Micellar nanoparticles and uses thereof

Abstract

The present disclosure includes cationic carrier units comprising (i) a water soluble polymer, (ii) a positively charged carrier, and (iii) an adjuvant moiety, wherein when the cationic carrier unit is mixed with an anionic payload (e.g., an antisense oligonucleotide) that electrostatically interacts with the cationic carrier unit, the resulting composition self-organizes into a micelle encapsulating the anionic payload in its core. The cationic carrier units can also comprise a tissue specific targeting moiety, which would be displayed on the surface of the micelle. The disclosure also includes micelles comprising the cationic carrier units of the disclosure, methods of manufacture of cationic carrier units and micelles, pharmaceutical compositions comprising the micelles, and also methods of treating diseases or conditions comprising administering the micelles to a subject in need thereof.

What is claimed is: 
     
         1 . A cationic carrier unit comprising
   [WP]-L1-[CC]-L2-[AM]  (Schema I)
     or     [WP]-L1-[AM]-L2-[CC]  (Schema II)
   wherein
 WP is a water-soluble biopolymer moiety; 
 CC is a positively charged carrier moiety; 
 AM is an adjuvant moiety; and, 
 L1 and L2 are independently optional linkers, and 
 wherein when mixed with a nucleic acid at an ionic ratio of about 1:1, the cationic carrier unit forms a micelle. 
   
     
     
         2 . The cationic carrier unit of  claim 1 , wherein the water-soluble polymer comprises poly(alkylene glycols), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyglycerol, polyphosphazene, polyoxazolines (“POZ”) poly(N-acryloylmorpholine), or any combinations thereof. 
     
     
         3 . The cationic carrier unit of  claim 1 , wherein the water-soluble polymer comprises polyethylene glycol (“PEG”), polyglycerol, or poly(propylene glycol) (“PPG”). 
     
     
         4 . The cationic carrier unit of any one of  claims 1  to  3 , wherein the water-soluble polymer comprises: 
       
         
           
           
               
               
           
         
         wherein n is 1-1000. 
       
     
     
         5 . The cationic carrier unit of  claim 4 , wherein then is at least about 110, at least about 111, at least about 112, at least about 113, at least about 114, at least about 115, at least about 116, at least about 117, at least about 118, at least about 119, at least about 120, at least about 121, at least about 122, at least about 123, at least about 124, at least about 125, at least about 126, at least about 127, at least about 128, at least about 129, at least about 130, at least about 131, at least about 132, at least about 133, at least about 134, at least about 135, at least about 136, at least about 137, at least about 138, at least about 139, at least about 140, or at least about 141. 
     
     
         6 . The cationic carrier unit of  claim 4 , wherein the n is about 80 to about 90, about 90 to about 100, about 100 to about 110, about 110 to about 120, about 120 to about 130, about 140 to about 150, about 150 to about 160. 
     
     
         7 . The cationic carrier unit of any one of  claims 1  to  6 , wherein the water-soluble polymer is linear, branched, or dendritic. 
     
     
         8 . The cationic carrier unit of any one of  claims 1  to  7 , wherein the cationic carrier moiety comprises one or more basic amino acids. 
     
     
         9 . The cationic carrier unit of  claim 8 , wherein the cationic carrier moiety comprises at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 11, at least 12, at least 13, at least 14, at last 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, at least 60, at least 61, at least 62, at least 63, at least 64, at least 65, at least 66, at least 67, at least 68, at least 69, at least 70, at least 71, at least 72, at least 73, at least 74, at least 75, at least 76, at least 77, at least 78, at least 79, or at least 80 basic amino acids. 
     
     
         10 . The cationic carrier unit of  claim 8 , wherein the cationic carrier moiety comprises at least 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, or at least about 150 basic amino acids. 
     
     
         11 . The cationic carrier unit of  claim 9 , wherein the cationic carrier moiety comprises about 30 to about 50 basic amino acids. 
     
