Biaminoquinolines and nanoformulations for cancer treatment

Abstract

To provide biaminoquinolines and nanoformulations for cancer treatment.SOLUTION: The present invention provides bisaminoquinoline compounds of Formula (I). The present invention also provides nanocarriers comprising compounds of the present invention, and methods of using the nanocarriers for treating diseases and imaging.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 902,156, filed on September 18, 2019, and the entire disclosure thereof is incorporated herein by reference for all purposes.

[0002] Declaration of Rights to Inventions Made Under Federally Sponsored Research and Development This invention was made with government support under grants numbered R01CA199668 and 5R01CA232845 from the National Institutes of Health and the National Cancer Institute, grant number R01DE029237 from the National Institutes of Health and the National Institute of Dental and Craniofacial Research, and grant number R01HD086195 from the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The government has certain rights in this invention.

Background Art

[0003] The increasing research in nanomedicine has significantly contributed to cancer treatment over the past few decades. Both carrier-assisted nanomedicine and carrier-free nanomedicine are being developed to improve the pharmacokinetics and safety profiles of drugs. However, there are several limitations associated with these nanotherapy approaches. First, the complexity and toxicity due to their multi-component nature have strongly hindered the clinical translation of many nanopharmaceuticals. Second, most of the drugs used in conventional delivery research were approved decades ago, and some are no longer first-line treatments. Third, nanopharmaceuticals designed for recently developed therapeutic agents (especially novel chemical entities) may encounter patent issues. Finally, not all drugs can be structurally modified. These limitations can be addressed in the context of medicinal chemistry. Medicinal chemistry focuses on the discovery of drug substances at the early stage, compared to nanomedicine which focuses on delivery profiles for drug research and development. Drug discovery technologies have generated numerous drug leads and candidates, but issues surrounding pharmacokinetics, metabolism, and toxicology remain as challenges. These challenges may also be relatively easily solved by nanotechnology from the field of nanomedicine. Leveraging this interdisciplinary connection, the principle from nanotechnology to initial drug design has been integrated, and a one-component non-prodrug nanomedicine (ONN) strategy has been developed (Figure 1). In this strategy, drug design follows both conventional drug design strategies and the principle of molecular self-assembly, so the designed drugs are endowed with advantages from both the perspectives of drug discovery and drug delivery.

[0004] Lysosomes have been selected as a target for cancer therapy. The lysosomes of cancer cells are abnormally enlarged and easily broken, making them more vulnerable than normal lysosomes. Lysosomal membrane permeabilization (LMP) can release proteolytic enzymes (i.e., cathepsins) into the cytoplasm, enabling direct initiation of cell death; thus, lysosomotropic detergents that can induce LMP have been developed for tumor treatment. Furthermore, lysosome inhibition has great potential as an anticancer strategy because it interferes with autophagy, an important pathway related to the stress response and drug resistance of established tumors. Chloroquine (CQ) and hydroxychloroquine (HCQ), which are lysosomotropic alkalizing agents, are commonly used autophagy inhibitors and have been tested in numerous clinical trials against various types of cancer. However, these effects are considered insufficient, especially when used as single agents.

[0005] A series of lipophilic cationic BAQ derivatives were designed by pharmacophore hybridization and molecular self-assembly (Figure 1 and Figure 7). BAQ12 and BAQ13 were selected to form ONN because they have the potential to be therapeutic agents and self-assembly building blocks. These BAQ ONNs showed excellent anticancer activity in vitro and enhanced effects regarding lysosome disruption, lysosome dysfunction, and autophagy inhibition. Furthermore, BAQ ONNs exhibit a predicted self-delivery profile as nanodrugs. These advantages from both the perspectives of drug discovery and drug delivery ultimately contribute to the significant anticancer activity of these compounds as single agents in in vivo gastrointestinal cancer models. In addition, BAQ ONNs are promising for use in combination therapy with napabucasin because BAQ ONNs play a dual role as both therapeutic agents and delivery carriers. Since BAQ ONNs integrate multiple fields and ingeniously overlap functions, they will emerge as excellent alternatives for improving cancer treatment.

[0006] Integrating the unique advantages of the fields of drug discovery and drug delivery is extremely beneficial for the progress of drug development. Herein, a novel chemical entity nanomedicine (ONN) strategy of self-delivery and single-component is described for improving cancer therapy by incorporating the self-assembly principle into drug design. A bisaminoquinoline derivative capable of hybridizing a lysosomal detergent (MSDH) and an autophagy inhibitor (Lys05) to autonomously form a nanoaggregate is developed. The selected ONNs of BAQ12 and BAQ13 are highly effective in inducing lysosomal disruption, lysosomal dysfunction, and autophagy inhibition, and exhibit an anti-proliferative activity 30-fold greater than that of hydroxychloroquine used in clinical trials. These single-drug nanoparticles show excellent pharmacokinetic and toxicological profiles and dramatic in vivo antitumor effects. In addition, since these single-drug nanoparticles can encapsulate additional drugs and deliver them to the tumor site, they are promising agents for combination therapy based on autophagy inhibition. Considering their cross-field advantages, these BAQ ONNs have great potential to improve cancer therapy. What is needed are new BAQ ONNs. Surprisingly, the present invention meets this and other needs.

Summary of the Invention

[0007] In one embodiment, the present invention provides a compound of formula (I):

Chemical formula

[0008] In another embodiment, the present invention provides a nanocarrier having an inner and an outer side, comprising a plurality of compounds of the present invention or a pharmaceutically acceptable salt thereof, wherein a hydrophobic pocket is formed inside the nanocarrier and a hydrophilic group self-assembles on the outside of the nanocarrier, and each compound self-assembles in an aqueous solvent to form the nanocarrier.

[0009] In another embodiment, the present invention provides a method for treating a disease, which comprises administering to a subject in need thereof a therapeutically effective amount of the nanocarrier of the present invention.

[0010] In another embodiment, the present invention provides a method for imaging, which comprises administering to a subject to be imaged an effective amount of the nanocarrier of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

Figure 1

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Figure 25

[0037] I. General

[0038] The present invention provides bis - aminoquinoline derivative compounds and nanocarriers formed from these compounds that are useful for the treatment of diseases. These compounds and nanocarriers can target lysosomes, resulting in lysosome disruption, lysosome dysfunction, and / or autophagy inhibition. Furthermore, the nanocarriers can be used in combination therapy by encapsulating additional drugs, or used for co - administration with additional drugs that may help overcome drug resistance. The nanocarriers can also be used for imaging of cells or organisms of interest. II. Definitions

[0039] Unless otherwise indicated, all scientific and technical terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In addition, the present invention can be practiced using any methods or materials similar to or equivalent to those described herein. For the purposes of this invention, the following terms are defined.

[0040] As used herein, the terms "a" or "the" include aspects having one member as well as aspects having two or more members. For example, the singular forms "a" and "the" include the plural, unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, and reference to "the agent" includes one or more agents known to those of ordinary skill in the art, and so on.

[0041] "Alkyl" means a straight-chain or branched saturated aliphatic group having the indicated number of carbon atoms. Alkyl can contain any number of carbons (C 1-2 、C 1-3 、C 1-4 、C 1-5 、C 1-6 、C 1-7 、C 1-8 、C 1-9 、C 1-10 、C 1-20 、C 1-30 、C 1-40 、C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 3-4 、C 3-5 、C 3-6 、C 4-5 、C 4-6 、and C 5-6 etc.). For example, C 1-6Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, hexyl, and the like. Alkyl can also mean an alkyl group having up to 40 carbon atoms, non-limiting examples of which include heptyl, octyl, nonyl, decyl, and the like. The alkyl group may or may not be substituted.

[0042] "Alkylene" means a straight-chain or branched saturated aliphatic group having the indicated number of carbon atoms and connecting at least two other groups, i.e., a divalent hydrocarbon group. These two moieties connected to the alkylene can be connected to the same atom or different atoms of the alkylene group. For example, as a straight-chain alkylene, a divalent group of -(CH2) n - is possible (where n is 1, 2, 3, 4, 5, or 6). Non-limiting examples of representative alkylene groups include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, s-butylene, pentylene, and hexylene. The alkylene group may or may not be substituted.

[0043] "Alkenyl" means a straight-chain or branched hydrocarbon having at least 2 carbon atoms and at least 1 double bond. Alkenyl can contain any number of carbons (C2, C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 2-7 、C 2-8 、C 2-9 、C 2-10 、C 2-20 、C 2-30 、C 2-40 、C3、C 3-4 、C 3-5 、C 3-6 、C4、C 4-5 、C 4-6 、C5、C 5-6and C6, etc.). The alkenyl group can have any suitable number (non-limiting examples of which include 1, 2, 3, 4, 5, or more) of double bonds. Non-limiting examples of the alkenyl group include vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. The alkenyl group may or may not be substituted.

[0044] "Alkenylene" means an alkenyl group as defined above that links at least two other groups, i.e., a divalent hydrocarbon group. These two moieties linked to the alkenylene can be linked to the same atom or different atoms of the alkenylene. Non-limiting examples of the alkenylene group include ethenylene, propenylene, isopropenylene, butenylene, isobutenylene, s-butenylene, pentenylene, and hexenylene. The alkenylene group may or may not be substituted.

[0045] "Alkynyl" means a straight-chain or branched-chain hydrocarbon having at least two carbon atoms and at least one triple bond. The alkynyl can contain any number of carbons (C2, C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 2-7 、C 2-8 、C 2-9 、C 2-10 、C 2-20 、C 2-30 、C 2-40 、C3、C 3-4 、C 3-5 、C 3-6 、C4、C 4-5 、C 4-6 、C5、C 5-6, and C6, etc.). Non-limiting examples of alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, butadynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadynyl, 1,4-pentadynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadynyl, 1,4-hexadynyl, 1,5-hexadynyl, 2,4-hexadynyl, or 1,3,5-hexatrinyl. The alkynyl group may or may not be substituted.

[0046] "Alkynylene" means an alkynyl group as defined above that links at least two other groups, i.e., a divalent hydrocarbon group. These two moieties linked to the alkynylene can be linked to the same atom or different atoms of the alkynylene. Non-limiting examples of alkynylene groups include ethynylene, propynylene, isopropynylene, butynylene, s-butynylene, pentynylene, and hexynylene. The alkynylene group may or may not be substituted.

[0047] "Cycloalkyl" means a saturated or partially unsaturated monocyclic, fused bicyclic, or bridged polycyclic structure containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can contain any number of carbons (C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12etc.). Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. The cycloalkyl group may be partially unsaturated and have one or more double or triple bonds within the ring. Non-limiting examples of representative partially unsaturated cycloalkyl groups include cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3-isomer and 1,4-isomer), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When the cycloalkyl is a saturated monocyclic C 3-8 cycloalkyl, non-limiting examples of representative groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl is a saturated monocyclic C 3-6 cycloalkyl, non-limiting examples of representative groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may or may not be substituted.

[0048] "Heterocycloalkyl" means a saturated ring system having 3 to 12 ring members and 1 to 4 heteroatoms which are N, O, and S. The heteroatoms may be oxidized (non-limiting examples thereof are -S(O)- and -S(O)2-). The heterocycloalkyl group can contain any number of ring atoms (e.g., 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members). The heterocycloalkyl group can contain any suitable number of heteroatoms (e.g., 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4). The following groups can be included in the heterocycloalkyl group, namely aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane, etc. The heterocycloalkyl group can also be condensed to an aromatic or non-aromatic ring system to form various members (a non-limiting example included therein is indoline). The heterocycloalkyl group may or may not be substituted. For example, the heterocycloalkyl group can be substituted with C 1-6 alkyl or oxo (=O), but there are also many other substituents.

[0049] "Aryl" means an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. An aryl group can contain any suitable number of ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, in addition to 6-10, 6-12, or 6-14 ring members). An aryl group can be monocyclic, fused to form a bicyclic or tricyclic group, or linked by bonds to form a biaryl group. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl having a methylene linking group. Some aryl groups have 6-12 ring members (such as phenyl, naphthyl, or biphenyl). Other aryl groups have 6-10 ring members (such as phenyl or naphthyl). Some other aryl groups have 6 ring members (such as phenyl). An aryl group may or may not be substituted.

[0050] "Heteroaryl" means a monocyclic, fused bicyclic or tricyclic aromatic ring structure containing 5 to 16 ring atoms, of which 1 to 5 ring atoms are heteroatoms (such as N, O, or S). The heteroatoms may be oxidized (non-limiting examples thereof are -S(O)- and -S(O)2-). The heteroaryl group can contain any number of ring atoms (e.g., 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members). The heteroaryl group can contain any suitable number of heteroatoms (e.g., 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5). The heteroaryl group can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Groups that can be included in the heteroaryl group are pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazolefuran, thiazole, isothiazole, oxazole, and isoxazole, etc. The heteroaryl group can also be condensed to an aromatic ring system (such as a phenyl ring) to form various members, and non-limiting examples included therein are benzopyrrole (such as indole and isoindole), benzopyridine (such as quinoline and isoquinoline), benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine (such as phthalazine and cinnoline), benzothiophene, and benzofuran. Also included in other heteroaryl groups are heteroaryl rings (such as bipyridine) linked by bonds. The heteroaryl group may or may not be substituted.

[0051] "Alkoxy" means an alkyl group having one oxygen atom connecting the alkyl group to the point of attachment, i.e., alkyl-O-. Similar to the alkyl group, the alkoxy group can have any suitable number of carbon atoms (C1-6 etc.). Examples of the alkoxy group include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, s-butoxy, t-butoxy, pentoxy, hexyloxy, etc. The alkoxy group can be further substituted with various substituents described herein. The alkoxy group may or may not be substituted.

[0052] "Hydroxyl" means the -OH functional group.

[0053] "Halogen" means fluorine, chlorine, boron, and iodine.

[0054] "Phosphor" means a compound that generally emits light in the range of 300 to 700 nm after excitation. When the phosphor absorbs the transferred light energy (e.g., photons), it becomes excited. When this molecule escapes from the excited state, it emits light energy in the form of lower-energy photons (e.g., fluoresces), returning this dye molecule to its ground state. Natural or synthetic compounds are possible as phosphors. Non-limiting examples of phosphors include DAPI, ethidium bromide, acridine orange, GFP, mCherry, hydroxycoumarin, fluorescein, LysoTracker (red and green), Dextran-Alexa Fluor 488, Premo (trademark) autophagy sensor LC3B-GFP, and Ac-DEVD-AMC.

[0055] "Photosensitizer" means a compound that can generate reactive groups (typically reactive oxygen species (ROS)) for photodynamic therapy upon activation by light, but can also generate reactive groups for polymerization, cross-linking, or decomposition. Photosensitizers may be useful in treating diseases by generating singlet oxygen to damage tumors. Non-limiting examples of photosensitizers include porphyrins, dyes, and chlorophyll.

[0056] "Porphyrin" refers to the following porphyrin core: [Chemistry] means any compound having (wherein the porphyrin core may or may not be substituted).

[0057] "Sterol" refers to the following core structure: [Chemistry] means a compound having (wherein the core may be further substituted).

[0058] "Drug" means an agent capable of treating and / or improving a condition or disease. A hydrophobic drug (any drug that repels water) is possible as a drug. Non-limiting examples of hydrophobic drugs useful in the present invention include hydroxychloroquine (HCQ), Lys05, bortezomib, β-lapachone, JQ1, napabucasin, rapamycin, paclitaxel, SN38, etoposide, lenalidomide, and apoptazol. Also included in other drugs are non-steroidal anti-inflammatory drugs and vinca alkaloids (such as vinblastine and vincristine). The drugs of the present invention also include prodrug forms. Those skilled in the art will recognize that other drugs may be useful in the present invention.

[0059] "Imaging agent" or "contrast agent" means a compound that enhances the contrast of a structure located in a cell or the body for an imaging method (non-limiting examples of which include MRI, PET, SPECT, and CT). An imaging agent can generate radiation, fluorescence, a magnetic field, or radio waves. Non-limiting examples of imaging agents include radiometal chelators, atoms or ions of radiometals, and phosphors.

[0060] "Chemotherapeutic agent" means a chemical drug that can be used for the treatment of diseases (non-limiting examples thereof include cancer, tumor, and neoplasm). In some embodiments, the chemotherapeutic agent can be in the form of a prodrug that can be activated to a cytotoxic form. Chemotherapeutic agents are generally known to those skilled in the art and can be used in the present invention. Non-limiting examples of chemotherapeutic agents include daunorubicin, doxorubicin, paclitaxel, docetaxel, abraxane, bortezomib, etoposide, lenalidomide, apoptazol, carboplatin, cisplatin, oxaliplatin, vinblastine, and vincristine.

[0061] "Molecular targeting agent" means a drug that can target specific molecules involved in the evolution, proliferation, and expansion of tumors and cancers. By targeting specific molecules involved in the evolution of tumors and cancers, it becomes possible to kill tumors and cancers, or inhibit the growth and expansion of tumors and cancers. Non-limiting examples of molecular targeting agents include trastuzumab, erlotinib, imatinib, nilotinib, and vemurafenib.

[0062] "Immunotherapeutic agent" means a type of drug that can change the immune response by stimulating or suppressing the immune system. Non-limiting examples of immunomodulatory agents include HCQ, Lys05, JQ1, rapamycin, napabucasin, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab.

[0063] "Radiation therapy agent" means a drug that can be used for the treatment of diseases using radiation therapy. Radiation therapy is a disease treatment method that uses radiation to kill or inhibit tumor cells and cancer cells. Non-limiting examples of radiation therapy agents include β-lapachone, cisplatin, nimorazole, cetuximab, misonidazole, and tirapazamine.

