each an amino acid independently selected from the group consisting of A, G, S, L, F, V, Amv, and Aib; X, X 11 , X 15 , and X 18 is independently selected from the group consisting of amino acids L, I, V, W, and F; 10 is an amino acid selected from the group consisting of A, G, S, Aib, Amv, V, and N; X 14 is an amino acid selected from the group consisting of A, G, S, V, Aib, and Amv (SEQ ID NO: 59), and the peptide is 20 to 24 amino acids in length.

[0100] Another embodiment of the first aspect of the disclosure provides a peptide that is the reverse of SEQ ID NO:24, the reverse peptide having the amino acid sequence: X1-X2-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 wherein X1 and X 19 are the amino acids V and Aib, respectively, and X2, X9, and X 17 are the amino acid Q, and X, X, and X 14 X is an amino acid selected from the group consisting of W, F, and L; X and X 13 are the amino acid E, and X7 and X 12 are each an amino acid independently selected from the group consisting of A, L, F, and Aib; X, X 11 , X 15, and X 18 are each an amino acid independently selected from the group consisting of L and F; 10 is an amino acid selected from the group consisting of A, Aib, and N; X 16 is an amino acid selected from the group consisting of A and Aib, and X 20 is the amino acid D (SEQ ID NO:37).

[0101] Additional peptides of the invention are listed in Table 3. The amino acid sequences of these peptides are the reverse of the amino acid sequences of SEQ ID NOs: 2-23 and 25-36. [Table 3-1] [Table 3-2] [Table 3-3]

[0102] One embodiment of the first aspect of the present disclosure is a peptide comprising any of the amino acid sequences of SEQ ID NOs: 38-58, the peptide being 20-24 amino acids in length. Yet another embodiment is a peptide consisting essentially of any of the amino acid sequences of SEQ ID NOs: 38-58. Yet another embodiment is a peptide consisting of any of the amino acid sequences of SEQ ID NOs: 38-58. In any of the above embodiments of the peptide of the present invention, optionally, the alpha amine of the N-terminal amino acid of the peptide is acylated, the terminal carboxyl group is amidated, or the alpha amine of the N-terminal amino acid of the peptide is acylated and the terminal carboxyl group is amidated.

[0103] One embodiment of the first aspect of the present disclosure is a peptide comprising any of the amino acid sequences of SEQ ID NOs: 60-72, wherein the peptide is 20-24 amino acids in length. Yet another embodiment is a peptide consisting essentially of any of the amino acid sequences of SEQ ID NOs: 60-72. Yet another embodiment is a peptide consisting of any of the amino acid sequences of SEQ ID NOs: 60-72. In any of the above embodiments of the peptide of the present invention, optionally, the alpha amine of the N-terminal amino acid of the peptide is acylated, the terminal carboxyl group is amidated, or the alpha amine of the N-terminal amino acid of the peptide is acylated and the terminal carboxyl group is amidated.

[0104] When a peptide of the present disclosure comprises an amino acid sequence of any of SEQ ID NOs: 1-72 and 1 to 4 additional amino acids independently added to either the N-terminus or C-terminus of the amino acid sequence, the additional amino acids are selected such that the addition of the amino acids does not adversely affect the amphipathic properties of the peptide.

[0105] The second aspect of the present disclosure provides a peptide amphiphilic molecule lipid micelle (PALM) moiety (also referred to herein as "PALM") formed by the combination of an amphipathic peptide and a phospholipid. The PALM of the second aspect of the present disclosure comprises one or more peptides of the first aspect of the present disclosure complexed with a lipid component, where the lipid component comprises sphingomyelin and one or more additional phospholipids. The PALM according to the present disclosure can be passively or actively delivered to a target cell population. In one embodiment of the second aspect of the present disclosure, the PALM comprises one or more peptides of the present disclosure, where the lipid component consists essentially of sphingomyelin and one or more additional phospholipids. In one embodiment, the PALM comprises a peptide of the present disclosure and a lipid component, wherein the lipid component comprises sphingomyelin and one or more additional phospholipids, the additional phospholipids being selected from the group consisting of phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine (PEG-PE), phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, cardiolipin, and any combination thereof. In another embodiment, the PALM comprises a peptide of the present disclosure and the lipid component comprises sphingomyelin and phosphatidylcholine. In another embodiment, the PALM comprises a peptide of the present disclosure, sphingomyelin, and 1-palmitoyl-2-oleoylphosphatidylcholine (POPC). In yet another embodiment, the PALM comprises a peptide of the present disclosure and the lipid component comprises sphingomyelin and phosphatidylethanolamine. In yet another embodiment, the PALM comprises a peptide of the present disclosure and the lipid component comprises sphingomyelin and poly(ethylene glycol) phosphatidylethanolamine. In yet another embodiment, the PALM comprises a peptide of the present disclosure and the lipid component comprises sphingomyelin and phosphatidylserine. In another embodiment, the PALM comprises a peptide of the present disclosure and the lipid component comprises sphingomyelin and cardiolipin.

[0106] In yet another embodiment of the second aspect of the present disclosure, the PALM comprises a peptide of the present disclosure, and the lipid component consists essentially of sphingomyelin and one or more additional phospholipids, the one or more additional phospholipids being selected from the group consisting of phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine (PEG-PE), phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, cardiolipin, and any combination thereof. In yet another embodiment, the PALM comprises a peptide of the present disclosure, and the lipid component consists essentially of sphingomyelin and phosphatidylcholine. In another embodiment, the PALM comprises a peptide of the present disclosure, and the lipid component consists essentially of sphingomyelin and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC).

[0107] In some embodiments of the second aspect of the present disclosure, the PALM comprises a peptide of the present disclosure, and the lipid component consists essentially of sphingomyelin and one or more additional phospholipids, the one or more additional phospholipids being selected from the group consisting of phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine (PEG-PE), phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, cardiolipin, and any combination thereof, and the molar ratio of phospholipid to sphingomyelin is about 95:5 to about 10:90. In another embodiment, the molar ratio of phospholipid to sphingomyelin is about 90:10 to about 20:80. In yet another embodiment, the molar ratio of phospholipid to sphingomyelin is about 25:75 to about 35:65. In another embodiment, the molar ratio of phospholipid to sphingomyelin is about 30:70. In another embodiment, the molar ratio of phospholipid to sphingomyelin is about 80:20 to about 60:40. In yet another embodiment, the molar ratio of phospholipid to sphingomyelin is about 75:25 to about 65:35. In yet another embodiment, the molar ratio of phospholipid to sphingomyelin is about 70:30.

[0108] The fatty acid component of the phospholipids includes fatty acids of the formula: R-COOH, where R is any of the C7 to C 21 ) alkyl group or (C7-C 21 ) alkenyl group, which may have 1-6 double bonds. Examples of suitable fatty acids include, but are not limited to, phytanic acid, linolenic acid, linoleic acid, docosatetraenoic acid, oleic acid, caprylic acid, lauric acid, arachidic acid, myristic acid, and palmitic acid. The pair of fatty acids esterified to the glycerol backbone of a particular phospholipid may be the same or may each be a different type of fatty acid.

[0109] The molar ratio of lipid component to peptide is about 10:1 to about 2:1. In one embodiment, the ratio is about 9:1 to about 2:1. In one embodiment, the molar ratio of lipid component to peptide is about 8:1 to about 2:1. In yet another embodiment, the molar ratio of lipid component to peptide is about 7:1 to about 3:1. In another embodiment, the molar ratio of lipid component to peptide is about 6:1 to about 4:1.

[0110] Complexes of phosphatidylcholine with amphipathic peptides are known. One method for producing these complexes is by initial co-lyophilization from a common solvent phase, followed by rehydration of the dried lyophilisate to form the complex in aqueous suspension.

[0111] Particle size is measured by DLS and expressed as hydrodynamic mean diameter ("mean diameter"). The PALM according to the second aspect of the present disclosure are nanometer-sized particles having a mean diameter of 200 nm or less, 50 nm or less, 40 nm or less, or 30 nm or less. In one embodiment, the mean particle diameter is about 5 nm to about 200 nm. In another embodiment, the mean particle diameter is about 5 nm to about 50 nm. In one embodiment, the mean particle diameter is about 5 nm to about 30 nm. In yet another embodiment, the mean particle diameter is about 7.5 nm to about 30 nm. In yet another embodiment, the mean particle diameter is about 10 nm to about 30 nm. In another embodiment, the mean particle diameter is about 5 nm to about 25 nm. In another embodiment, the mean particle diameter is about 7.5 nm to about 25 nm. In yet another embodiment, the mean particle diameter is about 10 nm to about 25 nm. In another embodiment, the mean particle diameter is about 5 nm to about 20 nm. In another embodiment, the average particle diameter is about 7.5 nm to about 20 nm. In yet another embodiment, the average particle diameter is about 10 nm to about 20 nm. In yet another embodiment, the average particle diameter is about 5 nm to about 15 nm. In another embodiment, the average particle diameter is about 7.5 nm to about 15 nm. In yet another embodiment, the average particle diameter is about 10 nm to about 15 nm. In yet another embodiment, the average particle diameter is about 7.5 nm to about 10 nm.

[0112] The third aspect of the present disclosure provides a PALM-cargo molecule composition comprising any of the embodiments of the PALM of the second aspect of the present disclosure and a cargo molecule. The cargo molecule includes, but is not limited to, a molecule having pharmaceutical or therapeutic properties. Non-limiting examples of cargo molecules include, collectively or individually, anti-cancer compounds such as all-trans retinoic acid, alcohol esters of all-trans retinoic acid including methyl alcohol ester, ethyl alcohol ester, and longer chain aliphatic alkyl chain alcohol esters of retinoic acid, and cholesteryl esters of retinoic acid; retinoic acid amides such as fenretinide; retinol, and methyl alcohol ester, ethyl alcohol ester, and longer chain aliphatic alkyl chain alcohol esters of retinoic acid; These include carboxylic acid esters of retinol, including alkyl chain alcohol esters; lipophilic antifungals, such as amphotericin B or nystatin; steroids, such as progesterone, testosterone, prednisolone, hydrocortisone, dexamethasone, and estradiol; analgesics, such as propofol and haloperidol; antipsychotics, such as fluphenazine decanoate and aripiprazole; the vitamin D analogs cholecalciferol and ergocalciferol; and isomers of vitamin E.

[0113] Cargo molecules also include molecules that enable diagnostic or imaging procedures, such as fluorescent contrast agents, radiolabeled contrast agents, and agents used in MRI, PET, CT, SPECT / CT, and X-ray examinations. MRI contrast agents include, but are not limited to, phosphatidylethanolamines having a diethylenetriaminepentaacetic acid moiety chelated to a contrast agent, such as gadolinium ion or similar lanthanide ion, or indium 111 or gallium 67 or lutetium 177 or samarium 153.

[0114] The cargo molecule may also be RNA or DNA of various types and lengths linked to cholesterol or other polycyclic aliphatic alcohols by known methods.