     
         12 . The cationic carrier unit of  claim 10 , wherein the cationic carrier moiety comprises about 60 to about 100, e.g., about 70 to about 90, e.g., about 80, basic amino acids. 
     
     
         13 . The cationic carrier unit of any one of  claims 9  to  12 , wherein the basic amino acid comprises arginine, lysine, histidine, or any combination thereof. 
     
     
         14 . The cationic carrier unit of any one of  claims 1  to  13 , wherein the cationic carrier moiety comprises about 40 lysine monomers. 
     
     
         15 . cationic carrier unit of any one of  claims 1  to  13 , wherein the cationic carrier moiety comprises about 70, about 75, about 80, or about 85 lysine monomers. 
     
     
         16 . The cationic carrier unit of any one of  claims 1  to  15 , wherein the adjuvant moiety is capable of modulating an immune response, an inflammatory response, and/or a tissue microenvironment. 
     
     
         17 . The cationic carrier unit of  claim 16 , wherein the adjuvant moiety is capable of modulating an immune response. 
     
     
         18 . The cationic carrier unit of  claim 16 , wherein the adjuvant moiety is capable of modulating a tumor microenvironment in a subject with a tumor. 
     
     
         19 . The cationic carrier unit of  claim 16 , wherein the adjuvant moiety is capable of inhibiting or reducing hypoxia in the tumor microenvironment. 
     
     
         20 . The cationic carrier unit of any one of  claims 17  to  18 , wherein the adjuvant moiety comprises an imidazole derivative, an amino acid, a vitamin, or any combination thereof. 
     
     
         21 . The cationic carrier unit of  claim 20 , wherein the adjuvant moiety comprises: 
       
         
           
           
               
               
           
         
         wherein each of G1 and G2 is H, an aromatic ring, or 1-10 alkyl, or G1 and G2 together form an aromatic ring, and wherein n is 1-10. 
       
     
     
         22 . The cationic carrier unit of  claim 21 , wherein the adjuvant moiety comprises nitroimidazole. 
     
     
         23 . The cationic carrier unit of  claim 22 , wherein the adjuvant moiety comprises metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azanidazole, benznidazole, or any combination thereof. 
     
     
         24 . The cationic carrier unit of  claim 16 , wherein the adjuvant moiety comprises an amino acid. 
     
     
         25 . The cationic carrier unit of  claim 16 , wherein the adjuvant moiety comprises 
       
         
           
           
               
               
           
         
         wherein Ar is 
       
       
         
           
           
               
               
           
         
       
       and
 wherein each of Z1 and Z2 is H or OH. 
 
     
     
         26 . The cationic carrier unit of  claim 16 , wherein the adjuvant moiety is capable of inhibiting or reducing an inflammatory response. 
     
     
         27 . The cationic carrier unit of  claim 26 , wherein the adjuvant moiety is a vitamin. 
     
     
         28 . The cationic carrier unit of  claim 27 , wherein the vitamin comprises a cyclic ring or cyclic hetero atom ring and a carboxyl group or hydroxyl group. 
     
     
         29 . The cationic carrier unit of  claim 28 , wherein the vitamin comprises: 
       
         
           
           
               
               
           
         
         wherein each of Y1 and Y2 is C, N, O, or S, and wherein n is 1 or 2. 
       
     
     
         30 . The cationic carrier unit of any one of  claims 27  to  29 , wherein the vitamin is selected from the group consisting of vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin C, vitamin D2, vitamin D3, vitamin E, vitamin M, vitamin H, and any combination thereof. 
     
     
         31 . The cationic carrier unit of any one of  claim 30 , wherein the vitamin is vitamin B3. 
     
     
         32 . The cationic carrier unit of any one of  claims 1  to  31 , wherein the adjuvant moiety comprises at least about two, at least about three, at least about four, at least about five, at least about six, at least about seven, at least about eight, at least about nine, at least about ten, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, or at least about 20 vitamin B3. 
     
     
         33 . The cationic carrier unit of any one of  claims 1  to  31 , wherein the adjuvant moiety comprises at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, or at least about 40 vitamin B3. 
     