[0064] "Nanocarrier" or "nanoparticle" means a micelle resulting from the aggregation of the compounds of the present invention. The nanocarriers of the present invention can have a hydrophobic core and a hydrophilic outer side.

[0065] "Inhibiting", "inhibit", and "inhibitor" mean a compound that blocks a particular action or function, or a method of blocking.

[0066] "Treating", "being treated", and "treatment" mean either some indication of success in treatment or an improvement in an injury, medical condition, state, or symptom (e.g., pain), which includes an improvement in any objective or subjective parameter (alleviation; remission; reduction of symptoms, making symptoms, injury, medical condition, or state more tolerable for the patient; reducing the frequency or duration of symptoms or states; or in some situations, preventing the onset of symptoms, etc.). Treatment or improvement of symptoms can be based on any objective or subjective parameter; parameters include, for example, the results of a physical examination.

[0067] "Disease" means abnormal cell function in an organism, not caused by the direct result of physical injury or external damage. Disease means any condition that causes unease, malfunction, disorder, abnormality, infection, pain, or even death. Non-limiting examples of diseases include genetic diseases (such as genetic and non-genetic diseases), infectious diseases, non-infectious diseases (such as cancer, deficiency diseases, etc.), and physiological diseases.

[0068] "Administering" means oral administration to a subject, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, or subcutaneous administration, intrathecal administration, or implantation of a sustained release device (e.g., a mini-osmotic pump).

[0069] "Subject" means an animal, which is, for example, a mammal, and non-limiting examples thereof include primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0070] "An effective amount or dose for treatment" or "a sufficient amount or dose for treatment" or "an effective or sufficient amount or dose" means an amount or dose that, when administered, produces a therapeutic effect. The exact amount will depend on the purpose of the treatment and can be determined by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the effective dose for treatment is often lower than the conventional effective dose for treatment in non-sensitized cells.

[0071] "Target" or "targeting" means using a compound, protein, or antibody that specifically or selectively binds to a cell, virus particle, viral protein, antigen, or biomolecule, or localizes to a specific cell type, tissue type, microorganism type, or virus type.

[0072] "Imaging" means using a device external to the subject to clarify the location of an imaging agent (such as a compound of the invention). Non-limiting examples of imaging tools include positron emission tomography (PET), magnetic resonance imaging (MRI), ultrasound, single photon emission computed tomography (SPECT), and x-ray computed tomography (CT). Positron emission tomography detects radiation from the emission of positrons by an imaging agent. III. Compounds

[0073] In some embodiments, the invention provides a compound of formula (I): [Chemical] or a pharmaceutically acceptable salt thereof is provided (wherein in this formula, R 1 is hydrogen, C 1-40 alkyl, C 2-40 alkenyl, C 2-4 alkynyl, -W, -(L-Y) p -Z, or -C(O)R 1a and each alkyl, alkenyl, and alkynyl therein is optionally substituted with C 1-20 alkoxy, hydroxyl, or -NR 1b R 1c ; W is C 3-12 cycloalkyl, C 6-12 aryl, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms each independently being N, O, or S, and each cycloalkyl, aryl, and heteroaryl therein is optionally substituted with C 1-40 alkyl, C 2-40 alkenyl, or C 2-40 alkynyl; each L is independently absent, C 1-20 alkylene, C 2-20 alkenylene, or C 2-20 alkynylene; each Y is independently absent, -O-, -NH-, -NHC(O)-, -NHC(O)NH-, -NHSO2-, -OC(O)-, -OC(O)NH-, -C(O)-, or -SO2-; Z is a phosphor, a photosensitizer, a porphyrin, a chemotherapeutic agent, a sterol, C 3-12 cycloalkyl, a 3- to 12-membered heterocycloalkyl having 1 to 4 heteroatoms each independently being N, O, or S, C 6-12 aryl, a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms each independently being N, O, or S, -OH, or -NH2; R 1a is C 1-40 alkyl, C 2-40 alkenyl, or C 2-40 alkynyl, and each alkyl, alkenyl, and alkynyl therein is optionally substituted with C 1-40is substituted with alkoxy, hydroxyl, or -NR 1b R 1c ; R 1b is hydrogen, C 1-40 alkyl, C 2-40 alkenyl, or C 2-40 alkynyl; R 1c is hydrogen, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, or -L-W; R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 1-40 alkoxy, halogen, -CN, or -NO2; m and n are independently integers from 1 to 10; p is independently an integer from 1 to 20; each X is independently absent or -O - ; provided that when X is absent and R 2a and R 2b are hydrogen, R 3a and R 3b are each independently hydrogen, -OMe, fluorine, chlorine, boron, or -NO2, then R 1 is C 2-40 alkyl, C 2-40 alkenyl, C 4-40 alkynyl, -W, -(L-Y) p -Z, or -C(O)R 1a ; provided that when X is absent and R 1 is -CH2CH2NH(7-chloro-4-quinolinyl) and R 2a and R 2b are hydrogen, then R 3a and R 3b are independently selected from hydrogen, C 1-20 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 1-40 alkoxy, fluorine, boron, iodine, -CN, or -NO2.

[0074] In some embodiments, the present invention provides a compound of formula (I), wherein R 1 is hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -W, -(L-Y) p -Z, or -C(O)R 1a wherein each alkyl, alkenyl, and alkynyl is optionally substituted with C 1-20 alkoxy, hydroxyl, or -NR 1b R 1c ; W is C 3-12 cycloalkyl, C 6-12 aryl, or C 4-12 heteroaryl, wherein each cycloalkyl, aryl, and heteroaryl is optionally substituted with C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl; each L is independently absent, C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; each Y is independently absent, -O-, -NH-, -NHC(O)-, -NHC(O)NH-, -NHSO2-, -OC(O)-, -OC(O)NH-, -C(O)-, or -SO2-; Z is a phosphor, a photosensitizer, a porphyrin, a chemotherapeutic agent, or a sterol; R 1a is C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl, wherein each alkyl, alkenyl, and alkynyl is optionally substituted with C 1-20 alkoxy, hydroxyl, or -NR 1b R 1c ; R 1b is hydrogen, C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl; R 1c is hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C2-20 is alkynyl, or -L-W; R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkoxy, halogen, -CN, or -NO2; m and n are each independently an integer from 1 to 10; p is independently an integer from 1 to 20; each X is independently absent or -O - but when X is absent and R 2a and R 2b are hydrogen and R 3a and R 3b are each independently hydrogen, -OMe, fluorine, chlorine, boron, or -NO2, then R 1 is C 2-20 alkyl, C 2-20 alkenyl, C 4-20 alkynyl, -W, -(L-Y) p -Z, or -C(O)R 1a but when X is absent and R 1 is -CH2CH2NH(7-chloro-4-quinolinyl) and R 2a and R 2b are hydrogen, then R 3a and R 3b are each independently selected from hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkoxy, fluorine, boron, iodine, -CN, or -NO2).

[0075] In some embodiments, R 1 is hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -W, -(L-Y) p -Z, or -C(O)R 1a wherein each alkyl, alkenyl, and alkynyl therein is optionally C 1-20is substituted with alkoxy, hydroxyl, or -NR 1b R 1c ; W is C 3-12 cycloalkyl, C 6-12 aryl, or 5- to 12-membered heteroaryl, and the 5- to 12-membered heteroaryl has 1 to 4 heteroatoms of N, O, and S, and each cycloalkyl, aryl, and heteroaryl is optionally substituted with C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl; each L is independently absent, C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; each Y is independently absent, -O-, -NH-, -NHC(O)-, -NHC(O)NH-, -NHSO2-, -OC(O)-, -OC(O)NH-, -C(O)-, or -SO2-; Z is a phosphor, photosensitizer, porphyrin, chemotherapeutic agent, or sterol; R 1a is C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl, and each alkyl, alkenyl, and alkynyl therein is optionally substituted with C 1-20 alkoxy, hydroxyl, or -NR 1b R 1c ; R 1b is hydrogen, C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl; R 1c is hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, or -L-W; R 2a R 2b R 3a and R 3b are each independently hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20is alkoxy, halogen, -CN, or -NO2; m and n are, independently, integers from 1 to 10; p is, independently, an integer from 1 to 20; each X is, independently, absent or -O - but when X is absent and R 2a and R 2b are hydrogen and R 3a and R 3b are, independently, hydrogen, -OMe, fluorine, chlorine, boron, or -NO2, then R 1 is C 2-20 alkyl, C 2-20 alkenyl, C 4-20 alkynyl, -W, -(L-Y) p -Z, or C(O)R 1a and when X is absent and R 1 is -CH2CH2NH(7-chloro-4-quinolinyl) and R 2a and R 2b are hydrogen, then R 3a and R 3b are, independently, selected from hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkoxy, fluorine, boron, iodine, -CN, or -NO2.

[0076] In some embodiments, R 1 is hydrogen, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, -W, -(L-Y) p -Z, or -C(O)R 1a In some embodiments, R 1 is C 1-40 alkyl, C 2-40 alkenyl, -(L-Y) p -Z, or -C(O)R 1a is.

[0077] In some embodiments, R 1 is C 1-40 alkyl. In some embodiments, R 1 is C 1-25is alkyl. In some embodiments, R 1 is C 1-20 alkyl. In some embodiments, R 1 is C 10-25 alkyl. In some embodiments, R 1 is C 10-20 alkyl. In some embodiments, R 1 is C 12-22 alkyl. In some embodiments, R 1 is C 12-18 alkyl.

[0078] In some embodiments, R 1 is C 2-40 alkenyl. In some embodiments, R 1 is C 20-40 alkenyl. In some embodiments, R 1 is C 30-40 alkenyl. In some embodiments, R 1 is C 2-40 alkynyl. In some embodiments, R 1 is C 20-40 alkynyl. In some embodiments, R 1 is C 30-40 alkynyl.

[0079] In some embodiments, R 1 is W. In some embodiments, W is C 3-12 cycloalkyl, C 6-12 aryl, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms each independently N, O, or S, wherein each of the cycloalkyl, aryl, and heteroaryl therein is optionally C 1-40 alkyl, C 2-40 alkenyl, or C 2-40 alkynyl substituted. In some embodiments, W is C 5-12 cycloalkyl, C 6-12Aryl, or a 5- to 12-membered heteroaryl having 1 to 4 heteroatoms each independently being N, O, or S. In some embodiments, W is C 5-12 Cycloalkyl. In some embodiments, W is C 5-8 Cycloalkyl. In some embodiments, W is cyclopentyl or cyclohexyl.

[0080] In some embodiments, R 1 Is -(L-Y) p -Z. In some embodiments, p is an integer from 1 to 20. In some embodiments, p is an integer from 1 to 10. In some embodiments, p is an integer from 1 to 5. In some embodiments, p is 1, 2, 3, 4, or 5. In some embodiments, p is 1.

[0081] In some embodiments, L is C 1-20 Alkylene, C 2-20 Alkenylene, or C 2-20 Alkynylene. In some embodiments, L is C 1-20 Alkylene. In some embodiments, L is C 1-10 Alkylene. In some embodiments, L is C 1-5 Alkylene.

[0082] In some embodiments, Y is absent, -O-, -NH-, -NHC(O)-, -NHC(O)NH-, -NHSO2-, -OC(O)-, -OC(O)NH-, -C(O)-, or -SO2-. In some embodiments, Y is absent, -NH-, -NHC(O)-, -NHC(O)NH-, -OC(O)-, -OC(O)NH-, or -C(O)-. In some embodiments, Y is absent, -NH-, -NHC(O)-, or -NHC(O)NH-. In some embodiments, Y is absent, -NH-, or -NHC(O)-.

[0083] In some embodiments, Z is a phosphor, a photosensitizer, a porphyrin, a chemotherapeutic agent, a sterol, C3-12 Cycloalkyl, 3- to 12-membered heterocycloalkyl having 1 to 4 heteroatoms each independently being N, O or S, C 6-12 Aryl, 5- to 12-membered heteroaryl having 1 to 4 heteroatoms each independently being N, O, or S, -OH, or -NH2.

[0084] Non-limiting examples of photosensitizers useful in the present invention include porphyrins, benzoporphyrins, corphins, chlorins, bacteriochlorophylls, corphins, or derivatives thereof. Representative photosensitizers are shown below:

Chemical formula

Chemical formula

[0085] In some embodiments, the photosensitizer is a porphyrin, benzoporphyrin, corphin, chlorin, bacteriochlorophyll, corphin, or a derivative thereof. In some embodiments, the photosensitizing compound is a porphyrin, pyropheophorbide-a, pheophorbide, chlorin e6, purpurin, purpurinimide, verteporfin, photofrin porfimer, rostaporfin, talaporfin, or temoporfin. In some embodiments, the photosensitizer is pyropheophorbide-a. In some embodiments, the photosensitizer is pheophorbide-a. In some embodiments, the photosensitizer is a porphyrin.

[0086] Any suitable porphyrin can be used in the compounds of the present invention. Non-limiting examples of representative porphyrins suitable for the present invention include pyropheophorbide-a, pheophorbide, chlorin e6, purpurin, or purpurinimide. In some embodiments, pheophorbide-a is possible as the porphyrin. In some embodiments, pyropheophorbide-a is possible as the porphyrin.

[0087] In some embodiments, Z is porphyrin, sterol, 6- to 12-membered heterocycloalkyl, 8- to 12-membered heteroaryl, -OH, or -NH2, wherein the 6- to 12-membered heterocycloalkyl and 8- to 12-membered heteroaryl have 1 to 4 heteroatoms of N, O, and S. In some embodiments, Z is porphyrin, cholic acid, indoline, isoindoline, 1-isoindolinone, phthalimide, phthalic anhydride, -OH, or -NH2.

[0088] In some embodiments, p is 1; L is C 4-5 alkylene; Y is absent, -NH-, or -NHC(O)-; and Z is porphyrin, cholic acid, isoindoline, phthalimide, -OH, or -NH2.

[0089] In some embodiments, R 1 is -C(O)R 1a In some embodiments, R 1a is C 1-40 alkyl, C 2-40 alkenyl, or C 2-40 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is optionally substituted with C 1-40 alkoxy, hydroxyl, or -NR 1b R 1c In some embodiments, R 1a is C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is optionally substituted with C 1-20 alkoxy, hydroxyl, or -NR 1b R 1c In some embodiments, R 1a is C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl. In some embodiments, R 1a is C 1-10is alkyl. In some embodiments, R 1a is C 1-5 alkyl. In some embodiments, R 1a is methyl, ethylene, propyl, or butyl.

[0090] In some embodiments, R 1b is C 1-40 alkyl, C 2-40 alkenyl, or C 2-40 alkynyl. In some embodiments, R 1b is C 1-20 alkyl, C 2-20 alkenyl, or C 2-20 alkynyl. In some embodiments, R 1b is C 1-10 alkyl. In some embodiments, R 1b is C 1-5 alkyl. In some embodiments, R 1b is methyl, ethylene, propyl, or butyl.

[0091] In some embodiments, R 1c is C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, or -L-W. In some embodiments, R 1c is C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, or -L-W. In some embodiments, R 1c is C 1-10 alkyl. In some embodiments, R 1c is C 1-5 alkyl. In some embodiments, R 1c is methyl, ethylene, propyl, or butyl.

[0092] In some embodiments, R 2a and R 2b are each independently hydrogen, C 1-20 alkyl, C 2-20Alkenyl, C 2-20 Alkynyl, C 1-20 is alkoxy, halogen, -CN, or -NO2. In some embodiments, R 2a and R 2b are each independently hydrogen, C 1-20 alkyl, or halogen. In some embodiments, R 2a and R 2b are each independently hydrogen or halogen. In some embodiments, R 2a and R 2b are each independently hydrogen, fluorine, chlorine, boron, or iodine. In some embodiments, R 2a and R 2b are each independently hydrogen.

[0093] In some embodiments, R 3a and R 3b are each independently hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkoxy, halogen, -CN, or -NO2. In some embodiments, R 3a and R 3b are each independently hydrogen, C 1-20 alkyl, or halogen. In some embodiments, R 3a and R 3b are each independently hydrogen or halogen. In some embodiments, R 3a and R 3b are each independently hydrogen, fluorine, chlorine, boron, or iodine. In some embodiments, R 3a and R 3b are each independently hydrogen.

[0094] In some embodiments, m and n are independently integers from 1 to 10. In some embodiments, m and n are independently integers from 1 to 5. In some embodiments, m and n are independently 1, 2, 3, 4, or 5. In some embodiments, m and n are each independently 1.

[0095] In some embodiments, each X is independently absent or -O - In some embodiments, each X is absent. In some embodiments, each X is -O - is - .

[0096] In some embodiments, each X is absent. In some embodiments, the compound is a compound of formula (Ia):

Chemical formula

[0097] In some embodiments, R 1 is C 1-20 alkyl, and the compound is of formula (Ia):

Chemical formula

[0098] In some embodiments, the compound has the structure:

Chemical formula

[0099] In some embodiments, the compound is

Chemical formula

[0100] In some embodiments, the compound is

Chemical formula

[0101] In some embodiments, the compound is

Chemical formula

[0102] In some embodiments, each X is -O - In some embodiments, the compound is a compound of formula (Ib): [Chemical formula] is

[0103] In some embodiments, the compound is [Chemical formula] selected from the group consisting of

[0104] In some embodiments, the compound is [Chemical formula] [Chemical formula] selected from the group consisting of

[0105] The present invention includes all tautomers and stereoisomers of the compounds of the present invention in the form of mixtures or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at the positions of carbon atoms, and thus the compounds of the present invention can exist in diastereomeric form or enantiomeric form, or in mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic mixtures of such isomers, diastereomeric mixtures, and other mixtures, as well as solvates, hydrates, polymorphs, and tautomers are included within the scope of the present invention. The compounds according to the present invention can be prepared using diastereomers, enantiomers, or racemic mixtures as starting materials. Furthermore, diastereomeric and enantiomeric products can be separated by chromatography, fractional crystallization, or other methods known to those skilled in the art.