[0115] In one embodiment of the third aspect, the cargo molecule is miriplatin, which has the chemical name cis[((1R,2R)-1,2-cyclohexanediamine-N,N')bis(myristat)]platinum(II). [ka]

[0116] Yet another embodiment of the third aspect of the present disclosure is a PALM-cargo molecule complex, wherein the cargo molecule is a compound conjugate of formula I:

[0117] ARLX (formula I) where A is a drug having a hydroxy or amine group, R is the hydroxyl or amine group of the drug, L is a linker, and X is an anchor moiety.

[0118] Another embodiment of the third aspect of the present disclosure is a PALM-cargo molecule complex, wherein the cargo molecule is a compound conjugate of formula I:

[0119] ARLX (formula I) In the formula, A is a drug having a hydroxyl or amine group, R is the hydroxyl or amine group of the drug, L is carbonic acid, succinic acid, or diglycolic acid, and X is cholesterol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, coprostanol, plant sterols (β-sitosterol, sitostanol, stigmasterol, stigmastanol, campesterol, brassicasterol), ergosterol, retinol, cholecalciferol, ergocalciferol, tocopherol, or tocotrienol.

[0120] Another embodiment of the third aspect of the present disclosure is a PALM-cargo molecule complex, wherein the cargo molecule is a compound conjugate of formula I: wherein A is a drug having a hydroxy or amine group, R is the hydroxy or amine group of the drug, L is selected from the group consisting of carbonic acid, succinic acid, or diglycolic acid, and X is selected from the group consisting of cholesterol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, cholesterol, coprostanol, plant sterols (β-sitosterol, sitostanol, stigmasterol, stigmastanol, campesterol, brassicasterol), ergosterol, retinol, cholecalciferol, ergocalciferol, α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol.

[0121] Another embodiment of the third aspect of the present disclosure is a PALM-cargo molecule complex, wherein the cargo molecule is a compound conjugate of formula I: wherein A is a drug having a hydroxy or amine group, R is the hydroxyl or amine group of the drug, L is a linker, and X is an anchor moiety selected from the group consisting of cholesterol, cholecalciferol, and δ-tocotrienol.

[0122] In one embodiment of the compound conjugate of formula (1), R is a hydroxy group of the drug and the anchor moiety is covalently attached to the drug via a carbonate bond. In another embodiment of the compound conjugate of formula (1), R is an amine group of the drug and the anchor moiety is covalently attached to the drug via a carbamate bond.

[0123] In another embodiment of the compound conjugate of formula (1), the anchor moiety is cholesterol. In yet another embodiment of the compound conjugate of formula (1), the anchor moiety is cholesterol, with the proviso that when the anchor moiety is cholesterol, the compound is not paclitaxel.

[0124] In yet another embodiment of the compound conjugate of formula (1), the anchor moiety is α-tocotrienol. In another embodiment of the compound conjugate of formula (1), the anchor moiety is β-tocotrienol. In yet another embodiment of the compound conjugate of formula (1), the anchor moiety is γ-tocotrienol. In yet another embodiment of the compound conjugate of formula (1), the anchor moiety is δ-tocotrienol. In yet another embodiment of the compound conjugate of formula (1), the anchor moiety is ergocalciferol.

[0125] In some embodiments of the compound conjugate of Formula (1), the agent is a drug.

[0126] In some embodiments of the compound conjugate of formula (1), the drug is a chemotherapeutic drug that causes and / or is associated with CIPN. In one embodiment of the compound conjugate of formula (1), the drug is a chemotherapeutic drug that causes CIPN, and the chemotherapeutic drug is covalently attached to the anchor by a carbonate bond.

[0127] In one embodiment of the compound conjugate of formula (1), the agent is a chemotherapeutic agent that causes CIPN, and the chemotherapeutic agent that causes CIPN is covalently attached to the anchor via a carbamate bond.

[0128] Non-limiting examples of CIPN-causing chemotherapeutic agents that have a hydroxyl group available to form a carbonate bond include vincristine, desacetylvinblastine, desacetylvinorelbine, tubulysin A, epothilone B, ixabepilone, eribulin, emtansine, docetaxel, cabazitaxel, or paclitaxel. Non-limiting examples of chemotherapeutic agents that cause CIPN that have an available amine to form a carbamate bond include gemcitabine and cytarabine.

[0129] In some embodiments of the PALM-chemotherapeutic agent conjugate nanoparticle composition of the third aspect of the present disclosure, the chemotherapeutic agent causing CIPN is paclitaxel 2'-cholesteryl carbonate. In another embodiment, the chemotherapeutic agent is paclitaxel 2'-δ-tocotrienyl carbonate.

[0130] In yet another embodiment, the chemotherapy agent causing CIPN is docetaxel 2'-cholesteryl carbonate. In another embodiment, the chemotherapy agent causing CIPN is the cholesteryl carbonate ester of gemcitabine. In another embodiment, the chemotherapy agent causing CIPN is the cholesteryl carbonate ester of tubulysin A.

[0131] In another embodiment of the PALM-chemotherapeutic agent conjugate nanoparticle composition of the third aspect of the present disclosure, the chemotherapeutic agent causing CIPN is a cholesteryl carbamate ester of gemcitabine (cholesteryl(N 4 )-gemcitabine carbamate).

[0132] In yet another embodiment, the chemotherapy agent causing CIPN is the cholesteryl carbonate ester of vincristine, the structure of which is: [ka]

[0133] In yet another embodiment, the chemotherapy agent causing CIPN is the delta-tocotrienyl carbamate ester of paclitaxel, the structure of which is: [ka]

[0134] In yet another embodiment, the chemotherapy agent causing CIPN is the delta-tocotrienyl carbonate ester of gemcitabine, the structure of which is: [ka]

[0135] Table 4 lists the structures of non-limiting examples of CIPN-causing chemotherapeutic agents (A) useful in the present invention, with a hydroxyl or amine group (R) indicated by an arrow. [Table 4]

[0136] Table 5 lists non-limiting examples of PALM-chemotherapeutic compositions of the formula ARLX. [Table 5-1] [Table 5-2] [Table 5-3]

[0137] A fourth aspect of the present disclosure provides a surprisingly effective co-lyophilization technique for producing PALM or PALM-chemotherapeutic nanoparticle compositions from a homogenous solvent phase composed of tert-butyl alcohol and water. The advantages of this approach are that 1) all PALM components, including peptides, phospholipids, and optionally lipophilic cargo (e.g., chemotherapeutic drugs causing CIPN), such as paclitaxel-2'-cholesteryl carbonate, are solubilized together in a single solvent phase, 2) the solvent components are completely compatible and well suited for removal by standard lyophilization procedures, 3) the procedure avoids potentially toxic materials due to the low toxicity of tert-butyl alcohol (Class 3 solvent), and 4) the resulting dry lyophilizate allows the opportunity for greater stability during storage than is possible with aqueous preparations.

[0138] The solvent mixture used to prepare PALM is preferably a mixture of tert-butyl alcohol (TBA) and water. In one embodiment, the percentage ratio of TBA to water is about 70%:30% to about 90%:10%. In another embodiment, the ratio is about 75%:25% to about 85%:15%. In yet another embodiment, the ratio is 80%:20%.

[0139] An embodiment of the fourth aspect comprises i) solubilizing an amphipathic peptide in a first solvent mixture to obtain a peptide solution; ii) solubilizing the sphingomyelin in a second solvent mixture to obtain a sphingomyelin solution; iii) solubilizing additional phospholipids in a third solvent mixture to obtain a phospholipid solution; iv) combining the peptide solution, the sphingomyelin solution, and the phospholipid solution to form a peptide / sphingomyelin / phospholipid solution; v) freeze-drying the peptide / sphingomyelin / phospholipid solution; wherein steps i), ii) and iii) are performed in any order, and the first, second, and third solvent mixtures comprise tert-butyl alcohol and water.

[0140] Another embodiment of the fourth aspect of the present disclosure comprises: i) combining an amphipathic peptide, a sphingomyelin, and an additional phospholipid to form a peptide / sphingomyelin / phospholipid mixture; ii) solubilizing the peptide / sphingomyelin / phospholipid mixture in a solvent mixture to form a peptide / sphingomyelin / phospholipid solution; iii) freeze-drying the peptide / phospholipid solution, Here, the solvent mixture comprises tert-butyl alcohol and water.

[0141] Further, the fourth aspect of the present disclosure provides a process for preparing PALM containing a chemotherapeutic agent that causes CIPN to form a PALM-chemotherapeutic agent nanoparticle. To prepare a PALM-chemotherapeutic agent nanoparticle, a peptide, a sphingomyelin, one or more additional phospholipids, and a chemotherapeutic agent that causes CIPN are each prepared separately in a solvent mixture and combined in a specific molar ratio depending on the desired formulation. Alternatively, a peptide, a sphingomyelin, one or more additional phospholipids, and a chemotherapeutic agent that causes CIPN can be directly combined without prior solubilization, and then brought into solution with a desired solvent mixture before lyophilization.

[0142] One embodiment of the fourth aspect of the present disclosure comprises: i) solubilizing an amphipathic peptide in a first solvent mixture to obtain a peptide solution; ii) solubilizing the sphingomyelin in a second solvent mixture to obtain a sphingomyelin solution; iii) solubilizing additional phospholipids in a third solvent mixture to obtain a phospholipid solution; iv) solubilizing the CIPN-causing chemotherapy drug in a fourth solvent mixture to obtain a cargo molecule solution; v) combining the peptide solution, the sphingomyelin solution, the phospholipid solution, and a CIPN-inducing chemotherapy drug solution to form a peptide / sphingomyelin / phospholipid / chemotherapeutic drug solution; vi) freeze-drying the peptide / sphingomyelin / phospholipid / chemotherapeutic drug solution; wherein steps i), ii), iii), and iv) are performed in any order, and wherein the first, second, third, and fourth solvent mixtures comprise tert-butyl alcohol and water.

[0143] Another embodiment for preparing PALM-chemotherapeutic drug nanoparticles comprises: i) combining an amphipathic peptide, a sphingomyelin, an additional phospholipid, and a cargo molecule to form a peptide / sphingomyelin / phospholipid / cargo molecule mixture; ii) solubilizing the peptide / sphingomyelin / phospholipid / cargo molecule mixture in a solvent mixture to form a peptide / phospholipid solution; iii) lyophilizing the peptide / sphingomyelin / phospholipid / chemotherapeutic drug solution; Here, the solvent mixture comprises tert-butyl alcohol and water.

[0144] The resulting lyophilized cake can be stored for long periods and remains stable. The lyophilized product is rehydrated by adding any suitable aqueous solution, e.g., water or saline, followed by gentle swirling of the contents. Reconstitution of the PALM lyophilisate can be improved by incubating the PALM solution at 50°C for 5-30 minutes. The solution is then filter-sterilized (0.2 μm) and stored at 4-8°C. Alternatively, the solvent mixture containing the peptide, phospholipid, and cargo molecule is filter-sterilized prior to lyophilization.