     
         34 . The cationic carrier unit of  claim 32  or  33 , wherein the adjuvant moiety comprises about 10 vitamin B3, about 20 vitamin B3, about 30 vitamin B3, about 40 vitamin B3, or about 50 vitamin B3. 
     
     
         35 . The cationic carrier unit of any one of  claims 1  to  34 , which comprises about a water-soluble biopolymer moiety with about 120 to about 130 PEG units, a cationic carrier moiety comprising a poly-lysine with about 30 to about 40 lysines, and an adjuvant moiety with about 5 to about 10 vitamin B3. 
     
     
         36 . The cationic carrier unit of any one of  claims 1  to  34 , which comprises about a water-soluble biopolymer moiety with about 120 to about 130 PEG units, a cationic carrier moiety comprising a poly-lysine with about 70 to about 90 lysines, e.g., about 80 lysines, and an adjuvant moiety with about 20 to about 40 vitamin B3, e.g., about 30 vitamin B3. 
     
     
         37 . The cationic carrier unit of any one of  claims 1  to  36 , further comprising an anionic payload, which interacts with the cationic carrier unit via an ionic bond. 
     
     
         38 . A micelle comprising the cationic carrier unit of any one of  claims 1  to  37  and an anionic payload, wherein the cationic carrier moiety of the cationic carrier complex and the anionic payload are associated with each other. 
     
     
         39 . The micelle of  claim 38 , wherein the association is a covalent bond. 
     
     
         40 . The micelle of  claim 38 , wherein the association is a non-covalent bond. 
     
     
         41 . The micelle of  claim 40 , wherein the association is an ionic bond. 
     
     
         42 . The micelle of any one of  claims 38  to  41 , wherein the cationic carrier unit of any one of  claims 1  to  36 , wherein the positive charge of the cationic carrier moiety of the cationic carrier unit is sufficient to form a micelle when mixed with an anionic payload in a solution, wherein the overall ionic ratio of the positive charges of the cationic carrier moiety of the cationic carrier unit and the negative charges of the anionic payload in the solution is about 1:1. 
     
     
         43 . The micelle of any one of  claims 38  to  41 , wherein the cationic carrier unit of any one of  claims 1  to  36 , wherein the positive charge of the cationic carrier moiety of the cationic carrier unit is sufficient to form a micelle when mixed with an anionic payload in a solution, wherein the overall ionic ratio of the positive charges of the cationic carrier moiety of the cationic carrier unit and the negative charges of the anionic payload in the solution is between about 1:3 and about 3:1. 
     
     
         44 . The micelle of any one of  claims 38  to  43 , wherein the cationic carrier unit is capable of protecting the anionic payload from degradation by a DNase and/or an RNase. 
     
     
         45 . The micelle of any one of  claims 38  to  44 , wherein the anionic payload is not conjugated to the cationic carrier unit by a covalent bond and/or the anionic payload interacts with the cationic carrier moiety of the cationic carrier unit only via an ionic interaction. 
     
     
         46 . The micelle of any one of  claims 38  to  45 , wherein the half-life of the anionic payload is extended compared to the half-life of a free anionic payload not incorporated into a micelle. 
     
     
         47 . The micelle of any one of  claims 36  to  46 , wherein the positive charges of the cationic carrier moiety of the cationic carrier unit and the negative charges of the anionic payload in the micelle are at an ionic ratio of about 2:1, about 1.9:1, about 1.8:1, about 1.7:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, or about 1:2. 
     
     
         48 . The micelle of any one of  claims 36  to  46 , wherein the positive charges of the cationic carrier moiety of the cationic carrier unit and the negative charges of the anionic payload in the micelle are at an ionic ratio of about 3:1, about 2.9:1, about 2.8:1, about 2.7:1, about 2.6:1, about 2.5:1, about 2.4:1, about 2.3:1, about 2.2:1, about 2.1:1, about 1:2.1, about 1:2.2, about 1:2.3, about 1:2.4, about 1:2.5, about 1:2.6, about 1:2.7, about 1:2.8, about 1:2.9, or about 1:3. 
     