[0106] The present invention also includes compounds of the invention labeled with isotopes, in which one or more atoms are replaced with one or more atoms having a specific atomic mass or mass number. Non-limiting examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine ( 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S, and 36 Cl, etc.). Compounds of the invention labeled with isotopes are useful in assays of the tissue distribution of those compounds and their prodrugs and metabolites; preferred isotopes for such assays include 3 H and 14 C. In addition, in some cases, metabolic stability can be increased by substituting with heavier isotopes (deuterium ( 2 H)), which provides therapeutic advantages such as an increase in in vivo half-life or a decrease in the required dose. Compounds of the invention labeled with isotopes can generally be prepared by replacing non-labeled reagents with labeled reagents according to methods known to those of ordinary skill in the art. The compounds of the invention can be labeled with isotopes at the positions adjacent to the methyl groups of the methoxy substituents and at the basic amines in the aromatic rings.

[0107] The compounds of the present invention can also be in the form of pharmaceutically acceptable salts (such as acid salts or base salts of the compounds of the present invention). Representative examples of pharmaceutically acceptable salts include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (such as methyl iodide, ethylene iodide, etc.). Pharmaceutically acceptable salts are understood to be non-toxic. Additional information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pennsylvania, 1985 (incorporated herein by reference). IV. Nanocarriers

[0108] In some embodiments, the present invention provides a nanocarrier having an inner and an outer side, the nanocarrier containing a plurality of the compounds of the present invention or pharmaceutically acceptable salts thereof, and when each compound self-assembles in an aqueous solvent, a hydrophobic pocket is formed inside the nanocarrier, and the hydrophilic groups self-assemble outside the nanocarrier to form the nanocarrier.

[0109] The diameter of the nanocarriers of the present invention can be any suitable size. In some embodiments, the nanocarrier can have a diameter of 5 - 200 nm. In some embodiments, the nanocarrier can have a diameter of 10 - 150 nm. In some embodiments, the nanocarrier can have a diameter of 50 - 150 nm. In some embodiments, the nanocarrier can have a diameter of 100 - 150 nm. In some embodiments, the nanocarrier can have a diameter of about 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, or 130 nm. In some embodiments, it can have a diameter of about 100 nm.

[0110] The outside of the nanocarrier can be utilized to target cells or lysosomes. The nanocarrier can target cells or lysosomes to inhibit autophagy. In some embodiments, the nanocarrier can target lysosome disruption, lysosomal dysfunction, autophagy inhibition, or combinations thereof. In some embodiments, the nanocarrier targets lysosomes.

[0111] In some embodiments, a hydrophobic pocket is formed from the R 1 group of the compounds of the invention. In some embodiments, the nanocarrier contains one or more hydrophobic drugs or imaging agents encapsulated within the hydrophobic pocket of the nanocarrier.

[0112] Any hydrophobic drug known to those skilled in the art can be used as the hydrophobic drug useful in the present invention. Non-limiting examples of hydrophobic drugs useful in the present invention include deoxycholic acid, deoxycholate, resiquimod, gardiquimod, imiquimod, taxanes (e.g., paclitaxel, docetaxel, cabazitaxel, baccatin III, 10-deacetylbaccatin, Hongdoushan A, Hongdoushan B, or Hongdoushan C), doxorubicin, etoposide, irinotecan, SN-38, cyclosporin A, podophyllotoxin, carmustine, amphotericin, ixabepilone, patupilone (epothilone class), rapamycin, and platinum drugs. Also included in other drugs are non-steroidal anti-inflammatory drugs and vinca alkaloids (such as vinblastine and vincristine).

[0113] Non-limiting examples of other hydrophobic drugs useful in the present invention include chemotherapeutic agents, molecular targeting agents, immunomodulatory agents, immunotherapeutic agents, radiation therapy agents, or combinations thereof.

[0114] In some embodiments, the hydrophobic drug is a chemotherapeutic agent, a molecular targeting agent, an immunotherapeutic agent, a radiotherapy agent, or a combination thereof. In some embodiments, the hydrophobic drug is an immunotherapeutic agent. Non-limiting examples of immunotherapeutic agents useful in the present invention include HCQ, Lys05, JQ1, rapamycin, napabucasin, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab.

[0115] In some embodiments, the hydrophobic drug is a radiotherapy agent. Non-limiting examples of radiotherapy agents useful in the present invention include β-lapachone, cisplatin, nimorazole, cetuximab, misonidazole, and tirapazamine.

[0116] In some embodiments, the hydrophobic drug is a chemotherapeutic agent or a molecular targeting agent. Non-limiting examples of chemotherapeutic agents or molecular targeting agents include daunorubicin, doxorubicin, paclitaxel, docetaxel, abraxane, bortezomib, etoposide, lenalidomide, apoptazol, carboplatin, cisplatin, oxaliplatin, vinblastine, vincristine, trastuzumab, erlotinib, imatinib, nilotinib, and vemurafenib.

[0117] In some embodiments, the hydrophobic drug is an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 regulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKT inhibitor, a JAK / STAT inhibitor, an inhibitor of checkpoint-1 or 2, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trapping antibody, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, Pemetrexed, Erlotinib, Dasatinib, Nilotinib, Decatnib, Panitumumab, Amrubicin, Oregovomab, Lep-etu, Noratrexed, azd2171, Batabulin, Ofatumumab, Zanubrutinib, Edotecarin, Tetrandrine, Rubitecan, Tesmilifene, Oblimersen, Tisilimab, Ipilimumab, Gosipol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Sirendide, Dimatecan, IL13-PE38QQR; INO 1001, IPdR1 KRX-0402, Lucanthone, LY 317615, Neoradiab, Vitespan, Rta 744, Sdx 102, Tarpanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Liposomal doxorubicin, 5'-Deoxy-5-fluorouridine, Vincristine, Temozolomide, ZK-304709, Sericlib; PD0325901, AZD-6244, Capecitabine, N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid disodium salt heptahydrate, Camptothecin, PEG-labeled irinotecan, Tamoxifen, Toremifene citrate, Anastrozole, Exemestane, Letrozole, DES (Diethylstilbestrol), Estradiol, Estrogen, Conjugated estrogen, Bevacizumab, IMC-1C11, CHIR-258); 3-[5-(Methylsulfonylpiperazinemethyl)-indolyl-quinoline, Bataranib, AG-013736, AVE-0005, Acetate of [D-Ser(Bu t) 6, Azgly 10] (Pyrro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 [C. 59 H 84N 18 O 14-(C2H4O2)X (where x = 1 to 2.4), goserelin acetate, leuprorelin acetate, tryptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, arbritux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl anilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, glevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxane, marimastat, COL-3, neovastat, BMS-275291,Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifene, Idoxifene, Spironolactone, Finasteride, Zidovudine, Trastuzumab, Denileukin difitox, Gefitinib, Bortezomib, Paclitaxel, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab (monoclonal antibody) and Arbitux, Cremophor-free Paclitaxel, Epothilone B, BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acorifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-Hydroxyethyl)-Rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779,450, PEG-Filgrastim, Darbepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Zoledronate, Prednisone, Cetuximab, Granulocyte Macrophage Colony-Stimulating Factor, Histrelin, Peginterferon alpha-2a, Interferon alpha-2a, Peginterferon alpha-2b, Interferon alpha-2b, Azacitidine, PEG-L-Asparaginase, Lenalidomide, Gemtuzumab, Hydrocortisone, Interleukin-11, Dexrazoxane, Alemtuzumab, All-trans Retinoic Acid, Ketoconazole, Interleukin-2, Megestrol, Immunoglobulin, Nitrogen Mustard, Methylprednisolone, Ibritumomab tiuxetan, Androgen, Decitabine, Hexamethylmelamine, Bexarotene, Tositumomab, Arsenic Trioxide, Cortisone, Etidronate, Mitotane, Cyclosporine, Liposomal Daunorubicin, Edwina-Asparaginase, Strontium 89, Casopitant, Netupitant,An NK-1 receptor antagonist, paroxetine, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, sspeg filgrastim, erythropoietin, epoetin alpha and darbepoetin alpha, ipilimumab, vemurafenib, or a combination thereof. In some embodiments, the hydrophobic drug is HCQ, Lys05, JQ1, rapamycin, napabucasin, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, β-lapachone, cisplatin, nimorazole, cetuximab, misonidazole, tirapazamine, daunorubicin, doxorubicin, paclitaxel, docetaxel, abraxane, bortezomib, etoposide, lenalidomide, apoptazol, carboplatin, cisplatin, oxaliplatin, vinblastine, vincristine, trastuzumab, erlotinib, imatinib, nilotinib, vemurafenib, or a combination thereof.,

[0118] In some embodiments, the nanocarrier comprises a plurality of the compounds of the invention having the structure of the compounds described above. V. Formulations and Administration

[0119] The compounds, nanocarriers, and compositions of the present invention can be prepared in a variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc. suitable for ingestion by a patient. The compositions of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. Additionally, the compositions described herein can be administered by inhalation (e.g., intranasally). In addition, the compositions of the present invention can be administered transdermally. The compositions of the present invention can also be administered by intraocular, intravaginal, and intrarectal routes, examples of which include suppositories, insufflations, powders, and aerosol formulations (see, e.g., Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Accordingly, the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable base or excipient and a compound of the present invention.

[0120] To prepare a pharmaceutical composition from the compounds of the present invention, a solid or a liquid can be used as a pharmaceutically acceptable base. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. One or more substances can be used as a solid base, which can also act as a diluent, flavoring agent, binding agent, preservative, tablet disintegrant, or encapsulating material. Details regarding formulation and administration techniques are well described in the academic and patent literature. See, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton, Pennsylvania ("Remington's").

[0121] In the powder, the base is a finely divided solid and is in a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a base having the necessary binding properties in an appropriate ratio and compressed into the desired shape and size. The powder and tablets preferably contain from 5% or 10% to 70% of the compounds of the present invention.

[0122] Non-limiting examples of suitable solid excipients include magnesium carbonate; magnesium stearate; talc, pectin; dextrin; starch; tragacanth gum; low melting point wax; cocoa butter; carbohydrates; sugars (non-limiting examples of which include lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants); celluloses (such as methylcellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose); and gums (including gum arabic and tragacanth gum); in addition, proteins (non-limiting examples of which include gelatin and collagen). If desired, a disintegrant or solvent can be added (such as cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts (such as sodium alginate)).

[0123] The core of the dragee is provided with a suitable coating (a concentrated sugar solution which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture, etc.). To identify the product or to characterize the amount of the active compound (i.e., the dosage), a dye or pigment can be added to the coating of the tablet or dragee. The pharmaceutical preparation of the present invention can also be used orally, which can be, for example, in addition to push-fit capsules made of gelatin, soft-sealed capsules made of gelatin and a coating (such as glycerol or sorbitol). The push-fit capsules can contain the compound of the present invention mixed with a filler or binder (such as lactose or starch), a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In the case of soft capsules, the compound of the present invention can be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin, or liquid polyethylene glycol) with or without a stabilizer.

[0124] To prepare a suppository, a low melting point wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted, and the compound of the present invention is uniformly dispersed therein, for example, by stirring. Then, the melted and uniform mixture is poured into a mold of a suitable size and solidified by leaving it to cool.

[0125] Preparations in liquid form include solutions, suspensions, and emulsions (such as water, or a water / propylene glycol solution). For parenteral injection, the liquid preparation can be formulated into a solution in an aqueous polyethylene glycol solution.

[0126] An aqueous solution suitable for oral use can be prepared by dissolving the compound of the present invention in water and adding appropriate colorants, flavoring agents, stabilizers, and thickeners if desired. An aqueous suspension suitable for oral use contains the finely divided active ingredient in water together with a viscous material (such as natural rubber or synthetic rubber, resin, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic, etc.), and a dispersing agent or wetting agent (such as natural phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxy cetanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide and partial esters derived from fatty acids and anhydrous hexitol (e.g., polyoxyethylene sorbitol monooleate), etc.) and can be made by dispersing them. The aqueous suspension can also contain one or more preservatives (such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, etc.), one or more colorants, one or more flavoring agents, and one or more sweetening agents (such as sucrose, aspartame, or saccharin, etc.). The osmotic pressure of the preparation can be adjusted.

[0127] Solid form preparations that are intended to be converted to liquid form preparations for oral administration shortly before use are included. Such liquid forms include solutions, suspensions, and emulsions. These preparations can contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial or natural sweetening agents, dispersing agents, thickeners, solvents, etc.

[0128] The oil suspension can be formulated by suspending the compound of the present invention in a vegetable oil (such as peanut oil, olive oil, sesame oil, or coconut oil), or a mineral oil (such as liquid paraffin); or a mixture thereof. The oil suspension can contain a thickening agent (such as beeswax, hard paraffin, or cetyl alcohol). A sweetening agent can be added to provide an orally palatable preparation (such as glycerol, sorbitol, or sucrose). These formulations can be preserved by adding an antioxidant (such as ascorbic acid). For an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparation of the present invention can also be in the form of an oil-in-water emulsion. As the oil phase, the above vegetable oil or mineral oil, or a mixture thereof is possible. Appropriate emulsifiers include natural rubbers (such as gum arabic and tragacanth gum), natural phosphatides (such as soybean lecithin), esters or partial esters derived from fatty acids and anhydrohexitols (such as sorbitan monooleate), and condensates of these partial esters and ethylene oxide (such as polyoxyethylene sorbitan monooleate). The emulsion can also contain a sweetening agent and a flavoring agent, as in the formulations of syrups and elixirs. Such formulations can also contain a lubricant, a preservative, or a coloring agent.

[0129] In another embodiment, the composition of the present invention can be formulated for parenteral administration (such as intravenous (IV) administration or administration into the lumen of a body cavity or organ). The formulation for administration will generally comprise a solution of the composition of the present invention dissolved in a pharmaceutically acceptable base. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride. In addition, sterile, non-volatile oils can usually be used as a solvent or suspension medium. For that purpose, any non-irritating, non-volatile oil containing synthetic monoglycerides or synthetic diglycerides can be used. In addition, fatty acids (such as oleic acid) can likewise be used in the preparation of injectable formulations. These solutions are sterile and generally free of undesirable substances. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations can contain pharmaceutically acceptable adjunct substances (such as pH adjusters, buffers, toxicity regulators, etc., for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate) necessary to mimic physiological conditions. The concentration of the composition of the present invention in these formulations can vary widely and will be selected primarily based on the volume of fluid, viscosity, body weight, etc., depending on the specific mode of administration selected and the needs of the patient. For IV administration, sterile injectable preparations (such as sterile injectable aqueous or oily suspensions) are possible as a formulation. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. As a sterile injectable preparation, a sterile injectable solution or suspension (such as a solution of 1,3-butanediol) in a non-toxic and parenterally acceptable diluent or solvent is also possible.

[0130] The composition of the present invention can be delivered by any suitable means, including oral, parenteral, and topical methods. Transdermal administration by the topical route can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0131] The pharmaceutical preparation is preferably in unit dosage form. In such a form, the preparation is divided into unit doses each containing an appropriate amount of the compound of the present invention. As unit dosage forms, packaged preparations, packages containing discrete amounts of the preparation (such as powders in packaged tablets, capsules, and vials or ampoules) are possible. Also, as unit dosage forms, capsules, tablets, cachets, or lozenges themselves, or appropriate numbers of any of these packaged forms are possible.

[0132] The compound of the present invention and the nanocarrier can be present in any appropriate amounts, which may depend on various factors, non-limiting examples of which include the body weight and age of the subject, the disease state, etc. The appropriate dosage range of the compound of the present invention includes from about 0.1 mg to about 10,000 mg, or from about 1 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 25 mg to about 500 mg, or from about 50 mg to about 250 mg. The appropriate dosages of the compound of the present invention include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg.

[0133] The compound of the present invention and the nanocarrier can be administered at any appropriate frequency, interval, and duration. For example, the compound of the present invention can provide a preferred dosage level by being administered once per hour, or two, three, or more times per hour, once per day, or two, three, or more times per day, or once every 2, 3, 4, 5, 6, or 7 days. When the compound of the present invention is administered more than once a day, typical intervals include in addition to 5, 10, 15, 20, 30, 45, and 60 minutes, 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The compound of the present invention can be administered once, twice, or three times, or more, for 1 hour, 1 - 6 hours, 1 - 12 hours, 1 - 24 hours, 6 - 12 hours, 12 - 24 hours, for 1 day only, 1 - 7 days, for 1 week only, 1 - 4 weeks, for 1 month, 1 - 12 months, for more than 1 year, or even infinitely.

[0134] The composition can also include other compatible therapeutic agents. The compounds described herein can be used in combination with each other, in combination with other active agents known to be useful for altering glucocorticoid receptors, or in combination with adjuvants that may not be effective alone but may contribute to the effect of the active agent.

[0135] The compounds of the present invention can be administered simultaneously with another active agent. Simultaneous administration includes administering the compound of the present invention and the active agent to each other within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours. Simultaneous administration also includes administering the compound of the present invention and the active agent simultaneously, almost simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Furthermore, the compounds of the present invention and the active agent can be administered once a day, or twice, three times, or more times a day to provide a preferred dosage level per day.

[0136] In some embodiments, simultaneous administration can be achieved by co-formulation, i.e., by preparing a single pharmaceutical composition containing both the compound of the present invention and the active agent. In other embodiments, the compound of the present invention and the active agent can be formulated separately.