[0145] A fifth aspect of the present disclosure provides a method for treating CIPN, e.g., PIPN (paclitaxel-induced peripheral neuropathy), comprising administering to a subject in need of treatment an effective amount of a composition containing a PALM-chemotherapeutic drug-containing nanoparticle composition according to any one of the embodiments of the present disclosure.

[0146] Scavenger receptor B-1 (SR-B1) is a membrane receptor that binds to apolipoprotein AI, the main protein component of HDL, to facilitate cellular transport of cholesterol. Cholesterol is an essential nutrient for proliferating cells, such as those found in malignant tumors. SR-B1 is highly expressed in many tumor cells, including, but not limited to, breast, prostate, colon, pancreatic, adrenal, skin, nasopharyngeal, and ovarian cancers. Some amphipathic peptides are also recognized and bound by SR-BI. PALM is formed from a combination of phospholipids and amphipathic peptides designed to bind to SR-BI and thereby selectively deliver chemotherapeutic drugs to SR-BI-positive cells.

[0147] For pharmaceutical use, lyophilized PALM can be provided in single-dose or multi-dose containers that can be easily reconstituted at the time of use, e.g., in a hospital or clinic, using standard diluents such as sterile water for injection, normal sterile saline, or sterile 5% dextrose solution. A suitable container is then aseptically filled with the sterile mixture, lyophilized, and appropriately sealed to maintain the sterility of the lyophilized material. Suitable containers include, but are not limited to, vials or equivalents that contain a rubber seal, allowing the introduction of diluents for reconstitution by syringe, for example. Such PALM preparations are suitable for parenteral administration, including intravenous, subcutaneous, intramuscular, and intraperitoneal injection.

[0148] The present invention is also directed, in part, to all compositions containing chemotherapeutic agents that cause PALM and CIPN, and methods of using them. PALM molecules and their chemotherapeutic agents that cause CIPN can be administered with or without excipients. Excipients include, but are not limited to, encapsulation devices and additives, such as absorption enhancers, antioxidants, binders, buffers, coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, moisturizing agents, lubricants, flavoring agents, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, mixtures thereof, and the like.

[0149] The total daily amount of the PALM of the present invention administered to a human or other mammalian host in a single or divided dose can be, for example, an amount of 0.1 to 300 mg / kg body weight per day, more usually an amount of 0.1 to 200 mg / kg body weight per day, or a dose of 0.1 to 100 mg / kg body weight per day.

[0150] In one embodiment of the invention, the (total) dose of PALM-chemotherapeutic nanoparticles is in the range of 0.1-300 mg / kg, in the range of 5-200 mg / kg, in the range of 10-100 mg / kg, or in the range of 10 mg / kg-50 mg / kg. In further embodiments of the invention, the (total) dose of PALM molecule and chemotherapeutic agent is about 5 mg / kg, 10 mg / kg, 20 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, or 100 mg / kg, 200 mg / kg, 300 mg / kg. The dose may be administered once a day. The dose may be administered three times a week. Alternatively, the dose may be administered twice a week. Alternatively, the dose may be administered once a week. In another embodiment, the dose may be administered once a month.

[0151] In related embodiments, the amount, or dose, of the chemotherapeutic agent in the combination of PALM and the chemotherapeutic agent may range from about 0.01 mg to about 35 mg per kilogram of patient body weight, about 0.01 mg to about 30 mg per kilogram of patient body weight, about 0.01 mg to about 25 mg per kilogram of patient body weight, about 0.01 to about 20 mg per kilogram of patient body weight, or about 0.01 to about 10 mg per kilogram of patient body weight. In further related embodiments, the amount of the chemotherapeutic agent in the composition with the PALM molecule is the prescribed, Food and Drug Administration (FDA USA) or European Medicines Agency (EMA) approved dose of the chemotherapeutic agent for the treatment of cancer that the patient may receive or is receiving.

[0152] In one embodiment, the CIPN is sensory. In one embodiment, the neuropathy is manifested as distal axonopathy. In another embodiment, the neuropathy is manifested as paresthesia, paresthesia, burning sensations, numbness, and / or pain.

[0153] In one embodiment, the CIPN is motor. In another embodiment, the neuropathy is manifested as muscle atrophy. In another embodiment, the neuropathy is manifested as loss of distal deep tendon reflexes.

[0154] In one embodiment, the CIPN is autonomic.

[0155] In one embodiment, the subject has a high risk of developing chemotherapy-induced peripheral neuropathy. The subject with a high risk of developing CIPN has a history of diseases including diabetes, nutritional deficiency, alcoholism, and past exposure to neurotoxic chemotherapy. In another embodiment, the subject has a history of neuropathy. The past neuropathy may be caused by diabetes, nutritional deficiency, alcoholism, genetic disease, and / or neurotoxic chemotherapy.

[0156] In one embodiment, the invention further comprises the step of administering one or more chemotherapeutic agents in addition to the chemotherapeutic agent associated with the PALM-containing composition.

[0157] In various embodiments, the chemotherapeutic agent or agents and / or cargo molecules in the composition containing PALM may include, for example, antimetabolites (i.e., folate antagonists, purine antagonists, and pyrimidine antagonists), bleomycin, DNA alkylating agents (i.e., nitrosoureas, cross-linking agents, and alkylating agents), hormones, aromatase inhibitors, monoclonal antibodies, antibiotics, platinum complexes, proteasome inhibitors, taxane analogs, vinca alkaloids, topoisomerase inhibitors (i.e., anthracyclines, camptothecins, podophyllotoxins), tyrosine kinase inhibitors, or combinations thereof.

[0158] In another embodiment, the chemotherapeutic agent or agents and / or cargo molecules in the composition containing PALM may include, for example, a platinum complex, a vinca analog, a taxane analog, an alkylating agent, an antimetabolite, a proteasome inhibitor, or a combination thereof.

[0159] Platinum complexes can include, for example, cisplatin, oxaliplatin, eptaplatin, lobaplatin, nedaplatin, carboplatin, satraplatin, picoplatin, miriplatin, and the like.

[0160] Vinca alkaloids can include, for example, vincristine, vinblastine, vinorelbine, vindesine, and the like.

[0161] Taxanes can include, for example, paclitaxel, docetaxel, cabazitaxel, and their various formulations and analogs.

[0162] Alkylating agents may include, for example, dacarbazine, procarbazine, temozolomide, thiotepa, mechlorethamine, chlorambucil, L-phenylalanine mustard, melphalan, ifosfamide, cyclophosphamide, mefosphamide, perfosfamide, trofosfamide, busulfan, carmustine, lomustine, thiotepa, semustine, and the like.

[0163] Antimetabolites include pemetrexed disodium, 5-azacytidine, capecitabine, carmofur, cladribine, clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, enocitabine, ethinylcytidine, fludarabine, and 5-fluorouracil alone or in combination with leucovorin. These include cyclosporine, gemcitabine, hydroxyurea, melphalan, mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolate, nelarabine, nolatrexed, oxfosfate, peritrexol, pentostatin, raltitrexed, ribavirin, triapine, trimetrexate, S-1, tiazofurin, tegafur, TS-1, vidarabine, and UFT.

[0164] Proteasome inhibitors can include, for example, bortezomib.

[0165] Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, irinotecan hydrochloride, camptothecin, dexrazoxane, diflomotecan, edotecarin, epirubicin, etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, raltotecan, mitoxantrone, orathecin, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan.

[0166] In another embodiment, the chemotherapeutic agent is bortezomib, carboplatin, cisplatin, misonidazole, oxaliplatin, procarbazine, thalidomide, docetaxel, hexamethylmelamine, paclitaxel, vincristine, vinblastine, or vinorelbine.

[0167] In one embodiment, the chemotherapeutic agents are docetaxel, paclitaxel, carboplatin, doxorubicin, cisplatin, oxaliplatin, capecitabine, 5-fluorouracil, and leucovorin.

[0168] In various embodiments, patients experiencing or likely to experience CIPN are undergoing or have previously been treated with one or more of the following chemotherapeutic agents, e.g., docetaxel, paclitaxel, carboplatin, cisplatin, gemcitabine, oxaliplatin, capecitabine, 5-fluorouracil, and leucovorin, which may cause CIPN in the patient to which they are administered, or may be associated with CIPN in the patient, or may cause CIPN in the patient. In these patients, methods of treating or preventing CIPN, e.g., PIPN, include providing the chemotherapeutic agent to which the patient is being administered or which has been administered, which is part of a new formulation, the formulation comprising a composition containing PALM, to treat CIPN in the patient or prevent the occurrence of CIPN in the treated cancer patient.

[0169] In another embodiment, the chemotherapeutic agent or agents are administered for the treatment of cancer.

[0170] In one embodiment of the present invention, the cancer to be treated is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (mononuclear, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, large intestine ... Intestinal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative abnormal changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelial sarcoma ( lymphagioendotheliosarcoma), lymphangiosarcoma, acute lymphocytic leukemia, lymphomas (Hodgkin's and non-Hodgkin's lymphomas), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, lymphoid neoplasms of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma , non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovium, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

[0171] In yet another embodiment of the invention, the cancer to be treated is selected from the group consisting of ovarian cancer, cervical cancer, colon cancer, prostate cancer, breast cancer, gastric adenocarcinoma, head and neck cancer, testicular cancer, leukemia, neuroblastoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and non-small cell lung cancer.

[0172] The composition comprising PALM and a chemotherapeutic agent, and the formulation thereof, can be administered before, immediately before, during, immediately after, or after administration of one or more chemotherapeutic agents. The composition comprising PALM and a chemotherapeutic agent can be administered prophylactically before CIPN is established, or to treat established CIPN. Established CIPN can be acute or chronic.

[0173] In various embodiments of the methods of preventing and treating CIPN contemplated herein, compositions administered to a cancer patient before, during, or after CIPN may contain an amount of a chemotherapeutic agent ranging from about 5 mg to about 5,000 mg, which may include an effective amount, or an ineffective amount, or a daily dose, or divided daily doses of the chemotherapeutic agent.

[0174] In some embodiments, cisplatin is administered at 20 mg / m for 1, 2, 3, 4, 5, 6, 7, or 8 cycles. 2 ~140mg / m 2 For example, cisplatin can be administered at a dose ranging from 20 mg / m2 daily for 5 days per cycle. 2 Cisplatin may be administered at 75-100 mg / m every 4 weeks (day 1) once per cycle. 2 Cisplatin may be administered at 50-70 mg / m2 once per cycle every 3-4 weeks (on day 1).

[0175] Carboplatin is administered once per cycle, at a dose of approximately 300 mg / m every 3 to 4 weeks (on day 1). 2 Less than or equal to about 360 mg / m 2 Carboplatin may be administered for 1, 2, 3, 4, 5, 6, 7, or 8 cycles.

[0176] Oxaliplatin is administered once per cycle at approximately 85 mg / m every 2 weeks. 2 The following may be administered: Oxaliplatin may be administered for 1, 2, 3, 4, 5, 6, 7, or 8 cycles.