     
         49 . The micelle of  claim 48 , wherein the positive charges of the cationic carrier moiety of the cationic carrier unit and the negative charges of the anionic payload in the micelle are at a charge ratio of 1:1. 
     
     
         50 . The micelle of any one of  claims 38  to  49 , where the diameter of the micelle is between about 1 nm and 100 nm, between about 10 nm and about 100 nm, between about 10 nm and about 90 nm, between about 10 nm and about 80 nm, between about 10 nm and about 70 nm, between about 20 nm and about 100 nm, between about 20 nm and about 90 nm, between about 20 nm and about 80 nm, between about 20 nm and about 70 nm, between about 30 nm and about 100 nm, between about 30 nm and about 90 nm, between about 30 nm and about 80 nm, between about 30 nm and about 70 nm, between about 40 nm and about 100 nm, between about 40 nm and about 90 nm, between about 40 nm and about 80 nm, or between about 40 nm and about 70 nm. 
     
     
         51 . The micelle of any one of  claims 38  to  50 , wherein the anionic payload comprises a nucleic acid. 
     
     
         52 . The micelle of  claim 51 , wherein the nucleic acid comprises mRNA, miRNA, miRNA sponge, tough decoy miRNA, antimir, small RNA, rRNA, siRNA, shRNA, gDNA, cDNA, pDNA, PNA, BNA, antisense oligonucleotide (ASO), aptamer, cyclic dinucleotide, or any combination thereof. 
     
     
         53 . The micelle of any one of  claims 1  to  52 , wherein the nucleic acid comprises at least one nucleoside analog. 
     
     
         54 . The micelle of any one of  claim 53 , wherein the nucleoside analog comprises Locked Nucleic Acid (LNA); 2′-0-alkyl-RNA; 2′-amino-DNA; 2′-fluoro-DNA; arabino nucleic acid (ANA); 2′-fluoro-ANA, hexitol nucleic acid (HNA), intercalating nucleic acid (INA), constrained ethyl nucleoside (cEt), 2′-0-methyl nucleic acid (2′-OMe), 2′-0-methoxyethyl nucleic acid (2′-MOE), or any combination thereof. 
     
     
         55 . The micelle of any one of  claims 51  to  54 , wherein the nucleic acid comprises a nucleotide sequence having 5 to 30 nucleotides in length. 
     
     
         56 . The micelle of  claim 55 , wherein the nucleotide sequence is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotides in length. 
     
     
         57 . The micelle of  claim 55  or  56 , wherein the nucleotide sequence has a backbone, which comprises a phosphodiester linkage, a phosphotriester linkage, a methylphosphonate linkage, a phosphoramidate linkage, a phosphorothioate linkage, and combinations thereof. 
     
     
         58 . The micelle of any one of  claims 38  to  57 , wherein the cationic carrier unit further comprises a targeting moiety, which is linked to the water soluble polymer optionally via a linker. 
     
     
         59 . The micelle of  claim 58 , wherein the targeting moiety is capable of targeting a tissue. 
     
     
         60 . The micelle of  claim 59  wherein the tissue is liver, brain, kidney, lung, ovary, pancreas, thyroid, breast, stomach, or any combination thereof. 
     
     
         61 . The micelle of  claim 59 , wherein the tissue is cancer tissue. 
     
     
         62 . The micelle of  claim 59 , wherein the tissue is liver. 
     
     
         63 . The micelle of  claim 62 , wherein the targeting moiety comprises cholesterol. 
     
     
         64 . The micelle of  claim 59 , wherein the tissue is pancreas. 
     
     
         65 . The micelle of  claim 59 , wherein the targeting moiety comprises a ligand targeting an integrin. 
     
     
         66 . The micelle of  claim 59 , wherein the targeting moiety targets the central nervous system. 
     