[0137] The compound of the present invention and the active agent can be present in any suitable weight ratio (about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1 (w / w), etc.) in the composition of the present invention. The compound of the present invention and other active agents can be present in any suitable weight ratio (about 1:100 (w / w), 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1, or 100:1 (w / w), etc.). Other dosages and dosage ratios of the compound of the present invention and the active agent are suitable for the compositions and methods of the present invention. VI. Method of Treatment

[0138] In some embodiments, the present invention provides a method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the nanocarrier of the present invention.

[0139] In some embodiments, the method further comprises combination therapy by using an additional agent for treating the disease. The additional agent is a therapeutic agent. Non-limiting examples of the combination therapy of the present invention include the use of the nanocarrier of the present invention and one or more additional agents.

[0140] Non-limiting examples of the combination therapy can be immunotherapy, radiotherapy, chemotherapy, molecular targeted therapy, or combinations thereof.

[0141] In some embodiments, the method further comprises one or more additional agents, which are chemotherapeutic agents, molecular targeting agents, immunotherapeutic agents, radiotherapy agents, or combinations thereof. In some embodiments, the additional agent is an immunotherapeutic agent. Immunotherapeutic agents useful in the present invention are shown above. In some embodiments, the additional agent is a radiotherapy agent. Radiotherapy agents useful in the present invention are shown above. In some embodiments, the additional agent is a chemotherapeutic agent or a molecular targeting agent. Chemotherapeutic agents and molecular targeting agents useful in the present invention are shown above.

[0142] In some embodiments, the one or more additional agents include two additional agents. In some embodiments, the additional agents are an immunotherapeutic agent and a radiotherapy agent. In some embodiments, the additional agents are an immunotherapeutic agent and a chemotherapeutic agent. In some embodiments, the additional agents are an immunotherapeutic agent and a molecular targeting agent. In some embodiments, the additional agents are a radiotherapy agent and a chemotherapeutic agent. In some embodiments, the additional agents are a radiotherapy agent and a molecular targeting agent.

[0143] In some embodiments, the additional agent is an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 regulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKT inhibitor, a JAK / STAT inhibitor, an inhibitor of checkpoint-1 or 2, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trapping antibody, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, Pemetrexed, Erlotinib, Dasatinib, Nilotinib, Decatnib, Panitumumab, Amrubicin, Oregovomab, Lep-etu, Noratrexed, azd2171, Batabulin, Ofatumumab, Zanubrutinib, Edotecarin, Tetrandrine, Rubitecan, Tesmilifene, Oblimersen, Tisilimab, Ipilimumab, Gosipol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Sirendide, Gematecan, IL13-PE38QQR; INO 1001, IPdR1 KRX-0402, Lukanton, LY 317615, Noirasib, Vitespan, Rta 744, Sdx 102, Tarpanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Liposomal Doxorubicin, 5'-Deoxy-5-fluorouridine, Vincristine, Temozolomide, ZK-304709, Seribulin; PD0325901, AZD-6244, Capecitabine, N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid disodium salt heptahydrate, Camptothecin, PEG-labeled Irinotecan, Tamoxifen, Toremifene citrate, Anastrozole, Exemestane, Letrozole, DES (Diethylstilbestrol), Estradiol, Estrogen, Conjugated Estrogen, Bevacizumab, IMC-1C11, CHIR-258); 3-[5-(Methylsulfonylpiperazinemethyl)-indolylj-quinoline, Batalanib, AG-013736, AVE-0005, Acetate of [D-Ser(Bu t) 6, Azgly 10] (Pyrro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 [C. 59 H84 N 18 O 14-(C2H4O2)X (where x=1-2.4)], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib ;Amifostine, NVP-LAQ824, suberoylanilide hydroxamate, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilben Bestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab , streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291,Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifene, Idoxifene, Spironolactone, Finasteride, Zidovudine, Trastuzumab, Denileukin diftitox, Gefitinib, Bortezomib, Paclitaxel, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab (monoclonal antibody) and Arbitux, Cremophor-free Paclitaxel, Epothilone B, BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acorifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-Hydroxyethyl)-Rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779,450, PEG-Filgrastim, darbepoetin, Erythropoietin, Granulocyte colony-stimulating factor, Zoledronate, Prednisone, Cetuximab, Granulocyte macrophage colony-stimulating factor, Histrelin, Peginterferon alpha-2a, Interferon alpha-2a, Peginterferon alpha-2b, Interferon alpha-2b, Azacitidine, PEG-L-Asparaginase, Lenalidomide, Gemtuzumab, Hydrocortisone, Interleukin-11, Dexrazoxane, Alemtuzumab, All-trans retinoic acid, Ketoconazole, Interleukin-2, Megestrol, Immunoglobulin, Nitrogen mustard, Methylprednisolone, Ibritumomab tiuxetan, Androgen, Decitabine, Hexamethylmelamine, Bexarotene, Tositumomab, Arsenic trioxide, Cortisone, Etidronate, Mitotane, Cyclosporine, Liposomal daunorubicin, Edwina-Asparaginase, Strontium 89, Casopitant, Netupitant,It is an NK-1 receptor antagonist, paroxetine, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, sspeg filgrastim, erythropoietin, epoetin alpha and darbepoetin alpha, ipilimumab, bemrafenib, or a combination thereof. In some embodiments, the additional agent is HCQ, Lys05, JQ1, rapamycin, napabucasin, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, β-lapachone, cisplatin, nimorazole, cetuximab, misonidazole, tirapazamine, daunorubicin, doxorubicin, paclitaxel, docetaxel, abraxane, bortezomib, etoposide, lenalidomide, apoptazol, carboplatin, cisplatin, oxaliplatin, vinblastine, vincristine, trastuzumab, erlotinib, imatinib, nilotinib, bemrafenib, or a combination thereof.,

[0144] Diseases treated by the method of the present invention include coronavirus, malaria, antiphospholipid antibody syndrome, lupus, rheumatoid arthritis, chronic urticaria or Sjögren's disease, and cancer (non-limiting examples thereof are carcinoma, glioma, mesothelioma, melanoma, lymphoma, leukemia, adenocarcinoma, breast cancer, ovarian cancer, cervical cancer, glioblastoma, leukemia, lymphoma, prostate cancer, and Burkitt lymphoma, head and neck cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, hepatobiliary tract cancer, gallbladder cancer, small intestine cancer, rectal cancer, kidney cancer, bladder cancer, prostate cancer, penile cancer, urethral cancer, testicular cancer, cervical cancer, vaginal cancer, uterine cancer, ovarian cancer, thyroid cancer, parathyroid cancer, adrenal cancer, pancreatic endocrine cancer, carcinoid cancer, bone cancer, skin cancer, retinoblastoma, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma (for additional cancers, see CANCER: PRINCIPLES AND PRACTICE (DeVita, V. T. et al. eds 2008))).

[0145] Other diseases that can be treated by the nanocarriers of the present invention include (1) inflammatory or allergic diseases (such as systemic anaphylaxis or hypersensitivity reactions, drug allergies, insect sting allergies, etc.); inflammatory bowel diseases (such as Crohn's disease, ulcerative colitis, ileitis, and enteritis, etc.); vaginitis; psoriasis and inflammatory skin diseases (such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, etc.); vasculitis; spondyloarthritis; scleroderma; respiratory allergic diseases (such as asthma, allergic rhinitis, hypersensitivity pneumonitis, etc.), etc., (2) autoimmune diseases (such as arthritis (rheumatoid and psoriatic), osteoarthritis, multiple sclerosis, systemic lupus erythematosus, diabetes, glomerulonephritis, etc.), etc., (3) graft rejection (including allograft rejection and graft-versus-host disease), and (4) other diseases in which an unwanted inflammatory response should be inhibited (such as atherosclerosis, myositis, neurological conditions (such as stroke and closed head injury, etc.), neurodegenerative diseases, Alzheimer's disease, encephalitis, meningitis, osteoporosis, gout, hepatitis, nephritis, sepsis, sarcoidosis, conjunctivitis, otitis media, chronic obstructive pulmonary disease, rhinosinusitis, and Behçet's syndrome).

[0146] In some embodiments, the disease is cancer. In some embodiments, the cancer is bladder cancer, brain tumor, breast cancer, cervical cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, glioblastoma, intestinal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, melanoma, myeloma, ovarian cancer, pancreatic cancer, prostate cancer, and uterine cancer. In some embodiments, the cancer is bladder cancer, brain tumor, breast cancer, cervical cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, glioblastoma, intestinal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, melanoma, myeloma, ovarian cancer, pancreatic cancer, and uterine cancer.

[0147] In some embodiments, the disease is coronavirus, malaria, antiphospholipid antibody syndrome, lupus, rheumatoid arthritis, chronic urticaria, or Sjögren's disease.

[0148] In some embodiments, the method of treating a disease comprises targeting autophagy and / or lysosomes. Targeting autophagy can result in autophagy inhibition or autophagy activation. Targeting lysosomes can result in lysosome disruption, lysosomal dysfunction, or both.

[0149] In some embodiments, the treatment targets lysosome disruption, lysosomal dysfunction, and / or autophagy inhibition. In some embodiments, the treatment targets lysosomes.

[0150] In some embodiments, the nanocarrier targets lysosome disruption, lysosomal dysfunction, and / or autophagy inhibition. In some embodiments, the nanocarrier targets lysosomes. VII. Method of Imaging

[0151] In some embodiments, the present invention provides a method of imaging comprising administering to a subject to be imaged an effective amount of the nanocarrier of the present invention.

[0152] As an imaging agent useful in the present invention, any imaging agent known to those skilled in the art is possible. Non-limiting examples of imaging agents include paramagnetic agents, optical probes, and radionuclides. A paramagnetic agent is an imaging agent that is magnetic under an externally applied field. Non-limiting examples of paramagnetic agents include iron particles containing nanoparticles. An optical probe is a fluorescent compound that can be detected by stimulating with radiation of one wavelength and detecting with radiation of a different second wavelength. Non-limiting examples of optical probes useful in the present invention include Cy5.5, Alexa 680, Cy5, DiD (1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate), and DiR (1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine iodide). Also included in other optical probes are quantum dots. A radionuclide is an element that undergoes radioactive decay. Non-limiting examples of radionuclides useful in the present invention include 3 H, 11 C, 13 N, 18 F, 19 F, 60 Co, 64 Cu, 67 Cu, 68 Ga, 82 Rb, 90 Sr, 90 Y, 99 Tc, 99m Tc, 111 In, 123 I, 124 I, 125 I, 129 I, 131 I, 137 Cs, 177 Lu, 186 Re, 188 Re, 211 At, Rn, Ra, Th, U, Pu, and 241 Am.

[0153] Non-limiting examples of imaging methods useful in the present invention include fluorescence microscopy, positron emission tomography (PET), magnetic resonance imaging (MRI), ultrasound, single photon emission computed tomography (SPECT), X-ray computed tomography (CT), echocardiography, and functional near-infrared spectroscopy. VIII. Examples Example 1: Compound

[0154] Materials and Apparatus. Chemicals (diethylenetriamine, dodecyl aldehyde, fatty alcohol, pyridinium dichromate, sodium cyanoborohydride, ammonium hydroxide solution, deuterated solvent, anhydrous solvent, and Z-Arg-Arg-AMC etc.) were purchased from Millipore-Sigma (Missouri, United States of America). 4,7-Dichloroquinoline, anhydrous sulfate, and bulk solvents were purchased from Fisher Scientific (Massachusetts, United States of America). All solvents were used directly without further purification. Water used in all experiments was purified by a Mill-Q filtration system. Other reagents or drugs were purchased as shown below: tridecanal (Alfa Aesar), HCQ (Specturm), Lys05 (MedchemExpress), bortezomib (eNovation chemical), DiD perchlorate and β-lapachone (Tocris Bioscience), JQ1 and napabucasin (ApExBIO), rapamycin, paclitaxel, and vinblastine (LC Laboratory), CN38 (Acros Organics), etoposide (AdipoGen), lenalidomide (Matrix Scientific), napabucasin (ApExBIO), and apoptazol (Selleck). Lysosome enrichment kit, LysoTracker (Red & Green), acridine orange, Dextran-Alexa Fluor 488, Premo™ autophagy sensor LC3B-GFP were purchased from Thermo Fisher (MA, United States of America). SensoLyte® homogeneous AMC caspase-3 / 7 assay kit and FITC-Annexin V / PI apoptosis kit were purchased from AnaSpec (California, United States of America) and Biolegend (California, United States of America), respectively. Compounds were characterized by a 600 MHz NMR spectrometer (Bruker, Germany) for NMR spectra and an LTQ-Orbitrap XL hybrid ion trap mass analyzer (Thermo Fisher, Massachusetts, United States of America) for ESI-HRMS spectra.Cell imaging studies were performed using a fluorescence microscope (Olympus, Tokyo, Japan) or an LSM800 confocal microscope (Carl Zeiss, Oberkochen, Germany). Absorbance and fluorescence intensity were determined using a SpectraMax M2 microplate reader (Molecular Devices, California, USA). Western blot was developed using a Power Pac 200 electrophoresis apparatus (Bio-Rad, California, USA). Studies including WB imaging, in vivo and in vitro fluorescence imaging were performed using a ChemiDocTM MP imaging system (Bio-Rad, California, USA). DLS experiments were performed using a Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK). TEM was performed using a Talos L120C TEM (FEI, Oregon, USA) with an acceleration voltage of 80 kV. Apoptosis assays were performed using a BD FACSCanto II flow cytometer (BD Biosciences, New Jersey, USA). Isolation of cancer stem cells was performed using a BD FACSAria II cell sorter (BD Biosciences, New Jersey, USA). Matrigel for 3D culture (Cat# 354230) and establishment of xenograft models (Cat# 354234) were both purchased from Corning (New York, USA). LC3B antibody (1:1000, catalog #2775), SQSTM1 / p62 antibody (1:1000, catalog #39749), and β-actin antibody (1:1000, catalog:#4970) were purchased from Cell Signaling, and Pacific Blue anti-CD44 antibody (5 μL per million cells in a 100 μL chromosome product, catalog #338823); APC anti-CD326 (EpCAM) antibody (5 μL per million cells in a 100 μL chromosome product, catalog #324207); PE / Cy7 anti-CD24 antibody (5 μL per million cells in a 100 μL chromosome product, catalog #311119) were obtained from Biolegend. [Chemical formula]

[0155] Synthesis of O-methyl-serine-dodecylamide hydrochloride (MSDH). MSDH was synthesized according to the published literature (Bioorg. Med. Chem. Lett. 1995, 5, 893 - 898). 1 H NMR (600 MHz, CDCl3): δ 7.40 (s, 1 H), 3.63 (m, 1 H), 3.58 (m, 2 H), 3.70 (s, 3 H), 3.26 (m, 2 H), 1.74 (s, 2 H), 1.51 (m, 2 H), 1.29 (m, 18 H), 0.89 (t, 3 H, J = 7.2 Hz). ESI-HRMS:C 16 H 35 N2O2 + for m / z [M + H] + calculated value 287.2693, measured value 287.2690. [Chemical formula]

[0156] Synthesis of BAQ. 4,7-Dichloroquinoline (1.2 g, 6.00 mmol) was maintained at 80 °C for 2 hours without stirring in a 10 mL flask, and then diethylenetriamine (0.22 mL, 2.00 mmol) was added. The reaction solution was stirred at 130 °C for 6 hours. The residue was collected using 30 mL of methanol, and a white solid was obtained as the BAQ compound. Yield, yield rate: 470 mg, 55%. 1 H NMR (600 MHz, DMSO-d6): δ 8.38 (d, 2 H, J = 6.0 Hz), 8.23 (d, 2 H, J = 10.8 Hz), 7.78 (d, 2 H, J = 1.8 Hz), 7.42 (dd, 2 H, J1 = 10.8 Hz, J2 = 2.4 Hz), 7.25 (s, 1 H), 6.51 (d, 2 H, J = 6.6 Hz), 3.40 (t, 4 H, J = 7.2 Hz), 2.94 (t, 4 H, J = 7.8 Hz). ESI-HRMS:C22 H 22 Cl2N5 + Regarding the m / z [M+H] + Calculated value 426.1247, measured value 426.1243.

[0157] General synthetic method for BAQ12 - 18. To a solution of BAQ (426 mg, 1.0 mmol) dissolved in 30 mL of anhydrous methanol and 10 mL of anhydrous dichloromethane, the corresponding aldehyde (2 mmol) and acetic acid (20 μL) were added. After stirring at room temperature for 20 minutes, sodium cyanoborohydride (126 mg, 2 mmol) was then added. The mixture was stirred for 12 hours and diluted with chloroform (100 mL). The organic phase was recovered, washed with water, and dried over anhydrous sodium sulfate overnight. The crude product was purified by silica gel chromatography using an eluent containing 0.1% triethylamine (dichloromethane:methanol = 30:1 - 10:1) to obtain the corresponding compound.

Chemical formula

[0158] BAQ12. Yield, percentage yield: 320 mg, 53.8%. 1 H NMR (600 MHz, CD3OD): δ 8.27 (d, 2 H, J = 5.4 Hz), 7.67 (d, 2 H, J = 2.4 Hz), 7.55 (d, 2 H, J = 9.0 Hz), 6.95 (dd, 2 H, J1 = 9.0 Hz, J2 = 1.8 Hz), 6.46 (d, 2 H, J = 5.4 Hz), 3.41 (t, 4 H, J = 6.0 Hz), 2.90 (t, 4 H, J = 6.0 Hz), 2.66 (t, 2 H, J = 6.6 Hz), 1.55 (m, 2 H), 1.33 (m, 20 H), 0.91 (t, 3 H, J = 7.2 Hz). 1313C NMR (150 MHz, CD3OD): δ 150.9, 150.8, 147.9, 134.8, 126.3, 124.4, 121.9, 117.0, 98.4, 54.1, 51.9, 40.3, 31.6, 29.5, 29.5, 29.4, 29.4, 29.1, 27.4, 27.3, 22.4, 13.1. ESI-HRMS: C 34 H 46 Cl2N5 + for m / z [M+H] + calculated value 594.3125, measured value 594.3134.