[0177] Docetaxel is approximately 60 mg / m for 1, 2, 3, 4, 5, 6, 7, or 8 cycles. 2 For example, docetaxel may be administered at 75 mg / m2 once per cycle, every 3 weeks (on day 1). 2 It may be administered at

[0178] Paclitaxel is approximately 100 mg / m for 1, 2, 3, 4, 5, 6, 7, or 8 cycles. 2 ~about 175mg / m 2 Paclitaxel can be administered at approximately 100 mg / m once per cycle every 3 weeks (on day 1). 2 Paclitaxel may be administered at approximately 135 mg / m once per cycle, every 3 weeks (day 1). 2 Paclitaxel may be administered at approximately 175 mg / m2 once per cycle, every 3 weeks (day 1). 2 It may be administered at

[0179] Vincristine is administered once per cycle at approximately 0.4 mg / m every 1 to 4 weeks (day 1). 2 ~1.4mg / m 2 Vincristine may be administered for 1, 2, 3, 4, 5, 6, 7, or 8 cycles.

[0180] Vinblastine is administered once per cycle at a dose of approximately 3.7 mg / m2 every 1 to 4 weeks (day 1). 2 ~about 18.5mg / m 2 For example, vinblastine can be administered at a dose ranging from 3.7 mg / m 2 , 5.5 mg / m 2 , 7.4 mg / m 2 , 9.25 mg / m 2 , or 11.1 mg / m 2 Vinblastine may be administered for 1, 2, 3, 4, 5, 6, 7, or 8 cycles.

[0181] Vinorelbine is administered once per cycle, at a dose of approximately 25 mg / m every 1 to 6 weeks (day 1). 2 ~about 120mg / m 2For example, vinorelbine can be administered at 30 mg / m 2 Vinorelbine may be administered for 1, 2, 3, 4, 5, 6, 7, or 8 cycles.

[0182] In one embodiment, compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered once daily during a treatment cycle, e.g., administered on day 1 of a cycle, where the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks long.

[0183] In one embodiment, compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered twice daily during a treatment cycle, e.g., administered on day 1 of a cycle, where the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks long.

[0184] In one embodiment, compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered twice weekly during a treatment cycle, e.g., administered on day 1 of a cycle, where the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks.

[0185] In one embodiment, the compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered once a week during a treatment cycle, e.g., administered on day 1 of the cycle, where the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks long.

[0186] In one embodiment, the compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered once a week during a treatment cycle, e.g., administered on day 1 of the cycle, where the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks long.

[0187] In one embodiment, compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered once daily during a treatment cycle, where the chemotherapeutic agent or agents are administered on day 1 of the cycle, and the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks long.

[0188] In one embodiment, compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered twice daily during a treatment cycle, where the chemotherapeutic agent or agents are administered on day 1 of the cycle, and the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks long.

[0189] In one embodiment, compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered twice weekly during a treatment cycle, where the chemotherapeutic agent or agents are administered on day 1 of the cycle, and the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks long.

[0190] In one embodiment, compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered once a week during a treatment cycle, where the chemotherapeutic agent or agents are administered on day 1 of the cycle, and the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks long.

[0191] In one embodiment, compositions comprising PALM and a chemotherapeutic agent and formulations thereof are administered once a week during a treatment cycle, where the chemotherapeutic agent or agents are administered on day 1 of the cycle, and the cycle is 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks long.

[0192] In another embodiment, the composition comprising PALM and a chemotherapeutic agent and its formulation is administered at least one day prior to chemotherapy. In another embodiment, the composition comprising PALM and a chemotherapeutic agent and its formulation is administered two days prior to chemotherapy. In another embodiment, the composition comprising PALM and a chemotherapeutic agent and its formulation is administered one week prior to chemotherapy. In yet another embodiment, the composition comprising PALM and a chemotherapeutic agent and its formulation is administered immediately prior to each chemotherapy treatment. In yet another embodiment, the composition comprising PALM and a chemotherapeutic agent and its formulation is administered simultaneously with each chemotherapy treatment. In yet another embodiment, the composition comprising PALM and a chemotherapeutic agent and its formulation is administered after chemotherapy.

[0193] In a subset of the above embodiments, chemotherapy and chemotherapy treatment may include single or multiple administrations of the disclosed compositions, e.g., compositions comprising PALM and a chemotherapy agent, in the absence of any additional chemotherapy agent. In other related embodiments exemplified above, chemotherapy and chemotherapy treatment include administration of a chemotherapy agent different from the chemotherapy agent present in the compositions and formulations comprising PALM and a chemotherapy agent, and reference to chemotherapy and chemotherapy treatment refers to administration of a chemotherapy agent different from the chemotherapy agent present in the composition containing PALM and a chemotherapy agent.

[0194] Furthermore, the present invention allows for the administration of higher doses of chemotherapy. Additionally, the present invention allows for the administration of additional cycles of chemotherapy. The present invention also allows for a reduction in the time between chemotherapy cycles.

[0195] The severity of the development of CIPN is reflected in a grade (i.e., 0, 1, 2, 3, or 4). The scale increases from grade 0 (normal and asymptomatic) to grade 4 (disabling and / or life-threatening). (Postma TJ, Annals of Oncology 1998 9:739-744). Grade 3 requires corrective measures, including dose reduction and / or delay of administration.

[0196] There are several Common Toxicity Criteria (CTC) scales used in clinical practice to assess the severity of CIPN: the World Health Organization (WHO) scale, the Eastern Cooperative Oncology Group (ECOG) scale, the National Cancer Institute Common Toxicity Criteria (NCI-CTC), and the Ajani scale. (Cavaletti G., et al., European Journal of Cancer 2010 46:479-494). The scales represent a combination of objective and patient assessment of the impact of CIPN.

[0197] One embodiment of the present invention provides a method of treatment comprising prophylactically treating chemotherapy-induced peripheral neuropathy with a composition of the present invention comprising PALM and a chemotherapeutic agent, wherein the incidence of grade 3 or 4 CIPN is reduced. In another embodiment, the incidence of grade 1 or 2 CIPN is reduced. In another embodiment, the incidence of grade 3 or 4 CIPN is reduced to grade 1 or 2 CIPN. In another embodiment, the incidence of grade 2 CIPN is reduced to grade 1.

[0198] The invention further provides a method for reducing the neurotoxic effects of a chemotherapeutic agent, wherein the incidence of grade 3 or 4 CIPN is reduced. In another embodiment, the incidence of grade 1 or 2 CIPN is reduced. In another embodiment, the incidence of grade 3 or 4 CIPN is reduced to grade 1 or 2 CIPN. In another embodiment, the incidence of grade 2 CIPN is reduced to grade 1.

[0199] Alternatively, CIPN can be assessed by quality of life assessment. One such assessment is the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 questionnaire. (Cavaletti G., et al., European Journal of Cancer 2010 46:479-494).

[0200] In one embodiment of the invention, when a cancer patient is administered one or more administrations of a composition of the invention containing PALM and a chemotherapeutic agent, CIPN is improved on the EORTC QLQ-CIPN 20 questionnaire, where the agent causing or associated with CIPN is the same chemotherapeutic agent present in the composition of the invention.

[0201] One embodiment of the present invention provides a method for treating or preventing chemotherapy-induced neuropathic pain using a composition of the present invention containing PALM and a chemotherapeutic agent. "Neuropathic pain" is intractable pain caused by dysfunction in the peripheral or central nervous system.

[0202] Pain can be assessed by quality of life assessments, one such assessment being the European Organization of Research and Treatment of Cancer (EORTC) EORTC QLQ-C30 / L13 questionnaire.

[0203] In one embodiment of the invention, pain is reduced based on assessment of the EORTC QLQ-C30 / L13 questionnaire.

[0204] In one embodiment of the invention, the pain is peripheral neuropathic pain or central neuropathic pain.

[0205] In another embodiment of the invention, the pain is chronic or acute.

[0206] In another embodiment of the invention, the use of supportive care for pain is reduced, such as, for example, NSAIDS or opioids.

[0207] All references cited in this specification, including publications, patent applications, and patents, are incorporated by reference herein to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0208] The terms "a" and "an" and "the" and similar referents used in the context of describing the present invention (particularly in the context of the claims below) should be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" should be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise noted. Unless otherwise indicated herein, the recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. Any examples provided herein, or the use of exemplary language (e.g., "such as"), are intended merely to better describe the invention and do not pose a limitation on the scope of the invention unless specifically required. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0209] Preferred embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of these preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect that such variations will be utilized by those of ordinary skill in the art, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, this invention encompasses any combination of the above-described elements in all possible variations thereof unless otherwise indicated herein or clearly contradicted by context. EXAMPLES

[0210] Example 1. Peptide synthesis and purification

[0211] Peptides were produced by standard Fmoc solid-phase synthesis techniques from GenScript USA, Inc. (Piscataway, NJ). The terminal amino acids of certain peptides were modified by N-terminal acetylation and C-terminal amidation by standard procedures. Peptides were purified chromatographically to greater than 95% purity by standard high performance liquid chromatography methods for peptide purification. Purity was confirmed by HPLC and mass spectrometry.

[0212] Example 2. Synthesis of paclitaxel 2'-cholesteryl carbonate (XC)

[0213] 50 mg of paclitaxel was dissolved in 2 mL of chloroform and then mixed with 1.5 molar excess of cholesterol chloroformate in 2 mL of chloroform, plus 4 mL of N,N-diisopropylethylamine and 2 mL of acetonitrile. The mixture was stirred overnight at ambient temperature and then dried on a rotary evaporator. The resulting off-white precipitate was then dissolved in ethyl acetate / hexane (3:1), extracted with water, dried, and then redissolved in chloroform. Thin layer chromatography using ethyl acetate / hexane (3:1) as the mobile phase confirmed the formation of the product (Rf for paclitaxel is 0.4, Rf for Tax-Chol is 0.92). The product was then further purified on a silica gel column using ethyl acetate / hexane (3:1) as the mobile phase to give the title compound (1). Mass and NMR analyses confirmed the structure. [ka]

[0214] Example 3. Synthesis of Paclitaxel 2'-δ-Tocotrienyl Carbonate (also known as XTT or XT3 or Compound 1)

[0215] Step 1. Synthesis of p-nitrophenyl carbonate of δ-tocotrienol [ka]

[0216] To a solution of δ-tocotrienol (25 mg, 0.0629 mmol) in anhydrous methylene chloride (1.5 mL), 4-nitrophenyl chloroformate (51 mg, 0.25 mmol) and triethylamine (35 μL, 0.25 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 24 hours, then concentrated and the desired product (2) was obtained using preparative TLC using ethyl acetate / heptane (10:90) as the eluent. The desired product was obtained as a yellow powder (18 mg). 1 H NMR (CDCl3): δ 8.30 (d, 2H), 7.45 (d, 2H), 6.80 (dd, 2H), 5.05-5.20 (m, 3H), 2.72-2.78 (t, 2H), 2.18 (s, 4H), 1.95 - 2.15 (m, 4H), 1.72 - 1.85 (m, 4H), 1.68 (s, 3H), 1.55-1.62 (br s, 12H), 1.30 (br s, 5H).