     
         67 . The micelle of  claim 66 , wherein the targeting moiety is capable of being transported by large neutral amino acid transporter 1 (LAT1). 
     
     
         68 . The micelle of  claim 67 , wherein the targeting moiety is an amino acid. 
     
     
         69 . The micelle of  claim 68 , wherein the targeting moiety comprises a branched-chain or aromatic amino acid. 
     
     
         70 . The micelle of  claim 68 , wherein the amino acid is valine, leucine, and/or isoleucine. 
     
     
         71 . The micelle of  claim 68 , wherein the amino acid is tryptophan and/or tyrosine. 
     
     
         72 . A composition comprising the cationic carrier unit of any one of  claims 1  to  37  and a negatively charged molecule. 
     
     
         73 . A pharmaceutical composition comprising the cationic carrier unit of any one of  claims 1  to  37 , the composition of  claim 72 , or the micelle of any one of  claims 38  to  71 , and a pharmaceutically acceptable carrier. 
     
     
         74 . A method of preparing the cationic carrier unit of any one of  claims 1  to  37  comprising synthesizing the cationic carrier unit. 
     
     
         75 . The method of preparing the micelle of any one of  claims 38  to  71 , comprising mixing the cationic carrier unit with the negatively charged molecule at an ionic ratio of 1:1 in solution. 
     
     
         76 . The method of preparing the micelle of any one of  claims 38  to  71 , comprising mixing the cationic carrier unit with the negatively charged molecule at an ionic ratio between about 1:3 and about 3:1 in solution. 
     
     
         77 . The method of  claim 76 , further comprising purifying the micelle. 
     
     
         78 . A method of treating a disease or condition in a subject in need thereof comprising administering the micelle of any one of  claims 38  to  71  to the subject. 
     
     
         79 . The method of  claim 78 , wherein the anionic payload in the core of the micelle exhibits a longer half-life than a corresponding anionic payload not integrated into a micelle. 
     
     
         80 . The method of  claim 78  or  79 , wherein the subject is a mammal. 
     
     
         81 . A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a micelle of any one of  claims 38  to  71  to the subject. 
     
     
         82 . The method of  claim 81 , wherein the cancer is glioma, breast cancer, pancreatic cancer, liver cancer, skin cancer, or cervical cancer. 
     
     
         83 . The method of  claim 82 , wherein the pancreatic cancer is pancreatic adenocarcinoma. 
     
     
         84 . A method to reduce inflammation in a subject suffering from a neurodegenerative disease comprising administering a therapeutically effective amount of a micelle of any one of  claims 38  to  71  to the subject. 
     
     
         85 . A method to recover and/or induce neurogenesis in a subject suffering from a neurodegenerative disease comprising administering a therapeutically effective amount of a micelle of any one of  claims 38  to  71  to the subject. 
     
     
         86 . A method to improve cognitive function in a subject suffering from a neurodegenerative disease comprising administering a therapeutically effective amount of a micelle of any one of  claims 38  to  71  to the subject. 
     
     
         87 . The method of any one of  claims 84  to  86 , wherein the neurodegenerative disease is Alzheimer's disease. 
     
     
         88 . A method to reduce amyloid plaque burden in a subject suffering from Alzheimer's disease comprising administering a therapeutically effective amount of a micelle of any one of  claims 38  to  71  to the subject. 
     
     
         89 . The method of any one of  claims 84  to  88 , wherein the micelle comprises a cationic carrier unit targeting LAT1 and a payload comprising an antisense oligonucleotide of SEQ ID NO: 18, or a fragment, variant, or derivative thereof. 
     
     
         90 . The method of  claim 89 , wherein the fragment comprises 14, 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides of SEQ ID NO: 18. 
     
     
         91 . The method of  claim 89 , wherein the variant has at least 70% sequence identity to SEQ ID NO: 18. 
     
     
         92 . The method of  claim 89 , wherein the derivative comprises at least one sugar modification and/or at least one backbone modification.