[0159] BAQ13. Yield: 350 mg, 57.5%. 1 1H NMR (600 MHz, CD3OD): δ 8.27 (d, 2 H, J = 5.4 Hz), 7.67 (d, 2 H, J = 1.8 Hz), 7.56 (d, 2 H, J = 9.0 Hz), 6.96 (dd, 2 H, J1 = 9.0 Hz, J2 = 2.4 Hz), 6.46 (d, 2 H, J = 5.4 Hz), 3.42 (t, 4 H, J = 6.0 Hz), 2.90 (t, 4 H, J = 6.0 Hz), 2.66 (t, 2 H, J = 7.2 Hz), 1.56 (m, 2 H), 1.32 (m, 23 H), 0.92 (t, 3 H, J = 7.2 Hz). 13 13C NMR (150 MHz, CD3OD): δ 151.0, 150.7, 147.8, 134.8, 126.1, 124.5, 121.9, 117.0, 98.4, 54.6, 51.9, 40.3, 31.7, 29.5, 29.5, 29.5, 29.4, 29.1, 27.4, 27.3, 22.3, 13.1. ESI-HRMS: C 35 H 48 Cl2N5 + for m / z [M+H] + calculated value 608.3281, measured value 608.3274.

[0160] BAQ14. Yield: 295 mg, 47.4%. 11H NMR (600 MHz, CD3OD): δ 8.56 (d, 2 H, J = 9.0 Hz), 8.48 (d, 2 H, J = 4.8 Hz), 7.86 (d, 2 H, J = 1.2 Hz), 7.60 (dd, 2 H, J1 = 9.0 Hz, J2 = 1.2 Hz), 7.06 (d, 2 H, J = 5.4 Hz), 4.16 (s, 4 H), 3.82 (s, 4 H), 3.48 (s, 2 H), 1.92 (s, 2 H), 1.44 (s, 2 H), 1.35 (m, 23 H), 0.93 (t, 3 H, J = 6.6 Hz). 13 13C NMR (150 MHz, CD3OD): δ 155.9, 143.0, 139.8, 138.2, 127.4, 125.3, 118.7, 115.5, 98.9, 54.6, 51.1, 38.3, 31.5, 29.2, 29.2, 29.2, 29.2, 29.1, 29.0, 28.9, 28.7, 26.1, 23.0, 22.2, 12.9. ESI-HRMS: C 36 H 50 Cl2N5 + for m / z [M + H] + calculated value 622.3438, measured value 622.3505.

[0161] BAQ15. Yield: 290 mg, 45.5%. 1 1H NMR (600 MHz, CD3OD): δ 8.56 (d, 2 H, J = 9.0 Hz), 8.48 (d, 2 H, J = 6.0 Hz), 7.86 (d, 2 H, J = 1.2 Hz), 7.59 (dd, 2 H, J1 = 9.0 Hz, J2 = 1.2 Hz), 7.07 (d, 2 H, J = 6.0 Hz), 4.16 (s, 4 H), 3.82 (s, 4 H), 3.48 (s, 2 H), 1.92 (s, 2 H), 1.44 (s, 2 H), 1.35 (m, 25 H), 0.93 (t, 3 H, J = 6.6 Hz). 1313C NMR (150 MHz, CD3OD): δ 155.8, 143.0, 139.7, 138.1, 127.3, 125.3, 118.7, 115.4, 98.9, 54.5, 51.0, 38.2, 31.5, 29.2, 29.2, 29.2, 29.1, 29.0, 28.9, 28.7, 26.1, 23.0, 22.2, 12.9. ESI-HRMS: C 37 H 52 Cl2N5 + for m / z [M+H] + calculated value 636.3594, measured value 636.3661.

[0162] BAQ16. Yield, percentage yield: 280 mg, 43.0%. 1 1H NMR (600 MHz, CD3OD): δ 8.56 (d, 2 H, J = 9.0 Hz), 8.48 (d, 2 H, J = 6.6 Hz), 7.86 (d, 2 H, J = 1.8 Hz), 7.59 (dd, 2 H, J1 = 9.0 Hz, J2 = 1.8 Hz), 7.07 (d, 2 H, J = 7.2 Hz), 4.17 (m, 4 H), 3.84 (m, 4 H), 3.50 (t, 2 H, J = 7.8 Hz), 1.92 (m, 2 H), 1.44 (m, 2 H), 1.30 (m, 27 H), 0.93 (t, 3 H, J = 7.2 Hz). 13 13C NMR (150 MHz, CD3OD): δ 155.9, 143.0, 139.7, 138.1, 127.3, 125.2, 118.7, 115.4, 98.8, 54.5, 51.0, 38.2, 31.5, 29.2, 29.2, 29.2, 29.1, 28.9, 28.9, 28.7, 26.1, 23.0, 22.1, 12.9. ESI-HRMS: C 38 H 54 Cl2N5 + for m / z [M+H] + calculated value 650.3751, measured value 650.3774.

[0163] BAQ18. Yield, percentage yield: 290 mg, 42.7%. 11H NMR (600 MHz, CD3OD): δ 8.56 (d, 2 H, J = 9.0 Hz), 8.48 (d, 2 H, J = 5.4 Hz), 7.86 (s, 2 H, J = 1.8 Hz), 7.56 (d, 2 H, J1 = 8.4 Hz), 7.06 (d, 2 H, J = 6.6 Hz), 4.16 (s, 4 H), 3.82 (m, 4 H), 3.48 (s, 2 H), 1.91 (s, 2 H), 1.43 (m, 2 H), 1.30 (m, 29 H), 0.93 (s, 3 H). 13 13C NMR (150 MHz, CD3OD): δ 155.9, 143.0, 139.8, 138.2, 127.4, 125.2, 118.7, 115.5, 98.8, 54.5, 51.1, 38.2, 31.5, 29.2, 29.1, 28.9, 28.9, 28.7, 26.1, 23.0, 22.2, 12.9. ESI-HRMS: C 38 H 54 Cl2N5 + for m / z [M + H] + calculated value 650.3751, measured value 650.3774. ESI-HRMS: C 40 H 56 Cl2N5 + for m / z [M + H] + calculated value 678.4064, measured value 678.4069.

Chemical Structure

[0164] Synthesis of Compound 1. Ethylene N-carboethoxyphthalimide (2.34 g, 10.7 mmol, 1.00 equivalent) and triethylamine (1.49 mL, 10.7 mmol, 1.00 equivalent) were added to a solution of 4,4-diethoxybutylamine (1.84 mL, 10.7 mmol, 1.00 equivalent) dissolved in THF (30 mL). The resulting reaction mixture was stirred at room temperature for 12 hours. After removing the solvent under reduced pressure, the obtained crude material was purified by silica column chromatography eluting with 1:20 EtOAc:hexane to give a clear oil. (2.9 g, 94.0 mmol, 93% yield). 11H NMR (600 MHz, DMSO-d6) δ 7.87 - 7.83 (m, 4H), 4.47 (t, J = 5.4 Hz, 1H), 3.58 - 3.51 (m, 4H), 3.43 - 3.38 (m, 2H), 1.61 - 1.60 (m, 2H), 1.54 - 1.51 (m, 2H). ESI-HRMS m / z 314.1361 [M+Na] + .

Chem.

[0165] Synthesis of Compound 2. A solution of Compound 1 (2.2 g, 7.6 mmol, 1.00 equiv) dissolved in acetone (20 mL) and 1 M aqueous HCl (15.2 mL, 15.2 mmol, 2.00 equiv) was refluxed (80 °C) and vigorously stirred for 1 hour. Acetone was evaporated under reduced pressure, and the resulting aqueous layer was extracted three times with Et2O. The combined organic layers were washed once with water, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and purified by column chromatography eluting with 1:2 EtOAc:hexane to give a waxy white solid. (1.2 g, 74% yield). 1 1H NMR (600 MHz, DMSO-d6) δ 9.64 (t, J = 1.2 Hz, 1H, NH2), 7.88 - 7.83 (m, 4H), 3.61 (t, J = 7.2 Hz, 2H), 2.54 - 2.51 (m, 2H), 1.85 - 1.83 (m, 2H).

Chem.

[0166] Synthesis of BAQ4q. To a solution of BAQ (426.5 mg, 1.0 mmol, 1.00 equiv) dissolved in methanol (40 mL), compound 2 (434 mg, 2 mmol, 2.0 equiv) and acetic acid (10 μL) were added, and the mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (126 mg, 2 mmol, 2 equiv) was slowly added and the mixture was stirred for 24 hours. The reaction solution was diluted with dichloromethane (150 mL), then washed with saturated sodium carbonate, water, and brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the mixture was purified by silica chromatography eluting with 20:1 dichloromethane:methanol to give a white solid. (520 mg, 83% yield). 1 H NMR (600 MHz, DMSO-d6) δ 8.27 (d, J = 5.4 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H), 7.78 (s, 4H), 7.67 (d, J = 2.4 Hz, 2H), 7.19 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 2H), 7.09 (m, 2H), 6.39 (d, J = 6.0 Hz, 2H), 3.51 (t, J = 7.2 Hz, 2H), 3.31 (t, J = 6.0 Hz, 4H), 2.77 (t, J = 6.6 Hz, 4H), 2.58 (t, J = 6.6 Hz, 2H), 1.60 - 1.55 (m, 2H), 1.45 - 1.40 (m, 2H). ESI-HRMS 627.2035 [M+H] + . [Chemical formula]

[0167] Synthesis of BAQ4a. BAQ4q (314 mg, 0.5 mmol, 1.0 equivalent) was dissolved in ethanol, and hydrazine (2.5 mmol, 5.0 equivalents) was added. Then, the reaction solution was refluxed and stirred for 12 hours. After that, the reaction mixture was left to come to room temperature. The precipitate was removed by filtration, and the filtrate was concentrated and then added to ether (100 mL), resulting in the formation of a white precipitate, which was recovered as Compound 5 (200 mg, yield 80%). 1 H NMR 8.30 (d, J = 5.4 Hz, 2H), 8.03 (d, J = 9.6 Hz, 2H), 7.78 (s, 4H), 7.71 (d, J = 2.4 Hz, 2H), 7.27 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 2H), 7.05 (t, J = 5.4 Hz, 2H), 6.40 (d, J = 5.4 Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 3.31 (t, J = 6.0 Hz, 4H), 2.78 (t, J = 7.2 Hz, 4H), 2.54 (t, J = 7.2 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 1.41 - 1.38 (m, 2H), 1.29 - 1.26 (m, 2H). ESI - HRMS 497.1981 [M + H] + .

Chemical Structure

[0168] Synthesis of PBC. Pheophorbide a (296 mg, 0.5 mmol, 1.0 equiv), 6-chloro-1-hydroxybenzotriazole (102 mg, 0.6 mmol, 1.2 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (93 mg, 0.6 mmol, 1.2 equiv), and N,N-diisopropylethylamine (174 μL, 1.0 mmol, 2 equiv) were suspended in anhydrous dichloromethane (75 mL) and stirred at room temperature for 30 min. Compound 5 (314 mg, 0.5 mmol, 1.0 equiv) was added to this reaction mixture and then stirred for 48 h. The mixture was purified by silica chromatography eluting with 20:1 dichloromethane:methanol to give a black solid (200 mg, 37% yield). 11H NMR (600 MHz, CD3OD) δ 8.94 (s, 1H), 8.78 (s, 1H), 8.58 (s, 1H), 7.86 (dd, J1 = 6.0 Hz, J2 = 3.6 Hz, 2H), 7.86 (dd, J1 = 6.0 Hz, J2 = 3.6 Hz, 2H), 7.81 (dd, J1 = 18.0 Hz, J2 = 11.4 Hz, 2H), 7.63 (m, 1H), 7.54 (d, J = 6.0 Hz, 2H), 7.18 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 1H), 6.88 (m, 2H), 6.55 (d, J = 8.4 Hz, 2H), 6.22 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 2H), 6.17 (d, J = 18.0 Hz, 1H), 6.10 (d, J = 11.4 Hz, 1H), 5.55 (d, J = 18.0 Hz, 1H), 4.52 - 4.51 (m, 1H), 4.15 - 4.14 (m, 1H), 3.88 (s, 3H), 3.72 - 3.67 (m, 2H), 3.30 (s, 3H), 3.2 (q, J2 = 7.2 Hz, 4H, triethylamine), 2.89 (m, 1H), 2.80 (s, 3H), 2.75 (m, 1H), 2.63 - 2.61 (m, 2H), 2.56 - 2.53 (m, 1H), 2.50 - 2.43 (m, 4H), 2.3 - 2.16 (m, 8H), 1.94 (s, 1H), 1.82 (d, J = 7.2 Hz, 3H), 1.47 (t, J = 7.8 Hz, 3H), 1.35 (m, 10H + 6H triethylamine), 1.11 (m, 4H). ESI-HRMS 1071.4576 [M+H] + 。

Chem.

[0169] Synthesis of CAB. Cholic acid (204 mg, 0.5 mmol, 1.0 equiv), 6-chloro-1-hydroxybenzotriazole (102 mg, 0.6 mmol, 1.2 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (93 mg, 0.6 mmol, 1.2 equiv), and N,N-diisopropylethylamine (174 μL, 1.0 mmol, 2 equiv) were suspended in anhydrous dichloromethane (75 mL) and stirred at room temperature for 30 minutes. After adding BAQ4a (314 mg, 0.5 mmol, 1.0 equiv) to this reaction mixture, it was stirred for 48 hours. The mixture was purified by silica chromatography eluting with 20:1 dichloromethane:methanol to give a black solid. (220 mg, 49.5% yield). ESI-HRMS 887.4774 [M+H] + . [Chemical formula]

[0170] Synthesis of BAQ5h. To a solution of BAQ (426.5 mg, 1.0 mmol, 1.00 equiv) dissolved in methanol (40 mL), glutaric dialdehyde (211 μL, 2.0 mmol, 2.00 equiv) and acetic acid (10 μL) were added and stirred at room temperature for 30 minutes. Sodium cyanoborohydride (126 mg, 2 mmol, 2 equiv) was added slowly and stirred for 24 hours. After diluting this reaction solution with dichloromethane (150 mL), it was washed with saturated sodium carbonate, water, and brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the mixture was purified by silica chromatography eluting with 20:1 dichloromethane:methanol to give a white solid. (520 mg, 83% yield). 11H NMR (600 MHz, CD3OD) δ 8.23 (d, J = 5.4 Hz, 2H), 7.60 - 7.56 (m, 4H), 7.02 (dd, J1 = 9.0 Hz, J2 = 1.8 Hz, 2H), 6.44 (t, J = 5.4 Hz, 2H), 3.58 (t, J = 6.6 Hz, 2H), 3.42 (t, J = 5.4 Hz, 4H), 2.91 (t, J = 6.0 Hz, 4H), 2.75 - 2.72 (m, 2H), 1.66 - 1.57 (m, 4H), 1.51 - 1.47 (m, 2H). ESI - HRMS 512.1961 [M + H] + .

Chem.