[0217] Step 2. Synthesis of δ-tocotrienol carbonate of paclitaxel (3) [ka]

[0218] A solution of compound (2) (18 mg, product of step 1) in methylene chloride (2 mL), paclitaxel (28 mg), and DMAP (10 mg) were combined at room temperature. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated and purified using preparative TLC using ethyl acetate / heptane (50:50) as the eluent. The desired product (3) (17 mg) was obtained as a colorless solid. TLC analysis (Rf: 0.25, EA / hexane=1:1). 11H NMR (CDCl3): δ 8.20 (d, 2H), 7.75 (d, 2H), 7.60 - 7.62 (m, 1H), 7.30 - 7.52 (m, 9H), 6.90 - 6.95 (d, 1H), 6.60 - 6.75 (dd, 2H), 6.20 - 6.30 (m, 2H), 6.00 - 6.05 (m, 1H), 5.70 - 5.75 (d, 1H), 5.50 (s, 1H), 5.10 - 5.20 (br s, 2H), 4.95 - 5.00 (d, 1H), 4.30 - 4.35 (br s, 1H), 4.20 - 4.30 (dd, 2H), 3.75 - 3.80 (d, 1H), 2.70 - 2.75 (m, 2H), 2.30 - 2.60 (m, 7H), 2.23 - 2.27 (m, 11H), 1.50 - 2.20 (m, 26H), 1.25 (m, 9H), 1.15 (s, 3H).

[0219] Example 4. Preparation of Peptide Amphiphile Lipid Micelles (PALM)

[0220] Separate stock solutions of peptide and phospholipid were prepared in a solvent mixture consisting of 80% tert-butyl alcohol (TBA) and 20% water to obtain separate solutions of 10 mM peptide, 20 mM 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or 20 mM 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC), and 20 mM egg SM. Aliquots of the stock solutions were mixed to obtain a final solution containing 10 molar equivalents of peptide, 42 molar equivalents of phosphatidylcholine, and 18 molar equivalents of SM. The solutions were mixed in 1.5 mL glass vials, frozen (-70°C), and lyophilized overnight at -5°C to -10°C. The resulting lyophilized cake was rehydrated by adding Dulbecco's phosphate buffered saline, followed by gentle swirling of the contents. PALM formation was completed by incubating the PALM solution at 50°C for 10 minutes. Some of the peptide conjugates remained cloudy upon heating and were also subjected to a cycle of freezing to -80°C followed by thawing to room temperature in an attempt to obtain a clear solution. The quality of the PALM preparations was apparent. The visually clear preparations indicated that any nanoparticles formed were less than about 40 nm in diameter based on the Tyndall effect. The results are shown in Table 5. [Table 6]

[0221] Example 5. Preparation of an exemplary PALM

[0222] A peptide having the amino acid sequence set forth in SEQ ID NO: 35 with acetate counterions was custom synthesized by standard FMOC solid phase peptide synthesis. Stock solutions of PALM components were prepared as follows: 10 mM solutions of peptide were prepared in t-butyl alcohol (TBA) / water / acetic acid (80:20:7). 20 millimolar solutions of POPC and SM were prepared in TBA / water (80 / 20). 10 mM solutions of XTT were prepared in TBA / water (95:5).

[0223] Preparation of PALM was initiated by mixing 10 mM XTT (1 molar equivalent), 20 mM POPC (5.6 molar equivalent), 20 mM SM (2.4 molar equivalent), and 10 mM SEQ ID NO: 35 (2 molar equivalent). The mixed amount was frozen by swirling in a dry ice / 2-propanol bath and further frozen by placing in a -76°C freezer for 1 hour. The mixture was lyophilized at -15°C for 24 hours, followed by an additional 20 hours at 15°C. An amount of sterile Dulbecco's phosphate buffered saline was added to the lyophilizate to obtain 6.3 mM XTT (5.4 mg / ml PTX equivalent). The sample was swirled briefly to dissolve the cake, then placed in a 55°C water bath for 30 minutes, and finally placed briefly (approximately 10-20 seconds) in the sonic node of a water bath sonicator. Samples were filter sterilized through 25 mm x 0.2 μm PES filters and combined. The sterile preparation was dispensed into pyrogen-free glass vials, sealed with aluminum crimped-top butyl rubber stoppers and stored at 4°C.

[0224] Example 6. Inhibition of SKOV-3 growth in vitro

[0225] SKOV-3 cells were plated in 96-well tissue culture plates at 5,000 cells / well in 100 μl of Dulbecco's minimum essential medium containing 10% fetal bovine serum and incubated in a 37° C. incubator containing 5% CO2 in a humidified atmosphere. After 24 hours, the medium was replaced with complete medium containing the test article. The highest concentration (10 μM) of paclitaxel in complete medium was prepared by adding 1 mM paclitaxel stock solution in DMSO. A PALM stock preparation of 3 mM XTT in PALM was diluted in medium to a 50 μM concentration. Serial dilutions of these test solutions into complete medium were performed to obtain lower concentrations of test solutions. The cells were incubated in the test article solution for 72 hours. Next, 5 mg / ml of blue tetrazolium thiazolyl bromide in 20 μl of phosphate-buffered saline was added to all wells, followed by incubation for 4 hours. All wells were washed with Dulbecco's phosphate buffered saline (containing calcium / magnesium) and supplemented with 100 μl DMSO. Plates were incubated for 30 minutes at 37° C., and then the optical density of each well was determined using a plate reader set at 590 nm. The concentration resulting in 50% growth inhibition (IC50) was determined by nonlinear regression fitting the data to a logistic equation. The mean optical density of the control wells was taken as 100% growth.

[0226] Example 7. Cytokine Production

[0227] SKOV-3 cells were plated in 96-well tissue culture plates at 10,000 cells / well in 100 μl Dulbecco's Minimum Essential Medium containing 10% fetal bovine serum. After 24 hours, the medium was removed. The cell layer was washed with Dulbecco's Phosphate Buffered Saline (containing calcium / magnesium). The wells were replenished with serum-free medium containing the test substance. The test groups were: 1) no addition, 2) 10 μg / ml lipopolysaccharide, 3) 10 μM paclitaxel (added to the medium from a stock solution in DMSO), and 4) PALM (XTT) equivalent to 10 μM paclitaxel prepared with peptide of SEQ ID NO: 25. The cells were incubated for 24 hours. The medium was then collected and centrifuged (1500 rpm in a microcentrifuge). The supernatant was collected and frozen for cytokine testing. Interleukin 6 (IL-6) content in the medium was determined using a human IL-6 assay kit from RayBiotech Life (Peachtree Corners, GA).

[0228] Example 8. SKOV-3 xenografts in mice

[0229] The experimental protocol was approved by the Institutional Animal Care and Use Committee. Thirty female NU(NCr)-Foxn1nu nude mice (Harlan Laboratories) were housed in gamma-sterilized IVC cages (up to five mice per cage) at 22-25°C and 40-60% humidity with a 12-h light and 12-h dark cycle. Cages were equipped with gamma-irradiated corncob bedding and sterile water. Diet consisted of gamma-sterilized dry pellets. Mice were allowed to acclimate for 7 days.

[0230] SKOV-3 (ATCC) human ovarian tumor cells were maintained in vitro as monolayer cultures in McCoy's 5A medium supplemented with 10% fetal bovine serum at 37° C. in an atmosphere of 5% CO2 in air. Cells were routinely subcultured twice weekly by trypsin-EDTA treatment (0.25% trypsin-EDTA). Exponentially growing cells were harvested and analyzed by GUAVA PCA flow cytometry for cell number and cell viability (99%) prior to xenografting.

[0231] To generate tumors, 30 9- to 11-week-old mice were inoculated into the flank region with SKOV-3 tumor cells (1.0 × 10 cells) in 0.1 ml of 1x PBS mixed with Matrigel (1:1). 6 ) were inoculated subcutaneously. 3 ) occurred 7 days later. Approximately 50-100 mm 3 Twenty-five animals bearing tumors of 10 ...

[0232] Mice were examined daily for morbidity, mortality, and any adverse effects of tumor growth and treatment on normal behavior such as mobility, visual assessment of food and water consumption, weight gain / loss, eye / hair matting, and any other abnormal effects.

[0233] Tail vein injections of test solutions were performed using a Genie Touch Syringe Pump (Kent Scientific). A Terumo Surshield safety winged infusion set (S25BLS, 25Gx3 / 4) was used to access the tail vein. A new syringe was used for each test article. All studies were performed in a biological safety cabinet.

[0234] Dosing was performed on days 7, 11, 15, 19, 23, and 27. Day 0 was the day of xenografting. All mice were dosed at 8 ml / kg. Solution groups were: 17% Cremophor EL / Ethanol (1:1) in saline (paclitaxel vehicle) (Group 1), 1.25 mg / ml paclitaxel in Cremophor EL / Ethanol / Saline (Group 2), PALM (XTT) at 1 mg / ml paclitaxel equivalent (Group 3), PALM (XTT) at 2.5 mg / ml paclitaxel equivalent (Group 4), and PALM without XTT at 1.25 times the amount of PALM components in Group 4 (Group 5). PALM was prepared using peptide of SEQ ID NO:35.

[0235] Tumor volumes were measured in two dimensions using electronic calipers on days 7, 12, 17, 22, 27, 32, 37, and 42. Volume was calculated according to the formula: V = 0.5a × b 2 Using mm 3 where a and b are the long and short diameters of the tumor, respectively.

[0236] Example 9. Chemotherapy-induced peripheral neuropathy (CIPN) in rats

[0237] Pharmaceutical grade paclitaxel (PTX, Teva Pharmaceuticals) was diluted to 1 mg / ml in saline from a stock solution of 6 mg / ml in a 1:1 mixture of Cremophor EL and ethanol. PTX was injected at 1 mg / kg, Q2Dx6. PALM prepared with peptide of SEQ ID NO:35 and containing XTT was administered using the same administration scheme as PTX at PTX-equivalent doses of 1 mg / kg and 2.7 mg / kg. Intraperitoneal injections of all drugs and vehicles were performed on days 2, 4, 6, 8, 10, and 12. Control and experimental male SD rats received equal volumes of the solutions. There were a total of 5 groups with a sample size of 10 animals per group. Group A received the same Cremophor EL / ethanol / saline solution as the dosing solution in which PTX was administered, Group B received 1 mg / kg paclitaxel, Group C received phosphate buffered saline (PALM vehicle), Group D received XTT in PALM equivalent to 1 mg / kg PTX, and Group E received XTT in PALM equivalent to 2.7 mg / kg PTX.

[0238] To control for compound exposure due to excretion of paclitaxel (and possibly test compounds) in urine and feces, animals were housed in pairs in a temperature-controlled room with free access to water and food under a 12:12-h (7:00 am to 7:00 pm) light-dark cycle, and animals in each pair belonged to the same group. All procedures were approved by the Institutional Animal Care and Use Committee and adhered to the guidelines set forth by the Committee for Research and Ethical Issues of the International Association for the Study of Pain (Zimmerman, 1983).

[0239] To test for the development of peripheral neuropathy, animals were examined for changes in paw withdrawal threshold (MPWT) to mechanical stimulation at baseline and then every other day during the 14-day protocol (days 1 (baseline), 3, 5, 7, 9, 11, 13). For this test, animals were placed in a Plexiglas chamber (20 cm x 10.5 cm x 40.5 cm) and allowed to habituate for 15 min. The chamber was positioned on a mesh screen to allow mechanical stimulation to be applied to the plantar surface of both hind paws. Up-and-down movements were used with eight calibrated von Frey monofilaments (3.85, 5.68, 9.74, 18.39, 39.42, 77.30, 135.30, and 251.34 mN) to obtain mechanical threshold measurements for each hind paw. Each test began with a von Frey force of 9.74 mN, applied for approximately 1 s to the right hind paw, followed by the left hind paw. If there was no withdrawal response, the next stronger force was applied. If a response occurred, the next weaker force was applied. This procedure continued until either no response was made at the strongest force (251.34 mN) or four stimuli were given after the first response. The withdrawal threshold of each paw was calculated using the following formula: [Xth]log=[vFr]log+ky, where [vFr] is the last von Frey force used, k=0.2593, which is the average spacing between von Frey monofilaments (in log units), and y is a value that depends on the pattern of withdrawal responses. If an animal does not respond to the strongest von Frey hair, then y=1.00, and the paw withdrawal threshold to mechanical stimulation of that paw is calculated to be 456.63 mN. MPWT testing was performed over three trials per session, and the withdrawal thresholds over the three trials were averaged to determine the average paw withdrawal threshold to mechanical stimulation for each animal.

[0240] Example 10. Preparation of PALM containing the fluorescent dye DiI

[0241] A 40 μL aliquot of 10 mM peptide was mixed with 56 μL of 20 mM POPC, 24 μL of 20 mM SM (egg), and 16 μL of 2.5 mM DiI in a small glass vial. Peptide and lipid solutions were prepared in 80% TBA / 20% water. A DiI stock solution was prepared in 92% TBA / 8% water. The combined solution was lyophilized and the resulting cake was rehydrated by adding 0.2 mL of Dulbecco's phosphate buffered saline. The solution was swirled briefly, sonicated in a water bath (approximately 15 seconds), and placed in a 50° C. heating block for 20 minutes.

[0242] Example 11. Preparation of miriplatin-containing PALM

[0243] A 50 μL aliquot of 10 mM peptide having the amino acid sequence of SEQ ID NO:25 in 80% TBA / 20% water, corresponding to 2.5 molar equivalents of peptide, was mixed with 3 molar equivalents of POPC and 7 molar equivalents of egg SM from 40 mM and 20 mM stock solutions, respectively, made up of the same solvent mixture. To this mixture was added 0.75 molar equivalents of miriplatin (MedKoo Biosciences, Raleigh, NC) from a 1 mM stock solution prepared with 100% TBA. The solution was lyophilized and the resulting cake was rehydrated by adding 0.4 mL of a 5% aqueous dextrose solution. The solution was swirled briefly, sonicated in a water bath (approximately 15 seconds), and placed in a 50° C. heating block for 20 minutes. The resulting clear solution was passed through a 0.2 μm pore size polyethersulfone sterile filter and stored at 4° C. Particle size analysis by DLS (Example 16) showed a mean hydrodynamic diameter of 8 nm. SEC confirmed a population of single particles similar in size to HDL, and the SEC chromatograms are shown in Figure 2 (miriplatin (solid line), human HDL (dashed line)).

[0244] Example 12. Preparation of paclitaxel cholesteryl carbonate (XC)-containing PALM

[0245] A 50 μL aliquot of peptide SEQ ID NO:25 at 10 mM in 80% TBA / 20% water, corresponding to 2.5 molar equivalents of peptide, was mixed with 7 molar equivalents of POPC from a 20 mM stock solution composed of the same solvent mixture and 3 molar equivalents of egg SM. To this was added 1 molar equivalent of XC from a 10 mM stock solution in 92% TBA / 8% water. The solution was lyophilized and the resulting cake was rehydrated with Dulbecco's phosphate buffered saline to a final concentration of 1 mM XC. The mean hydrodynamic diameter of this preparation as determined by DLS was 9 nm (Example 16). Particle size analysis by SEC showed a single particle population predominantly 10 nm in diameter (Figure 3).

[0246] Example 13. Preparation of paclitaxel δ-tocotrienyl carbonate (XTT)-containing PALM

[0247] A 50 μL aliquot of peptide of SEQ ID NO:25 at 10 mM in 80% TBA / 20% water, corresponding to 2.5 molar equivalents of peptide, was mixed with 7 molar equivalents of POPC from a 20 mM stock solution made up of the same solvent mixture and 3 molar equivalents of egg SM. To this was added 1 molar equivalent of XTT from a 10 mM stock solution in 92% TBA / 8% water. The lyophilized cake was rehydrated with 0.4 ml of Dulbecco's phosphate buffered saline.

[0248] Example 14. R4F is unsuitable for the preparation of PALM containing paclitaxel delta-tocotrienyl carbonate (XTT)

[0249] PALM preparations were performed as in Example 13 using peptide with amino acid sequence SEQ ID NO:25 and peptide R4F (Table 1). Unlike PALM made with peptide SEQ ID NO:25, which remained a clear solution at room temperature and 4°C, PALM containing peptide R4F was a clear solution at room temperature but became a cloudy gel at 4°C. Upon warming to room temperature, the gel returned to a clear liquid. The size of the PALM preparations was analyzed (Example 16). Dynamic light scattering showed that PALM with peptide SEQ ID NO:25 had a hydrodynamic mean diameter (volume intensity) of 8 nm. The same analysis of PALM with R4F showed that 94% of the particle population had a hydrodynamic mean diameter of 11 nm, the remainder 32 nm. SEC confirmed the homogeneous size distribution of PALM with peptide SEQ ID NO:25 (Figure 4). In contrast, PALM with R4F showed a range of elution peaks at sizes larger and smaller than PALM with SEQ ID NO:25. It is not surprising that smaller particles could not be detected by DLS, since the sensitivity for particles smaller than 7 nm is quite weak. These results indicate that R4F is not a suitable peptide for the preparation of PALM.

[0250] Example 15. Loading of fenretinide into PALMs prepared with peptide of SEQ ID NO:25

[0251] A 35 μL aliquot of peptide SEQ ID NO:25 at 10 mM in 80% TBA / 20% water, corresponding to 2.5 molar equivalents of peptide, was mixed with 3 molar equivalents of POPC and 7 molar equivalents of egg SM from 40 mM and 20 mM stock solutions, respectively, made up of the same solvent mixture. Two molar equivalents of 20 mM fenretinide in the same solvent mixture were also added. The solution was lyophilized and the resulting cake was rehydrated with 0.325 mL of phosphate buffered saline. The solution became clear within 20 minutes at 50° C. Analysis by SEC (Example 16) showed that all components eluted as a single peak in the diameter range of 8 nm to 10 nm (FIG. 5).

[0252] Example 16. Determination of PALM size

[0253] The size and size uniformity of the PALM preparations were determined by DLS and SEC. Size based on hydrodynamic mean diameter was determined by DLS using a Nicomp 370 particle size analyzer. The analyzer was calibrated with latex standards. Particle sizes referred to in the specification and claims are calculated by DLS as above, unless expressly indicated otherwise.

[0254] The relative hydrodynamic size of the PALM particles was also measured by SEC equipped with a GE Superose 6 Increase column (10 x 300 mm) connected to a Beckman / Coulter Model 126 pump and a Model 128 diode array detector. The flow rate of the mobile phase (150 mM NaCl, 6 mM NaPO4, pH 7.4) was 0.5 mL / min. The eluate was monitored at wavelengths of 215 and 280 nm. System performance was confirmed by injection of protein molecular weight standards (Figure 3).

[0255] Example 17. SR-BI selectivity of PALM in BHK (SR-BI) cells

[0256] SR-BI interaction studies are performed using BHK (SR-BI) cells stably transfected with an inducible human SR-BI gene using the GeneSwitch™ system (Invitrogen) (Vickers et al. (2011) Nat. Cell Biol. 13:423-433). Cells were plated (96-well plates) (8000 cells / well) in growth medium (Dulbecco's Modified Eagle Medium with 10% fetal bovine serum) containing 200ug / mL each of Zeocin and Hygromycin. After 24 hours of incubation, growth medium was removed and replaced with 0.2% bovine serum albumin in Dulbecco's Modified Eagle Medium. Culture medium for cells in which SR-BI expression was induced also contained 10nM mifepristone added from a DMSO stock solution. Culture medium for non-induced cells was supplemented with DMSO only. Induction medium was removed after 24 hours and replaced with medium (Kalen Biomedical, Montgomery Village, MD) containing DiI-labeled PALM (32 μg peptide / mL) or DiI-labeled HDL (19 μg protein / mL). Test medium was prepared by diluting aliquots of DiI-labeled PALM (Example 10) or DiI-labeled HDL in 0.2% bovine serum albumin in Dulbecco's modified Eagle's medium. Before use, the solution was passed through a 0.2 μm pore size polyethersulfone sterile filter. Cells were incubated for 4 hours. Cells were then washed three times with 0.1% albumin in Dulbecco's phosphate buffered saline (containing calcium and magnesium). The final wash was replaced with 200 uL / well of t-butanol / water (95% / 5%). Covered plates were left undisturbed for 30 minutes at room temperature (20-21°C) with occasional shaking. Fluorescence from each well was detected at 520 nm excitation and 580 nm emission using a 550 nm cutoff filter in a Molecular Dynamics Gemini fluorescent plate reader (Figure 9). [Table 7]

[0257] Example 18. Quantification of Paclitaxel

[0258] Paclitaxel, XTT, and XC were extracted from the aqueous samples by mixing one volume of the aqueous sample with four volumes of ethyl acetate / acetone / methanol (70 / 30 / 5 (v / v)). The upper organic layer obtained after shaking and centrifugation was collected, dried by solvent evaporation and reduced pressure, and redissolved in the HPLC mobile phase (methanol / water (65 / 35 (v / v)). A 20 μL aliquot of the reconstituted sample was injected into the HPLC at a flow rate of 1.2 mL / min through a Macherey-Nagel column (4×250 mm with Nucleosil 10-5 C18) and detected at a wavelength of 230 nm using a UV detector.