[0171] Synthesis of DCQO. 4,7 - Dichloroquinoline (DCQ) (2 g, 10 mmol) was dissolved in 50 mL and stirred vigorously (500 rmp) for 15 minutes over an ice - water bath. mCPBA (2.7 g, 12 mmol) was carefully added to the reaction solution in the bath (4 times). The resulting reaction mixture was stirred at room temperature for 12 hours (500 rpm). TLC showed that the starting material was completely converted into one major spot. Dichloromethane (100 mL) and potassium carbonate (4.1 g, 30 mmol) were added to this reaction solution and stirred at room temperature for 1 hour (300 rpm). This mixture was poured into a 500 mL beaker with 200 mL of water and stirred for an additional 1 hour (300 rpm). (The organic phase was recovered, washed with saturated sodium carbonate (75 mL×3), water (75 mL×3), brine (75 mL×3) respectively, and dried overnight using anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained crude material was recrystallized with 80 mL of acetonitrile. After filtering and recovering the obtained solid product, and drying it under vacuum, 1.8 g of DCQO was obtained as a white solid.) 1HNMR (600 MHz, CDCl3) δ 8.79 (d, J = 1.8 Hz, 2 H), 8.44 (d, J = 6.6 Hz, 2 H), 8.44 (d, J = 8.4 Hz, 2 H), 7.71 (d, J1 = 9.0 Hz, J2 = 2.4 Hz, 2 H), 7.38 (d, J = 6.0 Hz, 2 H). HRMS (ESI): C9H6Cl2NO [M + H] + Calculated m / z for + 213.9821, found 213.9834. [Chemical Structure]

[0172] Synthesis of BAQO. To a solution of DCQO (2.14 g, 10 mmol) dissolved in 30 mL of anhydrous ethanol, sodium bicarbonate (840 mg, 10 mmol) and diethylenetriamine (432 μL, 4 mmol) were added. The mixture was refluxed at 95 °C for 48 h. TLC was used to indicate the formation of the target material (TM, yellow spot). Ethanol was evaporated under reduced pressure, and the residue was resuspended in 30 mL of methanol, which was slowly added dropwise into a 300 mL beaker together with a mixed solution of 100 mL of hydrochloric acid (1 M) and 50 mL of dichloromethane. The aqueous phase was collected, washed with dichloromethane (50 mL × 2), and alkalized with 10 M NaOH (12 mL) to pH 10, resulting in the formation of a yellow precipitate. This precipitate was collected, washed with water (30 mL × 3), and dried under vacuum to obtain 850 mg of BAQO as a yellow solid. 1 HNMR (600 MHz, CD3OD) δ 8.51 (d, J = 1.8 Hz, 2H), 8.35 (d, J = 7.2 Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 7.55 (d, J1 = 9.0 Hz, J2 = 2.4 Hz, 2H), 6.63 (d, J = 7.2 Hz, 2H), 3.58 (t, J = 6.0 Hz, 4H), 2.94 (t, J = 6.0 Hz, 4H). HRMS (ESI): C 22 H 22 Cl2N5O2 [M + H]+ Calculated m / z value: 458.1145, measured value: 458.1126 for

Chemical formula

[0173] Synthesis of BAQ12O. A mixture of BAQO (916 mg, 2 mmol), dodecyl aldehyde (1.8 mL, 8 mmol), and acetic acid (20 μL) was vigorously stirred at room temperature for 30 minutes (500 rpm). Then sodium cyanoborohydride (377 mg, 6 mmol) was added slowly. The reaction mixture was stirred at room temperature for an additional 12 hours. TLC indicated that the starting material was completely converted into one major spot. After concentrating the solvent to 25 mL, the resulting residue was diluted with 75 ml of dichloromethane. The organic phase was washed three times with 100 mL of saturated sodium bicarbonate. After collecting the emulsion layer and filtering, a yellow solid was obtained, which was washed with water (30 mL × 3) and ethyl ether (30 mL × 3). The recovered yellow solid was dried under vacuum to obtain 1.2 g of BAQ12O. 1 HNMR (CD3OD, 600MHz) δ 8.43 (d, J = 1.8 Hz, 2H), 8.31 (d, J = 7.2 Hz, 2H), 7.82 (d, J = 9.0 Hz, 2H), 7.31 (d, J1 = 9.0 Hz, J2 = 2.4 Hz, 2H), 6.56 (d, J = 7.2 Hz, 2H), 3.50 (t, J = 6.0 Hz, 4H), 2.94 (t, J = 6.0 Hz, 4H), 2.71 (t, J = 7.2 Hz, 2H), 1.55 (m, 2H), 1.32 (m, 18H), 0.92 (t, J1 = 6.6 Hz, 3H). CNMR (CD3OD, 150MHz) δ 148.0, 140.1, 139.9, 138.4, 127.6, 123.9, 118.7, 117.9, 98.09, 54.9, 52.3, 41.5, 32.4, 30.2, 30.1, 30.1, 29.8, 28.1, 27.7, 23.1, 13.8. HRMS (ESI):C 34 H 46 Cl2 Calculated m / z value for N5O2[M+H]+: 626.3023, measured value: 626.3060.

Chem.

[0174] Synthesis of BAQ1O. This compound was prepared using the method of BAQ12O. Formaldehyde was used as the starting material. ESI-HRMS 472.1325 [M+H] + 。

Chem.

[0175] Synthesis of BAQAO. 5 mL of acetic anhydride containing BAQO (229 mg, 0.5 mmol) was refluxed for 6 hours. The excess acetic anhydride was removed under reduced pressure. The residue was taken up in cold diethyl ether to give a yellow solid as the product (180 mg). ESI-HRMS 500.1246 [M+H] + 。

Chem.

[0176] Synthesis of BAQ5hO. This compound was prepared using the method of BAQ5h. BAQO was used as the starting material. ESI-HRMS 544.1870 [M+H] + 。

Chem.

[0177] Synthesis of BAQ4qO. This compound was prepared using the method of BAQ4q. BAQO was used as the starting material. ESI-HRMS 659.1946 [M+H] + 。

Chem.

[0178] Synthesis of BAQ4aO. This compound was prepared using the method of BAQ4a. BAQ4qO was used as the starting material. ESI-HRMS 529.1884 [M+H] + 。

Chemical Structure

[0179] Synthesis of BAQ13O. This compound was prepared using the method of BAQ12O. Tridecanal was used as the starting material. 1 HNMR (800 MHz, DMSO-d6) δ 9.79 (s, 2 H), 8.91 (d, J = 7.2 Hz, 2H), 8.78 (d, J = 9.6 Hz, 2 H), 8.16 (d, J = 1.6 Hz, 2H), 7.80 (dd, J1 = 9.6 Hz, J1 = 1.8 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 4.04 (s, 4H), 3.68 - 3.62 (m, 6 H), 1.70 (s, 2 H), 1.27 - 1.17 (m, 21H), 0.87 (t, J = 7.2 Hz, 3H).

[0180] Synthesis of BAQ14O. This compound was prepared using the method of BAQ12O. Tetradecanal was used as the starting material. 1 HNMR (800 MHz, DMSO-d6) δ 9.62 (s, 2 H), 8.88 (d, J = 8.0Hz, 2H), 8.70 (d, J = 9.6Hz, 2 H), 8.15 (d, J = 2.4 Hz, 2H), 7.77 (dd, J1 = 8.8 Hz, J1 = 1.6 Hz, 2H), 6.95 (d, J = 7.2 Hz, 2H), 4.02 (s, 4H), 3.68 - 3.62 (m, 6 H), 1.68 (s, 2 H), 1.27 - 1.15 (m, 23H), 0.86 (t, J = 5.4 Hz, 3H).

[0181] Synthesis of BAQ15O. This compound was prepared using the method of BAQ12O. Pentadecanal was used as the starting material.1 1H NMR (800 MHz, DMSO-d6) δ 9.63 (s, 2 H), 8.88 (d, J = 8.0 Hz, 2H), 8.70 (d, J = 8.8 Hz, 2 H), 8.15 (d, J = 2.4 Hz, 2H), 7.77 (dd, J1 = 8.8 Hz, J1 = 1.6 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.01 (s, 4H), 3.68 - 3.62 (m, 6H), 1.68 (s, 2H), 1.28 - 1.15 (m, 25H), 0.86 (t, J = 5.4 Hz, 3H).

[0182] Synthesis of BAQ16O and BAQ18O. This compound was prepared using the method of BAQ12O. Hexadecanal was used as the starting material for BAQ16O, and octadecanal was used as the starting material for BAQ18O.

[0183] Additional BAQO derivatives can be prepared using the method of BAQ12O with appropriate aldehyde starting materials and ketone starting materials. Example 2: Nanocarrier

[0184] Preparation and characterization of BAQ ONN. NPs were prepared through the reprecipitation method. Methanol containing the BAQ derivative was added dropwise to MilliQ water while stirring for 5 minutes (volume ratio, 1:10), and uniform NPs were obtained after rotary evaporation (40 °C, 20 minutes), and then characterized using a Zetasizer Nano ZS (Malvern). A 0.5 mM NP was dropped onto a carbon square mesh and allowed to dry naturally to prepare a TEM sample, which was then observed with a Talos L120C TEM (FEI) at an acceleration voltage of 80 kV. To determine the drug content in the nanopharmaceutical, the prepared drug-loaded NPs were cut by a centrifugal filter (ultracel-10 kDa, Millipore), and the absorbance of the filtrate (diluted with DMSO, 1:10, volume ratio) was measured to calculate the drug concentration.

[0185] Discovery of BAQ derivatives as potential ONNs. BAQ12 - BAQ18 were designed by hybridization of the key structural elements of the lysosome - acting autophagy inhibitor Lys05 and the lysosome - acting detergent MSDH to achieve pharmacological integration (Figure 1). Based on the self - assembly principle, it was predicted that the head of the BAQ with a long hydrophobic tail containing a cationic BAQ head would promote the formation of nanoparticles (NPs). Since the BAQ head has a calculated pKa of 8.4, this self - assembly should be dependent on the surrounding pH, with NPs formed under neutral conditions and dissociating into free building blocks after protonation in an acidic environment.

[0186] The compounds (BAQ12 - BAQ18) were synthesized, 1 1H NMR, 13The structure was confirmed by 13C NMR and HRMS spectra (Figure 7). Unlike Lys05 and MSDH, BAQ12–BAQ18 could not be completely dissolved in water in the form of free base or hydrochloride. However, the lipophilic cation enabled spontaneous self-assembly through nano-precipitation in water, resulting in a uniform and opaque NP solution. The aggregated NPs of BAQ12–BAQ18 had similar nano-scale characteristics (the characteristics include their size (100–140 nm), a polydispersity index (PDI) value of less than 0.1, and a positive surface charge (about +40 mV)) (Table 1 and Figure 8A). Subsequently, the behavior of pH-responsive dissociation was evaluated by monitoring the particle size change (Figure 2A). All BAQ NPs were intact under near-neutral conditions and dissociated only under relatively acidic conditions. The critical dissociation pH was 5.5–6.0 for BAQ12–BAQ14 and 5.0–5.5 for BAQ15–BAQ18. Upon protonation in an acidic environment, the BAQ12–BAQ18 lipophilic cations became amphiphilic molecules and acquired surface activity. Subsequently, a hemolysis test was used to evaluate the pH-responsive biomembrane disruption ability of the compounds. None of the NPs had a hemolytic effect under almost neutral conditions (pH 6.5 or higher), but hemolysis induction began when the pH was less than 6.0 (Figure 2B and Figure 8B). Among the compounds, BAQ12 NP and BAQ13 NP showed the strongest hemolytic activity, inducing up to 90% hemolysis under simulated lysosomal conditions (pH 4.0–5.5); in contrast, BAQ14 NP induced moderate hemolysis (70%), and only BAQ15–BAQ18 NPs caused about 50% hemolysis. In the control group, the conventional lysosomal detergent MSDH showed only a weak hemolytic response to pH, and Lys05 without detergent did not induce observable hemolysis throughout the pH range at the same concentration. Since LMP is a potential stimulus for apoptosis, BAQ12 and BAQ13 (whose detergents may be activated within liposomes) may be effective in directly inducing cancer cell death.Furthermore, when titrated with hydrochloride (HCl), BAQ12 NP and BAQ13 NP showed a distinct pH plateau within a narrow pH range (around pH 6.0), indicating their strong pH buffering capacity (Figure 2C). In contrast, the pH values of the other NPs (BAQ14 - BAQ18) decreased proportionally, with only short pH plateaus observed at Lys05 (pH 7.2) and MSDH (pH 6.2). Since sufficient acidification is required for lysosomal degradation, the strong H. + BAQ12 and BAQ13, which have buffering capacity, showed greater potential than other compounds in inducing lysosomal dysfunction. Therefore, BAQ12 and BAQ13 may have the potential to weaken the growth of tumor cells.

Table 1

[0187] To verify the therapeutic effects of BAQ12 - BAQ18, a preliminary screening was performed using the MTS assay in various cancer cell lines. These derivatives showed different levels of anti - proliferative effects within 24 hours after treatment. BAQ12 and BAQ13 were very effective, showing potencies approximately 3 - fold, 20 - fold, and 10 - fold higher than Lys05, HCQ, and MSDH, respectively. However, the activity steadily decreased as the hydrophobic tail extended from 14 to 18 carbons (Table 1 and Figure 8C). This decrease was due to the gradual decline in the washing ability and H + buffering capacity of the compounds. Based on the above results, BAQ12 and BAQ13 were selected as representatives for constructing BAQ ONN in the following studies.

[0188] pH-responsive assembly and large drug-loading capacity. The dissociation phase transition of the pH-responsive assembly of BAQ ONN was subsequently revealed by transmission electron microscopy (TEM). At pH 7.4, the NPs showed a strong Tyndall effect and exhibited a liposome-like nanostructure with a diameter of approximately 100 nm and a bilayer thickness of approximately 5 nm (Figure 2D). These results were consistent with dynamic light scattering (DLS) measurements. In contrast, at pH 5.0, the solution lost its Tyndall effect and vesicles were absent under TEM, demonstrating that the NPs dissociated under this condition (Figure 2E). Subsequently, the behavior of BAQ ONN release at physiological pH (7.4) and lysosomal pH (5.0) was investigated. As shown in Figure 2F, BAQ12 NPs and BAQ13 NPs were almost completely released (approximately 90%) over 8 hours at pH 5.0, while only approximately 10% of the drug was released over 24 hours under neutral conditions. Considering that lysosomes maintain a pH in the range of 4.0 - 5.5, it is thought that BAQ ONN dissociates upon reaching these compartments and enters into the released small molecules, thus exerting a therapeutic effect. The critical aggregation concentrations (CACs) of BAQ12 NPs and BAQ13 NPs were measured to be 0.76 μM and 0.25 μM, respectively (Figure 2G). The three-fold difference observed between these indicated that BAQ13 could form NPs more readily than BAQ12, despite the difference in their molecular structures being only one methylene unit. The two NPs also showed sufficient stability in particle size over a relatively long period at room temperature even in the presence of 10% serum or 0.5 mM bovine serum albumin (Figures 9A - 9F). In addition, BAQ13 NPs showed greater stability than BAQ12 NPs during such long-term storage. This is likely due to the difference in their CACs.

[0189] The following study was to determine whether liposome-like BAQ ONN could encapsulate additional agents. When BAQ13 and various agents were nano-precipitated, uniform NPs with a unimodal size distribution were spontaneously formed (Table 2 and Figure 9G). BAQ13 NPs showed a large drug loading capacity (up to 50%, mass ratio) and an approximately 90% drug encapsulation efficiency (Table 2). This indicated that BAQ13 NPs could overcome the drug loading limitations of conventional liposome-based drug delivery systems and polymer-based drug delivery systems. It is very encouraging that these single NPs consisting of a single small molecule therapeutic substance exhibit such a strong drug loading capacity.

Table 2

[0190] Accumulation in lysosomes and lysosome disruption. To verify the accumulation of BAQ ONN in lysosomes, the near-infrared fluorescent dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine (DiD) was loaded for labeling and tracking. As expected, the lysosomal puncta (green) in MIA PaCa-2 cells stained with Dextran-Alexa Fluor 488 (AF488) overlapped precisely with the NPs labeled with DiD (red). This suggested that BAQ ONN was rapidly taken up by the cells and accumulated in the lysosomes (Figure 3A and Figure 10A). When this accumulation occurred, BAQ ONN decreased the LysoTracker-positive puncta, indicating the ability of BAQ ONN to deacidify lysosomes similar to Lys05 and MSDH (Figure 3B and Figure 10B - 10C).

[0191] The induction of LMP by BAQ12 and BAQ13 was examined by staining live cells with the dye acridine orange (AO). Compared to cells treated with Lys05 and MSDH, cells treated with BAQ12 NP or BAQ13 NP showed a decrease in the number of red spots and an increase in the ratio of green fluorescence to red fluorescence, suggesting that BAQ ONN has an enhanced ability to induce lysosomal disruption in cancer cells (Figure 3C and Figure 10D - 10E). This LMP effect was further confirmed by detecting the release of Dextran - AF488 from lysosomes. As shown in Figure 3D, treatment with BAQ ONN resulted in a diffuse staining pattern throughout the cytoplasm (indicating lysosomal leakage), while the fluorescence in control cells appeared to be limited to punctate structures (representing intact lysosomes). BAQ ONN was demonstrated to induce the release of cathepsin B (one of the important triggers of apoptosis) from isolated lysosomes with its LMP function (Figure 3E). Since LMP was not observed in cells treated with MSDH, the results suggested that BAQ12 and BAQ13 represent the next generation of lysosomotropic detergents.

[0192] Autophagy inhibition. To examine the effect of BAQ ONN on autophagy, the levels of microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (SQSTM1) / p62 protein were measured. These are often used to monitor changes in the autophagy process. During autophagy, the cytosolic form of LC3 (LC3-I) is converted to the lipid-modified form (LC3-II), which is then recruited to the autophagosome membrane. During this time, the autophagy substrate SQSTM1 / p62 protein is degraded through selective incorporation into autophagosomes. Therefore, an increase in the levels of both LC3-II and SQSTM1 / p62 should be observed upon inhibition of autophagy, while an increase in the level of LC3-II and a decrease in the level of SQSTM1 / p62 should be observed when autophagy is activated. As shown in Figures 3F - 3G, compared with untreated cells and cells treated with Lys05, MIA PaCa-2 cells treated with BAQ ONN showed a concentration-dependent and significant increase in the levels of both LC3B-II protein and SQSTM1 / p62 protein. Such an increase was also observed after treatment with bafilomycin A1 (BfA1), a known autophagy inhibitor. These findings indicate that BAQ ONN can inhibit cellular autophagy more effectively than Lys05.

[0193] Subsequently, the autophagy inhibitory effect was confirmed using LC3B-GFP imaging. This is because the accumulation of autophagosomes can be visualized by utilizing the formation of fluorescent LC3-II puncta within cells. Cells treated with BAQ ONN generated prominent LC3B-GFP puncta in a concentration-dependent manner (Figs. 3H and 10F). Quantification of LC3B-GFP puncta per cell revealed that the autophagy inhibitory potency of BAQ ONN was greater than that of Lys05 (Fig. 3I). To further verify, TEM was used to monitor changes in the fine morphology of cells. As expected, compared with Lys05 and MSDH, BAQ ONN induced the formation of larger autophagic vesicles (AVs) or autophagosomes in cells, further confirming the improved autophagy inhibitory effect of BAQ ONN (Figs. 3J - 3K). Collectively, these findings indicate that BAQ12 NP and BAQ13 NP outperform the parental Lys05 in autophagy inhibition; thus, BAQ ONN represents the generation of an autophagy inhibitor formulated as a nanoparticle.