[0259] Example 19. PALM containing miriplatin inhibits PC-3 cell proliferation similarly to cisplatin

[0260] PC-3 cells (American Type Culture Collection, CRL-1435) were cultured at 5 × 10 per well (100 μL). 3 Cells were seeded at a density of 10 cells in 96-well plates and grown to approximately 70% confluence (24 hours) in growth medium consisting of F-12K medium supplemented with 10% fetal bovine serum. The growth medium was then replaced with either 100 μL of fresh growth medium (control), or growth medium supplemented with various concentrations of cisplatin (e.g., 0 μM and 0.1-100 μM final concentrations in medium) added from a 100-fold concentrated stock solution prepared in 5% dextrose, or growth medium supplemented with an equal amount of miriplatin in PALM as prepared in Example 11. Each condition was tested in triplicate. Plates were incubated for 48 hours. Cell viability was analyzed by blue tetrazolium thiazolyl bromide (MTT) assay by adding 20 μL of 5 mg / mL MTT in Dulbecco's phosphate-buffered saline (containing calcium and magnesium) and incubating for 3 hours. The medium was then carefully removed and replaced with 200 μL of dimethyl sulfoxide (DMSO). The plate was gently agitated on an orbital shaker for 15 min. The absorbance of each well was read at 570 nm. The concentration resulting in 50% growth inhibition (IC50 ) was determined by nonlinear regression fitting of the data to a logistic equation. The mean absorbance of the control wells was taken as 100% proliferation (Figure 6).

[0261] Example 20. SR-BI antibody attenuates PC-3 cell proliferation inhibition by PALM containing miriplatin

[0262] PC-3 cells were grown as in Example 19. Cells to be tested in the presence of SR-BI antibody (Novus Biologics, NB400-113) were pre-incubated for 1 hour in growth medium containing a 1 / 400 dilution of the antibody stock solution. Then, all medium was removed and replaced with growth medium containing the indicated amount of platinum compound prepared as in Example 13. Growth medium containing PALM (MP) for cells treated with antibody contained the antibody at a 1 / 400 dilution of the antibody stock solution. Cells were incubated for 5 hours. Then, all medium was removed and cells were washed once with medium and then incubated in growth medium for another 43 hours. Cell viability was determined by MTT assay as in Example 19 (Figure 7).

[0263] Example 21. XTT in PALM was more active in inhibiting SKOV-3 cell proliferation than XC in PALM

[0264] SKOV-3 ovarian cancer cells (American Type Culture Collection, HTB-77) were cultured at 5 × 10 per well (100 μL). 3Cells were seeded at a density of 100 cells in 96-well plates and grown to approximately 70% confluence (24 hours) in growth medium consisting of McCoy's medium supplemented with 10% fetal bovine serum. The growth medium was then replaced with 100 μL of either fresh growth medium (control) or growth medium supplemented with various concentrations of paclitaxel, PALM(XC), or PALM(XTT). 20 μM paclitaxel test solutions were prepared by diluting a 5 mM stock solution of paclitaxel in DMSO into growth medium followed by filter sterilization (0.2 μm filter). An aliquot of the 20 μM solution was diluted 5-fold into growth medium to obtain 4 μM paclitaxel. The 5-fold dilution process was continued with 4 μM paclitaxel to obtain an 800 nM paclitaxel solution. This process was continued until the concentration of paclitaxel in the growth medium was 0.051 nM. For each of the nine solutions thus obtained, four 100 μL aliquots were added to separate wells containing cells. A similar but modified process was used for the preparation of PALM(XC) and PALM(XTT) test solutions. The highest concentration tested was 50 μM, which was prepared by diluting 1 mM preparations of PALM(XC) and PALM(XTT) in growth medium followed by filter sterilization. The lowest concentration obtained during the course of 5-fold dilutions of each of the most recent dilutions, repeated eight times, was 0.13 nM. The cells were incubated with the test solutions for 72 hours. At the end of this period, cell viability was determined by MTT assay as in Example 19. (Figure 8).

[0265] Example 22. Inhibition of BHK(SR-BI) cell proliferation by PALM(XTT) is SR-BI dependent

[0266] BHK (SR-BI) cells were plated (3000 cells / well) in 96-well plates containing growth medium (Dulbecco's Modified Eagle Medium containing 10% fetal bovine serum and 200ug / mL each of Zeocin and Hygromycin) and incubated for 24 hours. Growth medium was replaced with 0.2% bovine serum albumin in Dulbecco's Modified Eagle Medium containing either 10nM mifepristone added from a DMSO stock solution (induction) or an equal amount of DMSO only (control). Cells were incubated for 24 hours. Next, medium was replaced with the indicated concentrations of PTX or PALM (XTT) in 0.2% bovine serum albumin in Dulbecco's Modified Eagle Medium and cells were incubated for 12 hours. Their medium was then replaced with regular growth medium and cells were incubated for an additional 36 hours. Percent cell proliferation relative to cells without test drug was determined by MTT assay (Figure 10).

[0267] Example 23. δ-Tocotrienyl (N 4 )-Gemcitabine carbamate

[0268] The hydroxyl groups of gemcitabine are protected by conversion to the tert-butoxycarbonyl (BOC) ester using di-tert-butyl dicarbonate according to the procedure of Guo and Gallo (J. Org. Chem. 1999, 64, 8319) to give (1). [ka]

[0269] Compound 4 is dissolved in anhydrous dichloromethane to a final concentration of compound (4) of 0.2M. For each mole of compound (4) in the solution, 1.2 molar equivalents of compound (2) at a concentration of 0.5M in methylene chloride and 3 molar equivalents of DMAP are mixed at room temperature. The mixture is stirred at room temperature for 24 hours. The resulting product is deprotected with trifluoroacetic acid as cited. The pure compound is obtained by flash column chromatography using dichloromethane and methanol eluents starting with 100% dichloromethane and gradually increasing the concentration to 10% methanol to give the title compound (5). [ka]

[0270] Example 24. Using α, β, or γ-tocotrienol isomers (N 4 The synthesis of 4-gemcitabine carbamate is carried out analogously to Example 24.

[0271] Example 25. Cholesteryl (N 4 )-Gemcitabine carbamate

[0272] Cholesteryl (N) was prepared in the same manner as described in Example 25, except that compound (4) was reacted with cholesterol chloroformate (commercially available) and deprotected as in Example 19 to give the title compound (6). 4 )-Gemcitabine carbamate (6) is synthesized. [ka]

[0273] Example 26. Paclitaxel linked to aliphatic alcohols via succinic and diglycolic acids

[0274] The synthesis of paclitaxel linked to an aliphatic alcohol via a succinic or diglycolic acid diester bond is achieved by reacting the aliphatic alcohol with 4-(dimethylamino)pyridine and succinic or diglycolic anhydride in anhydrous pyridine under constant stirring at room temperature for 24 hours. The reaction is quenched with 0.1N HCL in dichloromethane. The product is obtained by preparative TLC or flash column chromatography using ethyl acetate in petroleum ether. The alcohol-succinic or alcohol-diglycolic acid conjugate is mixed with 4-(dimethylamino)pyridine and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide in dry dichloromethane. Paclitaxel is added to the reaction mixture. After 24 hours, the reaction is quenched with water and extracted with dichloromethane. The product is obtained by preparative TLC using ethyl acetate / heptane (50:50) as the eluent.

[0275] Example 27. Effect of SR-BI antibodies on PALM (XTT) cytotoxicity in SKOV-3 cells

[0276] SKOV-3 were plated and incubated for 24 hours as in Example 16. Growth medium was then replaced with serum-free medium containing 0.5% albumin and the indicated concentrations of test agents, with or without anti-SRBI (1 / 250 dilution) (NB400-113, Novus Biologicals). Cells were incubated for 12 hours. Cells were then washed with serum-free medium containing 0.5% albumin and grown in growth medium for an additional 60 hours. Cell proliferation was detected by MTT assay (Figure 11).

[0277] The present invention also includes the following aspects and embodiments. [1] 1. A method for treating or preventing chemotherapy-induced peripheral neuropathy (CIPN) in a cancer patient who has been or will be treated with a chemotherapeutic agent that causes CIPN, the method comprising: administering to said cancer patient a therapeutically effective amount of a composition comprising peptide amphiphilic molecule lipid micelle (PALM) nanoparticles, said PALM nanoparticles comprising PALM containing a chemotherapeutic agent causing said CIPN, said PALM comprising a peptide and a lipid component comprising sphingomyelin and one or more additional phospholipids; The peptide in the PALM has the amino acid sequence: 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7-X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 wherein X 1 is an amino acid selected from the group consisting of D and E, and X 2 and X 20 are each an amino acid independently selected from the group consisting of V, Aib, I, and L; 3 、X 6 、X 10 , and X 13 are each an amino acid independently selected from the group consisting of L, I, V, W, Y, Aib, Amv, and F; 4 、X 12 , and X 19 are each an amino acid independently selected from the group consisting of Q and N, 5 、X 16 , and X 18 are each an amino acid independently selected from the group consisting of K, R, H, and Orn; 7 is selected from the group consisting of A, G, S, V, Aib, and Amv; 8 and X 15 is independently selected from the group consisting of amino acids E and D; 9 and X 14 is an amino acid independently selected from the group consisting of A, G, S, L, F, V, Amv, and Aib; X 11 is an amino acid selected from the group consisting of A, G, S, Aib, Amv, V, and N; X 17 is an amino acid selected from the group consisting of W, F, Y, I, V, and L (SEQ ID NO: 24), the peptide is optionally acylated at the N-terminus, amidated at the C-terminus, or both acylated at the N-terminus and amidated at the C-terminus, and the peptide is 20 to 24 amino acids in length. [2] The peptide of [1], wherein the peptide in the PALM consists of an amino acid sequence selected from the group consisting of SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31, SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35, and SEQ ID NO:36, and the peptide is optionally acylated at the N-terminus, amidated at the C-terminus, or both acylated at the N-terminus and amidated at the C-terminus. [3] 1. A method for treating or preventing chemotherapy-induced peripheral neuropathy (CIPN) in a cancer patient who has been or will be treated with a chemotherapeutic agent that causes CIPN, the method comprising: administering to said cancer patient a therapeutically effective amount of a composition comprising peptide amphiphilic molecule lipid micelle (PALM) nanoparticles, said PALM nanoparticles comprising PALM containing a chemotherapeutic agent causing said CIPN, said PALM comprising a peptide and a lipid component comprising sphingomyelin and one or more additional phospholipids; The method, wherein the peptide in the PALM comprises the amino acid sequence of SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; SEQ ID NO:6; SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; or SEQ ID NO:23, the peptide is optionally acylated at the N-terminus, amidated at the C-terminus, or both acylated at the N-terminus and amidated at the C-terminus, and the peptide is 20 to 24 amino acids in length. [4] The method according to [1], wherein the chemotherapeutic agent contained by the PALM is a chemotherapeutic agent that causes, may cause, or is associated with the CIPN in the cancer patient. [5] The method of [1], further comprising administering one or more additional chemotherapeutic agents or multiple chemotherapeutic agents, wherein the one or more additional chemotherapeutic agents or multiple chemotherapeutic agents are compatible with the CIPN-causing chemotherapeutic agent contained by the PALM. [6] The method according to [4], wherein the chemotherapeutic drug that causes CIPN contained in the PALM is selected from the group consisting of bortezomib, carboplatin, cisplatin, gemcitabine, misonidazole, oxaliplatin, procarbazine, thalidomide, docetaxel, hexamethylmelamine, paclitaxel, vincristine, vinblastine, vinorelbine, ixabepilone, eribulin, and mertansine. [7] The method according to [6], wherein the CIPN-causing chemotherapeutic drug contained in the PALM is carboplatin, cisplatin, paclitaxel, or vinorelbine. [8] The method according to [1], wherein the cancer patient has a cancer selected from the group consisting of ovarian cancer, cervical cancer, endometrial cancer, colorectal cancer, prostate cancer, breast cancer, pancreatic cancer, head and neck cancer, testicular cancer, leukemia, neuroblastoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and non-small cell lung cancer. [9] The method according to [8], wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, and non-small cell lung cancer.

[10] The method of [1], wherein the PALM nanoparticles are administered before the onset of CIPN, or during CIPN, or after recovery from CIPN, or any combination thereof.

[11] The method of [1], wherein the lipid component of the PALM consists essentially of sphingomyelin and one or more additional phospholipids.

[12] The method of claim 1, wherein the one or more additional phospholipids are selected from the group consisting of phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine (PEG-PE), phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, cardiolipin, or any combination thereof.

[13] The method of claim 12, wherein the one or more additional phospholipids comprise phosphatidylcholine.

[14] The method according to

[13] , wherein the phosphatidylcholine is 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC).

[15] The method according to [1], wherein the molar ratio of phospholipid to sphingomyelin is about 90:10 to about 5:95.

[16] The method according to

[15] , wherein the molar ratio of phospholipid to sphingomyelin is 30:70.

[17] The method according to

[15] , wherein the molar ratio of phospholipid to sphingomyelin is about 80:20 to about 60:40.

[18] The method according to

[17] , wherein the molar ratio of phospholipid to sphingomyelin is about 70:30.

[19] The method according to [1], wherein the molar ratio of lipid component to peptide is about 10:1 to about 2:1.

[20] The method according to

[19] , wherein the molar ratio of lipid component to peptide is about 6:1 to about 4:1.

[21] The method according to [1], wherein the composition further comprises a contrast agent.

[22] The contrast agent is selected from the group consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-diethylenetriaminepentaacetic acid (gadolinium salt) (PE-DTPA(Gd)), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-diethylenetriaminepentaacetic acid (manganese salt) (PE-DTPA(Mn)), or 111 The method according to

[21] , wherein the compound is In-DTPA-A.

[23] The method according to any of [1] to

[20] , wherein the composition further comprises at least one cargo molecule.

[24] The method according to

[23] , wherein the at least one cargo molecule is an imaging agent.

[25] The method according to

[23] , wherein the at least one cargo molecule is a drug.

[26] The method according to

[25] , wherein the drug is miriplatin or fenretinide.

[27] The at least one cargo molecule is a compound conjugate having the following formula (I): ARLX (formula I) wherein A is a drug having a hydroxyl or amine group, R is the hydroxyl or amine group of the drug, L is a linker, and X is an anchor moiety selected from the group consisting of cholesterol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, cholecalciferol, or ergocalciferol.

[28] The method of

[27] , wherein R is a hydroxy group and the anchor moiety is covalently attached to the drug via a carbonate bond.

[29] 27. The method of claim 27, wherein R is an amine group and the anchor moiety is covalently attached to the drug via a carbamate bond.

[30] The method according to any one of

[27] to

[29] , wherein the anchor moiety is cholesterol.

[31] The method according to any of

[27] to

[29] , wherein the anchor moiety is δ-tocotrienol.

[32] The method according to any of

[27] to

[29] , wherein the drug is a chemotherapeutic drug selected from the group consisting of adenosine, bortezomib, hydroxycamptothecin, daunorubicin, doxorubicin, topotecan, gemcitabine, misonidazole, docetaxel, paclitaxel, vincristine, vinblastine, vinorelbine, ixabepilone, eribulin, mertansine, and combinations thereof.

[33] The method of

[32] , wherein the chemotherapeutic drug conjugated to PALM is hydroxycamptothecin, daunorubicin, doxorubicin, topotecan, paclitaxel, or docetaxel.

[34] The method according to

[33] , wherein the chemotherapeutic drug conjugated to PALM is paclitaxel. Although a number of embodiments of the present disclosure have been described, it is apparent that the basic examples may be modified to provide other embodiments that use or incorporate the methods and processes of the present invention. The embodiments and examples are for illustrative purposes and should not be construed as limiting the present disclosure; rather, the appended claims define the scope of the invention.

Claims

1. 1. A pharmaceutical composition comprising peptide amphiphilic molecule lipid micelle (PALM) nanoparticles for preventing or delaying chemotherapy-induced peripheral neuropathy (CIPN) in cancer patients who have been or will be treated with a chemotherapy agent that causes CIPN, comprising: The PALM nanoparticles comprise PALM containing a chemotherapeutic agent that causes said CIPN, the PALM comprising a peptide and a lipid component comprising sphingomyelin and one or more additional phospholipids; A pharmaceutical agent, wherein the peptide in PALM comprises an amino acid sequence selected from the group consisting of SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31, SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35 and SEQ ID NO:36, and the peptide may be acylated at the N-terminus, amidated at the C-terminus, or both acylated at the N-terminus and amidated at the C-terminus.

2. 1. A pharmaceutical composition comprising peptide amphiphilic molecule lipid micelle (PALM) nanoparticles for preventing or delaying chemotherapy-induced peripheral neuropathy (CIPN) in cancer patients who have been or will be treated with a chemotherapy agent that causes CIPN, comprising: The PALM nanoparticles comprise PALM containing a chemotherapeutic agent that causes said CIPN, the PALM comprising a peptide and a lipid component comprising sphingomyelin and one or more additional phospholipids; A pharmaceutical agent wherein the peptide in PALM comprises the amino acid sequence of SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; SEQ ID NO:6; SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; or SEQ ID NO:23, and the peptide may be acylated at the N-terminus, amidated at the C-terminus, or both acylated at the N-terminus and amidated at the C-terminus, and the peptide is 20-24 amino acids in length.

3. The pharmaceutical composition of claim 1 or 2, further comprising one or more additional chemotherapeutic agents, wherein the one or more additional chemotherapeutic agents are compatible with the chemotherapeutic agent causing the CIPN contained by the PALM.

4. The pharmaceutical described in claim 3, wherein the chemotherapeutic drug causing CIPN contained in the PALM is selected from the group consisting of bortezomib, carboplatin, cisplatin, gemcitabine, misonidazole, oxaliplatin, procarbazine, thalidomide, docetaxel, hexamethylmelamine, paclitaxel, vincristine, vinblastine, vinorelbine, ixabepilone, eribulin, and mertansine.

5. The pharmaceutical composition described in claim 4, wherein the chemotherapeutic drug that causes CIPN contained in the PALM is carboplatin, cisplatin, paclitaxel or vinorelbine.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the cancer patient has a cancer selected from the group consisting of ovarian cancer, cervical cancer, endometrial cancer, colon cancer, prostate cancer, breast cancer, pancreatic cancer, head and neck cancer, testicular cancer, leukemia, neuroblastoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and non-small cell lung cancer.

7. The pharmaceutical composition according to claim 6, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer and non-small cell lung cancer.

8. The pharmaceutical of any one of claims 1 to 7, wherein the PALM nanoparticles are administered before the onset of CIPN, or during CIPN, or after resolution of CIPN, or any combination thereof.

9. The method of any one of claims 1 to 8, wherein the lipid component of the PALM consists essentially of sphingomyelin and one or more additional phospholipids.

10. The pharmaceutical of any one of claims 1 to 9, wherein the one or more additional phospholipids are selected from the group consisting of phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine (PEG-PE), phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, cardiolipin, or any combination thereof.

11. The pharmaceutical of claim 10, wherein the one or more additional phospholipids comprises a phosphatidylcholine.

12. The pharmaceutical composition according to claim 11, wherein the phosphatidylcholine is 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC).

13. The pharmaceutical according to any one of claims 1 to 12, wherein the molar ratio of phospholipid to sphingomyelin is from about 90:10 to about 5:

95.

14. The pharmaceutical composition of claim 13, wherein the molar ratio of phospholipid to sphingomyelin is 30:

70.

15. The method of claim 13, wherein the molar ratio of phospholipid to sphingomyelin is from about 80:20 to about 60:

40.

16. The pharmaceutical composition of claim 15, wherein the molar ratio of phospholipid to sphingomyelin is about 70:

30.

17. The method of any one of claims 1 to 16, wherein the molar ratio of lipid component to peptide is from about 10:1 to about 2:

1.

18. The method of claim 17, wherein the molar ratio of lipid component to peptide is from about 6:1 to about 4:

1.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the composition further comprises a contrast agent.

20. The contrast agent is selected from the group consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-diethylenetriaminepentaacetic acid (gadolinium salt) (PE-DTPA(Gd)), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-diethylenetriaminepentaacetic acid (manganese salt) (PE-DTPA(Mn)) or １１１ The pharmaceutical according to claim 19, which is In-DTPA-A.

21. The CIPN-causing chemotherapy agent is a compound conjugate having the following formula (I): A-R-L-X (Formula I) 4. The pharmaceutical composition according to claim 1, wherein A is a chemotherapeutic agent that induces CIPN having a hydroxyl group or an amine group, R is a hydroxyl group or an amine group of the chemotherapeutic agent that induces CIPN, L is a linker, and X is an anchor moiety selected from the group consisting of cholesterol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, cholecalciferol, ergocalciferol, α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol.

22. 22. The medicament of claim 21, wherein R is a hydroxy group and the anchor moiety is covalently attached to the drug by a carbonate bond.

23. 22. The medicament of claim 21, wherein R is an amine group and the anchor moiety is covalently attached to the drug by a carbamate bond.

24. The pharmaceutical agent according to any one of claims 21 to 23, wherein the anchor moiety is cholesterol.

25. The pharmaceutical according to any one of claims 21 to 23, wherein the anchor moiety is δ-tocotrienol or δ-tocopherol.

26. The pharmaceutical composition of any one of claims 21 to 25, wherein the chemotherapeutic drug that causes CIPN is selected from the group consisting of adenosine, bortezomib, hydroxycamptothecin, daunorubicin, doxorubicin, topotecan, gemcitabine, misonidazole, miriplatin, fenretinide, docetaxel, paclitaxel, vincristine, vinblastine, vinorelbine, ixabepilone, eribulin, mertansine, and combinations thereof.

27. ​​The pharmaceutical composition described in claim 26, wherein the chemotherapy drug that causes the CIPN is hydroxycamptothecin, daunorubicin, doxorubicin, topotecan, paclitaxel or docetaxel.

28. The pharmaceutical composition described in claim 27, wherein the chemotherapy drug that causes the CIPN is paclitaxel.

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