[0194] Proton sponge effect and lysosomal dysfunction. As cationic molecules, both BAQ12 and BAQ13 have a strong H, an important feature of materials with the proton sponge effect +It has buffering capacity (Figure 2C). Since the above TEM results showed that BAQ ONN could significantly enlarge lysosomes (Figures 3J - 3K), this demonstrated the proton sponge effect of BAQ ONN. To further investigate these effects, the changes in the transcriptome of MIA PaCa - 2 cells after treatment were characterized using RNA sequencing (RNA - seq). A total of 13,234 genes were examined, and their expression levels were compared among the vehicle group, Lys05 group, and BAQ13 group. Using volcano plot analysis, 165 differentially expressed genes (DEGs) (fold change ≥ 2 and p - value ≤ 0.05) were found in the Lys05 group compared to the vehicle group, including 62 up - regulated genes and 103 down - regulated genes. In the comparison, 390 DEGs were found in the cells treated with BAQ13, including 209 up - regulated genes and 181 down - regulated genes (Figure 11A). From gene set enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG), it was revealed that BAQ13 NP induced robust up - regulation of lysosome - related genes (such as V - ATPase, Cl - channel, protease, and lysosome - associated membrane protein (LAMP) genes) (Figures 4A - 4C and Figure 11B). Up - regulation of V - ATPase and Cl - channel genes was also confirmed by qPCR analysis, which significantly indicated that BAQ ONN had strong proton sponge properties (Figures 4D - 4E).

[0195] Upregulation of important lysosomal enzyme genes (such as cathepsin and NEU1) also clarified lysosomal dysfunction caused by BAQ ONN (Figures 4B - 4C). Since the LAMP gene, which is thought to be partly responsible for maintaining lysosomal integrity, was also upregulated, this indicates the function of BAQ ONN in lysosomal disruption (Figure 11C). The BAQ ONN - treated group showed high levels of the transcriptomes of apoptosis - promoting genes (BAX, BAK1, BAD, BIM, and PUMA), thus revealing an enhanced apoptosis - promoting effect (Figures 11C - 11D). Subsequently, lysosomal dysfunction induced by BAQ ONN was confirmed using lipidomic analysis. BAQ13 NP induced the accumulation of acidic sphingomyelinase (ASM) precursor sphingomyelin (SM), leading to a decrease in the level of its product, ceramide (Cer) (Figure 11E). In addition, the levels of phospholipase A (PLA) precursors (including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PI)) decreased, while the levels of their corresponding products, lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and lysophosphatidylserine (LPI), increased (Figure 11F).

[0196] The nanocarriers of the present invention include R 1 can also include a complex in which is pheophorbide - a and forms a pheophorbide - a bis - aminoquinoline complex (PBC). PBC nanoparticles are nanoscale aggregates that target lysosomes and can change their morphology. PBC nanoparticles had a liposome - like morphology under physiological conditions and could transform into nanofibers after accumulating in lysosomes. The nanofibers formed in lysosomes can cause lysosomal dysfunction and initiate apoptosis in cancer cells. Since these nanoparticles contain a photosensitizing group in their structure, they also support a very effective lysosome - based photodynamic therapy that can essentially overcome autophagy - related drug resistance. Example 3: In Vitro Study

[0197] Cell lines and cell cultures. Human pancreatic cancer cell lines (MIA PaCa-2, BXPC3, and PANC-1) were originally purchased from ATCC and were kindly provided by Dr. Shiro Urayama's laboratory. HT29 cell line, HCT116 cell line, H460 cell line, MCF7 cell line, NIH / 3T3 cell line, and IMR-90 cell line were purchased from ATCC. Bone marrow cells were harvested from the femur bone marrow of FVB / N mice. All cells were cultured at 37°C in a humidified atmosphere of 5% CO2 / 95% air using the corresponding medium supplemented with 10% fetal bovine serum, 100 μg / mL -1 of penicillin, and 100 units / mL -1 of streptomycin, according to the ATCC protocol. All cell lines were regularly examined for mycoplasma contamination.

[0198] Establishment of patient-derived pancreatic cancer stem cells (PCSCs). The patient's pancreatic tissue was donated from the laboratory of Dr. Shiro Urayama at UC Davis Medical Center. Patient consent was obtained using "Remnant Clinical Biospecimens" in accordance with the Institutional Review Board (UC Davis IRB Protocol #244896). The patient's tumor tissue was recovered using collagenase IV and dispase (Stem Cell Technologies, Vancouver, Canada) and deformed by passing through a 70 μm filter. Cells were isolated using a BD FACSAria II cell sorter by labeling with the following antibodies (Biolegend, California, USA): anti-CD44 (IM7, Cat: #338823), anti-CD326 (9C4, Cat: #324207), and anti-CD24 (ML5, Cat: #311119) (Figure 16). The purified PCSCs were recovered, maintained in Essential 8 Flex medium (Thermo Fischer), and trypsinized using Gentle Cell Dissociation reagent (Stem Cell Technologies, Vancouver, Canada). In the tumorsphere formation assay, Essential 8 Flex medium containing a cold single-cell suspension of PCSCs was mixed with cold Matrigel (1:1, volume ratio), and then it (100 μL) was slowly and uniformly dropped onto the center of the wells on a 24-well plate (5,000 cells per well). After leaving the Matrigel to solidify by placing it in a humid incubator at 37 °C for 45 - 60 minutes, warm medium (500 μL) was added to each well. Tumorspheres were formed in 2 weeks. To determine the tumor-forming ability in vivo, PCSCs were counted, resuspended in a mixture of PBS and Matrigel (1:1), and then subcutaneously injected into the flanks of NRG mice.

[0199] Cell viability, cell proliferation, and colony formation. Cell viability was examined by the MTS assay. Briefly, cells in 96-well plates (4,000 cells per well) were treated as indicated and then incubated with the MTS reagent for 4 hours. The OD value (490 nm) was determined using a microplate reader. The results are shown as the mean cell viability calculated from the formula [(OD treat - OD blank ) / (OD control - OD blank ) × 100%]. The drug combination data were analyzed by Combenefit 2.02. In the cell proliferation assay, cells in 6-well plates (50,000 cells per well) were treated as indicated and counted manually every 24 hours. The colony formation assay was also performed in 6-well plates at an initial density of 1,000 - 2,000 cells per well. After incubation for 10 - 20 days as indicated, the cells were washed with PBS and stained with a solution of crystal violet and methanol for 20 minutes.

[0200] Apoptosis and caspase-3 / 7 activity. Cell apoptosis was measured using an FITC-Annexin V / PI apoptosis kit (AnaSpec). Briefly, the treated cells were stained according to the manufacturer's instructions and detected using a BD FACSCanto II flow cytometer. The data were analyzed by FlowJo 7.6.1. In the caspase 3 / 7 activity assay, cells in 96-well plates (10,000 cells per well) were treated as indicated and then the AMC caspase-3 / 7 assay kit (50 μL per well, AnaSpec) was added. The fluorescence intensity (λ ex = 356 nm, λ em = 442 nm) was recorded using a microplate reader.

[0201] Cell uptake and deacidification. To determine cell uptake, lysosomes were labeled with Alexa Fluor 488-dextran (10 kDa, 100 μg mL-1 After labeling with Thermo Fisher for 36 hours, it was incubated with DiD-loaded BAQ NPs (10 μM, 1:10, mass ratio) for 2 hours. In lysosomal deacidification analysis, cells were treated for 2 hours and incubated with LysoTracker Red (100 nM, Thermo Fisher) for 1 hour. Cell images were acquired using a Zeiss confocal microscope and analyzed by Zen 2.3 and ImageJ 1.51s.

[0202] Lysosomal integrity. Lysosomal integrity was measured in live cells by using AO (Thermo Fisher) or Alexa Fluor 488-dextran (10 kDa) staining. For AO staining, the treated cells were incubated with AO (2 μg mL -1 ) for 1 hour. For dextran staining, cells loaded with dextran were treated for 12 hours. Images were captured under a Zeiss confocal microscope and analyzed by Zen 2.3 and ImageJ 1.51s.

[0203] LC3B-GFP imaging. Autophagy sensor LC3B-GFP (Thermo Fisher) was transfected into cells (5,000 cells per well) in a 96-well plate for 12 hours. After treatment for 4 hours as shown, the cells were visualized by a fluorescence microscope (Olympus). The number of puncta per well was quantified using ImageJ 1.51s.

[0204] Isolation of lysosomes and release of cathepsin. Lysosomes were isolated using a lysosome enrichment kit (Thermo Fisher) according to the manufacturer's protocol. Equal amounts of isolated lysosomes were incubated at 37 °C for 12 h as indicated and then pelleted to obtain intact lysosomes by centrifugation at 15,000×g for 30 min at 4 °C. After incubation with 200 μM of the fluorogenic cathepsin B substrate III (Z-Arg-Arg-AMC) for 2 h, the release of cathepsin B into the supernatant was determined (Ex = 380 nm, Em = 460 nm).

[0205] Hemolysis. PBS (10 mM, pH 7.4) containing red blood cells (2%) was incubated with NP at 37 °C for 4 h. After centrifugation at 500×g for 5 min, the degree of hemolysis was determined from the amount of hemoglobin (540 nm) in the supernatant by spectrophotometry. The pH-dependent washing ability and toxicity of NP were evaluated using the hemolysis assay.

[0206] Western blot. Cell or tumor samples were lysed in RIPA buffer (Thermo Fisher). After centrifugation at 4 °C (15 min, 12,000×g), the protein concentration in the supernatant was determined by Bradford protein assay dye (Bio-Rad). Immunoblotting was performed routinely and developed using a ChemiDoc™ MP imaging system.

[0207] TEM of cells and tumor tissues. MIA PaCa-2 cells (30,000 cells per well, Lab-Tek) in 8-well slide plates were treated as indicated for 48 h. Freshly harvested tumors were cut into 1 mm 3 fragments. Samples were fixed in 0.1 M cacodylate buffer containing 2.5% glutaraldehyde + 2% paraformaldehyde, transferred onto carbon square meshes, and then observed under a Talos L120C TEM.

[0208] RNA-seq. Total RNA was extracted from treated MIA PaCa-2 cells (5 μM, 24 hours) using the RNeasy Mini Kit (Qiagen, Germany). Samples were sent to the UC Davis Comprehensive Cancer Center’s Genomics Shared Resource (GSR) for RNA-Seq analysis. Standard RNA-Seq libraries were prepared from 100 ng of total RNA using the NEBNext Ultra Directional RNA Library Prep Kit (New England BioLabs). Subsequently, the libraries were pooled and multiplexed sequenced on an Illumina HiSeq 4000 system (2×150 bp, paired-end, >20×10 6 reads per sample). Normalized gene read count data were analyzed using fold change and t-tests. Differentially expressed genes (DEGs) were retrieved for signaling pathway enrichment using Funrich software 3.1.3. Gene sets were from the MSigDB database (Broad Institute). Gene Set Enrichment Analysis (GSEA) version 3.0 was performed using the online KEGG gene set categories with the following parameters: n = 1,000 permutations, and adjusted p<0.05 and FDR<0.05 were considered significant.

[0209] qPCR. Total RNA was isolated using TRIzol reagent (Invitrogen) and phenol-chloroform extraction. cDNA was synthesized using SuperScript II reverse transcriptase (Invitrogen) with 2 μg of total RNA in a 20 μL reaction. The resulting cDNA was diluted 1:20 in nuclease-free water, and 4 μL per reaction was used in triplicate. qPCR was performed using Power SYBR Green PCR Master Mix (Thermo Fisher) on a CFX96 Real-Time PCR Detection System (Bio-Rad) including non-template negative controls. The levels of mRNA expression were normalized using amplification of GAPDH. Primer sequences are listed in Table 3.

Table 3

[0210] Lipidomics. MIA PaCa-2 cells were treated with the compound (2.5 μM) for 48 h, and 1.5 million cells were collected from each group for RPLC-QTOF analysis and the samples were prepared by a standard method. After the samples were analyzed with a Vanquish UHPLC system, data were acquired using a Q-Exactive HF hybrid quadrupole Orbitrap mass spectrometer. LC-MS data were processed using MS-DIAL 3.70. Statistical analysis was performed by first normalizing the data using the sum of known values or mTIC normalization to scale each sample. Then, R 3.5.1 was performed on the normalized peak heights for statistical analysis. ANOVA analysis was performed with FDR correction and post hoc tests.

[0211] In vitro antitumor activity of BAQ derivatives. To systematically examine the antitumor effect in vitro, three pancreatic cancer cell lines (MIA PaCa-2, BxPC-3, and PANC-1) and two colorectal cancer cell lines (HT29 and HCT116) were selected for the MTS assay for 48 h. BAQ ONN had an IC of 1 - 3 μM 50Since it showed values, it was approximately 5-fold, 30-fold, and 20-fold more potent than Lys05, HCQ, and MSDH, respectively (Figure 4F, Figure 12, and Table 4). These results also showed that treatment with either BAQ12 or BAQ13 alone was more effective than combination therapy with Lys05 and MSDH. This suggests that a significant pharmacodynamic synergistic effect occurred when the pharmacophores were fused. The results of the cell proliferation and colony formation assays further demonstrated the inhibitory effect of BAQ ONN on tumor cells (Figure 4G - 4H). This improved anti-cancer activity of BAQ ONN can be attributed to its multifunctionality in inducing LMP, lysosomal dysfunction, and autophagy inhibition in cancer cells; these effects are considered important triggers of apoptosis. To examine the apoptosis-promoting effect of BAQ ONN, apoptosis signals in MIA PaCa-2 cells and HT29 cells were subsequently detected. As a result of treatment with BAQ ONN, both the levels of caspase 3 / 7 activity and apoptosis increased significantly (Figure 4I - 4J). The control, Lys05, showed an increase in the apoptosis signal in a concentration-dependent manner, but its effect at high concentrations close to the IC 50 was still weaker than that of low-concentration BAQ ONN. These results demonstrate that cancer cells are more prone to apoptosis when treated with multifunctional BAQ substances than when treated with Lys05, whose main function is autophagy inhibition. In addition, compared with the above group of cancer cell lines, non-cancerous cell lines (including IMR-90 cells, NIH / 3T3 cells, and bone marrow cells) are relatively insensitive to BAQ ONN, thus indicating that the safety of these compounds is relatively high (Figure 12 and Table 4).

Table 4

[0212] In vitro antitumor activity of BAQO derivatives. The in vitro antitumor effect of BAQO derivatives was examined in pancreatic cancer stem cells (PCSCs). BAQ12O ONN had an IC 50While showing values (Fig. 22B), other BAQO derivatives did not show toxicity up to a concentration of 100 μM. These results indicate that BAQO derivatives may have wide applications as therapeutic agents or drug delivery agents without contributing to cytotoxicity. Example 4: In Vivo Study

[0213] Animal model. To establish a subcutaneous xenograft model, 5×10 6 MIA PaCa-2 cells, 2×10 6 HT29 cells, or 2×10 4 PCSCs were suspended with Matrigel (Corning), and the PBS mixture (1:1, volume ratio) was subcutaneously injected into the right flank of nude mice or NRG mice, respectively.

[0214] Feeding of animals. All animal experiments were carried out according to the protocol (#20265) approved by the Institutional Animal Care and Use Committee of the University of California, Davis. Female mice (4 - 6 weeks old) (including BALB / c nude mice (Envigo), NRG mice (Jackson Laboratory), and FVB / N mice (Charles River)) were purchased and group-housed under standard conditions (22 ± 1 °C, humidity 50 - 60%, 12-hour light / 12-hour dark cycle, free access to food and water).

[0215] Schedule of in vivo treatment. After randomly dividing NRG mice with MIA PaCa-2 xenograft tumors (about 100 mm 3 ) into five groups (n = 6), iv injection was performed as shown every three days. For the HT29 xenograft model, nude mice (n = 6) with tumors of 100 mm 3 were administered vehicle (saline, iv), Lys05 (ip), BAQ12 NP (iv), BAQ13 NP (iv), irinotecan (ip) every three days, respectively. Treatment in the HT29 model was stopped on day 24, and then the survival of mice in each group was recorded until 1,000 mm3 Mice with larger tumors were considered dead. For the co-delivery study, NRG mice (n = 5) bearing PCSC tumors were treated every three days with vehicle (saline, iv), napabucasin (iv), BAQ13 NP (iv), BAQ13 NP + napabucasin (iv and ip, respectively), and BAQ13 NP@napabucasin (iv). Tumor volume and body weight were recorded before each drug administration. At the end of the treatment, the mice were euthanized and the tumors were harvested for further analysis.

[0216] In vivo toxicity study. The toxicity of BAQ NPs was investigated in female FVB / N mice by iv injection. Mice were administered various concentrations (10 mg kg -1 , 20 mg kg -1 , or 40 mg kg -1 ) of Lys05, liposome@Lys05, BAQ12 NP, and BAQ13 NP every two days. The condition of the mice was monitored daily and body weight was recorded every two days. Blood samples were collected and sent to the UCD Comparative Pathology Laboratory for a complete blood count (CBC) and serum chemistry examination.

[0217] In vivo pharmacokinetic study. A catheter (Harland, Indianapolis, Indiana, USA) for drug injection and blood collection was implanted into the jugular vein of female Sprague-Dawley rats (200 - 250 g). Rats (n = 3) were injected with free DiD, BAQ12 NP@DiD (10:1, mass ratio), and BAQ13 NP@DiD (10:1, mass ratio), each containing an equivalent dose of DiD (0.5 mg kg -1 ). After blood samples were collected at the indicated time points, they were centrifuged to obtain plasma. The plasma was diluted with DMSO (1:100), and the fluorescence intensity (λ Ex = 595 nm, λ Em = 665 nm) was measured using a microplate reader (SpectraMax M2).

[0218] In Vivo / In Vitro Distribution. Nude mice bearing HT29 tumors were administered with BAQ13 NP@DiD (10:1, mass ratio) at a dose of 1.0 mg kg -1 of DiD. In vivo imaging studies were performed at the corresponding time points. Organs (brain, heart, lung, liver, spleen, kidney, intestine, and muscle) and tumors were harvested from the mice for in vitro imaging. BAQ13 NP@NAPA+DiD (10 / 2.5 / 1.0 mg kg -1 , iv) The in vivo distribution was examined in NRG mice bearing PCSC tumors. Imaging studies were performed both in vivo and in vitro as described above.

[0219] Statistics. Statistical analysis was performed using GraphPad Prism 7.0. Data are shown as mean ± SD, where n = biological replicates, or independent nanoparticle sample replicates. As described in the legend of each figure, one-way ANOVA using Tukey's multiple comparison test or two-sided Student's t-test was used to calculate the p-value. ns., no significant difference; *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

[0220] Data Availability. RNA-seq data are deposited in the Gene Expression Omnibus (GEO) database under accession code GSE154323 [https: / / www.ncbi.nlm.nih.gov / geo / query / acc.cgi?acc=GSE154323].

[0221] Pharmacokinetics, biodistribution, and toxicity. The pharmacokinetics of BAQ ONN following intravenous (iv) injection were studied in Sprague-Dawley rats. As shown in Figure 5A and Table 5, the serum concentration of BAQ ONN was higher than that of free DiD at the same time points up to 48 hours, indicating that the plasma clearance of BAQ ONN was slower than that of DiD due to the nanoscale characteristics of BAQ ONN. BAQ13 NP labeled with DiD was also used to investigate the biodistribution of NPs in nude mice bearing HT29 tumors. As expected, both in vivo and in vitro imaging showed that the fluorescence signal of BAQ13 NP could be clearly distinguished in the tumor region rather than in the surrounding normal tissues at 12 and 24 hours after injection, indicating that BAQ ONN is distributed in vivo targeting tumors (Figures 5B - 5C and Figures 13A - 13B). This ability to target may be due to the relatively high ability to penetrate tumor blood vessels and enable passive accumulation of nanotherapeutics. The free DiD (control) group showed a higher signal in the lungs than in the tumor site (Figures 13A - 13B). In particular, the fluorescence tumor / lung ratio in the BAQ13 NP group was approximately 4-fold greater than that in the free DiD group. These results demonstrated that BAQ ONN has a biodistribution targeting tumors.

Table 5

[0222] Next, a hemolysis assay was performed to evaluate the safety of BAQ ONN. Under physiological conditions, red blood cells were treated with Lys05, BAQ12 NP, or BAQ13 NP at concentrations of 0.25 - 1 mg mL -1 close to the working concentrations used in animal treatment studies (Figure 13C). Treatment with the control drug Lys05 resulted in a significantly higher hemolysis rate than treatment with BAQ12 NP or BAQ13 NP at a concentration of approximately 0.5 mg mL -1 indicating that the safety of BAQ ONN is greater than that of Lys05. In the following animal toxicity studies in FVB / N mice, Lys05 treatment resulted in 10 mg kg-1 was found to cause sudden death in mice even at such low concentrations; in contrast, the results of BAQ ONN treatment showed low mortality and no weight loss, indicating that BAQ ONN is safe when administered by injection (Figures 13D - 13E). BAQ ONN did not result in any deaths at 40 mg kg -1 and BAQ13 NP was better tolerated by mice than BAQ12 NP. This result is likely attributable to the high stability and low CAC of BAQ13 NP. Encapsulating Lys05 (Liposome@Lys05) using liposomes was found to be safe for iv injection (Figures 13E - 13F). Since autophagy plays an important role in intestinal homeostasis, intraperitoneal (ip) administration of BAQ12 NP or BAQ13 NP may increase the autophagy inhibitory effect and cause intestinal damage and weight loss in mice. H&E staining of tissue sections and hematological indices showed no obvious abnormal changes in mice treated with 20 mg kg -1 of BAQ NP via the tail vein, further suggesting that iv administration of BAQ ONN is well tolerated (Figures 14A - 14E). Therefore, BAQ ONN should be administered by iv injection rather than ip injection to study its in vivo advantages.

[0223] Antitumor effect as a single agent in mice. After demonstrating the safety of BAQ ONN, the NPs were evaluated for their anticancer effects in a pancreatic xenograft model of MIA PaCa - 2 cells. NRG mice with MIA PaCa - 2 tumors (approx. 100 mm 3 ) were randomly assigned to five groups (n = 6), namely the saline (iv) group, Lys05 (ip) group, Liposome@Lys05 (iv) group, BAQ12 NP (iv) group, and BAQ13 NP (iv) group. The mice were then treated with 20 mg kg every 3 days -1Treated at the dosage of. The results in Figures 5D - 5F show that treatment with BAQ12 NP or BAQ13 NP significantly decelerates tumor growth without interfering with body weight. The control drug Lys05 did not show a therapeutic effect under this condition, but its nanoparticle formulation, Liposome@Lys05, induced an increase in tumor inhibition, thus highlighting the advantages of nanomedicine in drug delivery. It should also be emphasized that the self - assembling single - component formulations of BAQ12 NP or BAQ13 NP were significantly more effective than either free Lys05 or nanoparticle - formulated Lys05. These findings clearly demonstrate the potential advantages of BAQ ONN with respect to both drug discovery and drug delivery.

[0224] To further understand the in - vivo effects of BAQ ONN, tumor tissues were harvested for histological evaluation. Dramatic cell destruction, increased levels of cleaved caspase - 3, and decreased Ki67 expression were observed in both BAQ ONN groups, suggesting that tumors treated with BAQ ONN tend to die, undergo apoptosis or become dormant (Figures 5G - 5H). LC3 expression increased in both BAQ ONN groups (Figure 5H); this finding is an important clue to explain the in - vivo autophagy - inhibitory effect of both BAQ ONN. Subsequent immunoblot analysis further demonstrated that autophagy in tumors was blocked by BAQ ONN (Figure 5I). In addition, tissue ultrastructure was observed by TEM, and tumors treated with BAQ ONN were found to contain a greater number of large AVs than the tumor group (Figure 5J). In the above assays, the Lys05 nanoparticle formulation, Liposome@Lys05, also showed some effects not observed with the vehicle or free Lys05. However, the effect of Liposome@Lys05 was much weaker than that of either BAQ12 NP or BAQ13 NP. From these tissue - level results, the excellent autophagy - inhibitory effect of BAQ ONN in vivo was revealed.

[0225] The therapeutic effect of BAQ ONN in vivo was further demonstrated in another animal model consisting of mice with colorectal HT29 tumors. Administration of BAQ ONN significantly inhibited tumor growth compared to administration of vehicle or Lys05 (Figures 15A - 15B). And BAQ13 NP showed a better effect than BAQ12 NP. Interestingly, this result was in contradiction with the result obtained in the in vitro amplification assay (which demonstrated that BAQ12 NP was more effective than BAQ13 NP). This difference may be explained by the differences in the self - assembly behavior and pharmacokinetic profiles among BAQ ONNs (Figures 2G, 5A). Furthermore, BAQ13 NP was also effective at the reported therapeutic doses compared to irinotecan approved by the FDA, while BAQ12 NP showed an effect similar to that of irinotecan. From the survival analysis, it was revealed that treatment with BAQ13 NP resulted in a significantly longer survival time (median survival period was 48 days) compared to the vehicle group and the irinotecan group (median survival periods were 21 or 36 days, respectively) (Figure 15C and Table 6). Hybrid BAQ ONN integrates a number of advantages regarding both pharmacodynamic effects and pharmacokinetic profiles, thus showing great potential for in vivo cancer treatment as a single agent.

Table 6

[0226] The dual role of BAQ ONN in combination therapy. Combination therapy based on autophagy inhibition is thought to make tumors sensitive to conventional therapeutic agents, but the current limitation is the insufficient effect of autophagy inhibitors. Furthermore, the drugs used in combination therapy have different pharmacokinetics and dosing schedules, which is inconvenient. Since BAQ ONN has an anti-cancer efficacy 30 times greater than that of HCQ and a large ability to encapsulate additional drugs, BAQ ONN may be able to simultaneously address these two issues of pharmacodynamics and pharmacokinetics. To test this hypothesis, a pancreatic cancer stem cell (PCSC) line from patient-derived pancreatic adenocarcinoma tissue was used to establish a xenograft model with high heterogeneity and a large proportion of tumor stroma (Figures 6A - 6B and Figure 16). In vitro results demonstrated that BAQ ONN has a similar function regarding the inhibition of lysosomes and autophagy in PCSCs and thus exhibits strong apoptosis-promoting and anti-proliferative activities (Figures 6C - 6E and Figures 17A - 17C). For combination therapy, napabucasin, a STAT3 inhibitor that can be encapsulated in BAQ13 NPs, was selected because it can induce autophagy and act synergistically with BAQ13 NPs (Figure 6F and Figure 17D). Mice were randomly divided into five groups (including a vehicle (saline) group, a napabucasin group, a BAQ13 NP group, a mixture (BAQ13 NP + napabucasin) group, and a BAQ13 NP@napabucasin group) (Figures 6G - 6I). BAQ13 NPs moderately inhibited tumor growth, while napabucasin alone showed no anti-tumor effect under these conditions. The mixture group did not show enhanced effects in vivo, although in vitro synergy between napabucasin and BAQ13 NPs was observed. This lack of in vivo effect was probably due to the low solubility and inefficient delivery of napabucasin. Nanonized napabucasin, when loaded into BAQ13 NPs (BAQ13 NP@napabucasin), achieved a satisfactory anti-tumor effect by acting synergistically with BAQ13 NPs. Marked changes in tumor histology were also observed in the BAQ13 NP@napabucasin group, where cells showed low proliferative activity (Figure 6J). In addition, none of the mice in the treatment groups showed obvious systemic toxicity (Figure 6I and Figure 17E).To further verify the ability of BAQ13 NPs to deliver napabucasin, another imaging study was conducted on a PCSC model using DiD-labeled BAQ13 NP@napabucasin. The results showed that NPs accumulated significantly more in tumor sites than in normal organs (Figs. 6K–6L and 17F). These interesting results demonstrate that BAQ13 NPs can function not only as therapeutic agents but also as delivery carriers in combination therapies; thus, BAQ13 NPs show promise for improving cancer treatment.

[0227] Antitumor effects of BAQO derivatives in mice. BAQO derivatives can form nanoparticles and can be used for in vivo mouse studies. For example, BAQ12O NPs were used to treat mice with PCSC tumors. As shown in Fig. 24A, mice treated with BAQ10O NPs had smaller tumor volumes, and there was a significant difference in tumor volume by day 27. Fig. 24B shows that the tumor weight at the end of treatment with BAQ12O NPs was 50% less than the tumor weight of the control. These interesting results demonstrate that BAQO derivatives can function as promising agents for drug discovery and drug delivery.

[0228] Based on the ONN strategy and the principles of pharmacophore hybridization and molecular self-assembly, BAQ ONN, a novel self-delivery chemical entity, was developed. These agents had enhanced abilities to induce lysosome disruption, lysosomal dysfunction, and autophagy blockade, in addition to improved properties regarding drug delivery and in vivo distribution targeting tumors; thus, these agents showed significant anticancer effects. Surprisingly, single BAQ13 NPs were found to have a large drug-loading capacity and to synergize strongly with and deliver additional drugs, making them promising for use in combination therapies.

[0229] Typically, in contrast to conventional NPs with an active pharmaceutical ingredient (API) content of less than 20% and which are difficult to synergize, BAQ ONN has an API content of 100% and is easy to synergize and scale up. Since BAQ ONN is a non-prodrug chemical substance, it is also superior to emerging single-component prodrug NPs. All of these advantages make it very easy to bridge BAQ ONN to clinical trials. This is an important attempt to expand nanotechnology to the design of new chemical substances. With the seamless connection between drug discovery and nanotechnology-assisted drug delivery, researchers will be able to develop increasingly advanced nanomedicine with cancer-targeted therapies and marketable advantages.

[0230] So far, the present invention has been described in some detail by way of illustration and examples for clarity of understanding, but it will be understood by those skilled in the art that some changes and modifications can be made within the scope of the appended claims. In addition, each reference presented in this specification is incorporated by reference in its entirety as if each reference were individually incorporated by reference. In the event of any conflict between this application and the references presented in this specification, this application shall prevail.

Claims

1. structure: 【Chemistry 1】 (wherein n is an integer from 1 to 7). or a pharma- ceutically acceptable salt thereof. 【Request 2】 【Chemistry 2】 2. The compound of claim 1, selected from the group consisting of: 【Request 3】 【Chemistry 3】 2. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

4. 4. A nanocarrier having an interior and an exterior, comprising a plurality of compounds according to any one of claims 1 to 3, or pharma- ceutically acceptable salts thereof, each compound self-assembles in an aqueous solvent to form the nanocarrier such that a hydrophobic pocket is formed on the interior of the nanocarrier and hydrophilic groups self-assemble on the exterior of the nanocarrier.

5. The nanocarrier of claim 4, further comprising one or more hydrophobic drugs or imaging agents sequestered in the hydrophobic pocket.

6. The nanocarrier of claim 5 , wherein the hydrophobic drug is a chemotherapeutic agent, a molecular targeted agent, an immunotherapeutic agent, a radiotherapeutic agent, or a combination thereof.

7. The nanocarrier of claim 6 , wherein the hydrophobic drug is an immunotherapeutic agent.

8. The nanocarrier of claim 6 , wherein the hydrophobic drug is a radiotherapeutic agent.

9. The nanocarrier of claim 6, wherein the hydrophobic drug is a chemotherapeutic agent or a molecular targeted agent.

10. The hydrophobic drug is selected from the group consisting of FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, inhibitors of checkpoint-1 or 2, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF capture antibodies, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, butabulin, ofatumumab, zanolibumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Dimatecan, IL13-PE38QQR; INO 1001, IPdR1 KRX-0402, Lucanton, LY 317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl l]-L-glutamic acid disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperazinemethyl)-indolyl j-quinolone, vatalanib, AG-013736, AVE-0005, acetate of [D-Ser(Bu t) 6, Azgly 10] (Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate [C. 59 H 84 N 18 O 14 -(C 2 H 4 O 2 )X (where x = 1 to 2.4)], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifosti , NVP-LAQ824, suberoylanilide hydroxamate, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, Epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozotocin Syn, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine,Endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin difitox, gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab Cizumab (monoclonal antibody) and Erbitux, Cremophor-free paclitaxel, Epithilon B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, interferon alpha-2c, interferon alpha-2d, interferon alpha-2e, interferon alpha-2f, interferon alpha-2g, interferon alpha-2h ... -feron alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibrittonomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium 89, casopitant, netupitant,The nanocarrier according to any one of claims 5 to 9, which is an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, sspeg filgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, or a combination thereof.

11. A nanocarrier according to any one of claims 4 to 7, comprising a plurality of compounds according to any one of claims 1 to 3.

12. A pharmaceutical composition for treating a disease, comprising the nanocarrier according to any one of claims 4 to 11.

13. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is administered in combination with one or more additional agents, wherein the additional agents are a chemotherapeutic agent, a molecular targeted agent, an immunotherapeutic agent, a radiotherapeutic agent, or a combination thereof.

14. 14. The pharmaceutical composition of claim 13, wherein the additional pharmaceutical agent is an immunotherapeutic agent.

15. The pharmaceutical composition of claim 13, wherein the additional agent is a radiotherapeutic agent.

16. The pharmaceutical composition of claim 13, wherein the additional drug is a chemotherapeutic agent or a molecular targeted agent.

17. The additional agent is an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an Aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKT inhibitor, a JAK / STAT inhibitor, an inhibitor of checkpoint-1 or 2, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF capture antibody, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, butabulin, ofatumumab, zanolibumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Dimatecan, IL13-PE38QQR; INO 1001, IPdR1 KRX-0402, Lucanton, LY 317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl l]-L-glutamic acid disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperazinemethyl)-indolyl j-quinolone, vatalanib, AG-013736, AVE-0005, acetate of [D-Ser(Bu t) 6, Azgly 10] (Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 [Acetate]. 59 H 84 N 18 O 14 -(C 2 H 4 O 2 )X (where x = 1 to 2.4)], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifosti , NVP-LAQ824, suberoylanilide hydroxamate, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, Epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozotocin Syn, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine,Endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin difitox, gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab Cizumab (monoclonal antibody) and Erbitux, Cremophor-free paclitaxel, Epithilon B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, interferon alpha-2c, interferon alpha-2d, interferon alpha-2e, interferon alpha-2f, interferon alpha-2g, interferon alpha-2h ... -feron alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibrittonomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium 89, casopitant, netupitant,The pharmaceutical composition according to any one of claims 13 to 16, which is an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, sspeg filgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, or a combination thereof.

18. The pharmaceutical composition of claim 12, wherein the disease is cancer.

19. 19. The pharmaceutical composition of claim 18, wherein the cancer is bladder cancer, brain cancer, breast cancer, cervical cancer, bile duct cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, glioblastoma, intestinal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, melanoma, myeloma, ovarian cancer, pancreatic cancer, prostate cancer, and uterine cancer.

20. 13. The pharmaceutical composition of claim 12, wherein the disease is coronavirus, malaria, antiphospholipid syndrome, lupus, rheumatoid arthritis, chronic urticaria, or Sjogren's disease.

21. The pharmaceutical composition of any one of claims 12 to 20, which targets lysosomal disruption, lysosomal dysfunction, and / or autophagy inhibition.

22. 22. The pharmaceutical composition of claim 12 or 21, which targets the lysosome.

23. A pharmaceutical composition for imaging, comprising the nanocarrier according to any one of claims 4 to 11.

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