Sacrificial cell-permeable complexes for nucleic acid delivery to the lung

Abstract

Provided herein are, inter alia, complexes, compositions, and methods for the delivery of therapeutic, diagnostic, and imaging agents, including nucleic acids, to cells. The complexes, compositions, and methods can facilitate the complexation, protection, delivery, and release of oligonucleotides and polyanionic cargos to lung cells and tissues both in vitro and in vivo.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 800,406, filed on February 1, 2019, which is hereby incorporated by reference in its entirety for all purposes.

[0002] Statement regarding rights in inventions made under government sponsorship in the course of research This invention was made with government support under Contract No. DE - SC0018168 awarded by the U.S. Department of Energy, Contract No. CHE - 1607092 awarded by the National Science Foundation of the United States, and Contract Nos. CA031841 and CA031845 awarded by the National Institutes of Health of the United States. The government has certain rights in this invention.

Background Art

[0003] There is a need for new materials and strategies that enable or facilitate the delivery of therapeutic agents, diagnostic probes, and / or research tools across the plasma membrane of cells and other biological barriers, as required for a wide range of clinical, diagnostic, and / or research applications. Delivery of such cargo, e.g., nucleic acids, has significant clinical potential in relation to vaccination strategies against infectious diseases, cancer immunotherapy, protein therapy, and gene editing. Solutions to these and other problems in the art are provided herein.

Summary of the Invention

[0004] In a first aspect, a cell - permeable complex is provided that includes a nucleic acid non - covalently bound to a cationic amphiphilic polymer, the cationic amphiphilic polymer including a pH - sensitive sacrificial domain and a lipophilic polymer domain, and the cationic amphiphilic polymer having the following formula:

Chemical formula

[0005] In Formulas (XII) and (XIII), R 1A is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0006] R 2A is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0007] L 1and L 2 is, independently, a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0008] LP 1 and LP 2 is, independently, a lipophilic polymer domain.

[0009] X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R 6 )-C(R 7 )(R 8 ).

[0010] X 2 is -O- or -S-.

[0011] R 1 、R 2 、R 5 、R 6 、R 7 、and R 8 is, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0012] L 4is a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, a substituted or unsubstituted alkylene, or a substituted or unsubstituted heteroalkylene.

[0013] R 40 、R 41 、and R 42 are independently hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl.

[0014] Z is -S-, -S + R 13 -, -NR 13- 、or -N + (R 13 )(H)-.

[0015] R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0016] n1 is an integer from 0 to 50.

[0017] z1 and z3 are independently integers from 0 to 100, and at least one of z1 or z3 is not 0.

[0018] z4 is an integer from 1 to 100.

[0019] z2 is an integer from 2 to 100, and z5 is an integer from 1 to 10.

[0020] In another aspect, there is provided a cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer, the cationic amphiphilic polymer comprising a pH-sensitive sacrificial domain and a lipophilic polymer domain, and the cationic amphiphilic polymer has the following formula: [Chemical formula] having the same.

[0021] In Formulas (XIV) and (XV), R 1A is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0022] R 2Ais hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0023] L 1 and L 2 are independently a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0024] LP 1 and LP 2 are independently lipophilic polymer domains.

[0025] X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R6 )-C(R 7 )(R 8 )-.

[0026] X 2 is -O- or -S-.

[0027] R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0028] L 4 is a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0029] R 40 and R 41 are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0030] Z is -S-, -S + R 13 -, -NR 13- , or -N + (R 13 )(H)-.

[0031] R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0032] n1 is an integer from 0 to 50.

[0033] z1 and z3 are independently integers from 0 to 100, and at least one of z1 or z3 is not 0.

[0034] z4 is an integer from 1 to 100.

[0035] z2 is an integer from 2 to 100, and z5 is an integer from 1 to 10.

[0036] In one aspect, a complex is provided that includes a nucleic acid non-covalently bound to a cationic amphiphilic polymer, and the cationic amphiphilic polymer has the following formula:

Chemical formula

[0037] R 1A is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0038] R 2A is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, independently, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, independently, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0039] L 1 and L 2 are independently a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene,

[0040] LP 1 and LP 2 are, independently, lipophilic polymer domains,

[0041] X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R 6 )-C(R 7 )(R 8 )-,

[0042] X 2 is -O- or -S-,

[0043] R 1 、R 2 、R 5 、R 6 、R 7 、and R 8 are, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0044] L 4 are, independently, a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene,

[0045] R 40 、R 41 、and R 42 are, independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,

[0046] Z is -S-, -S + R 13 -, -NR 13- or -N + (R 13 )(H)-, and

[0047] R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0048] n1 is an integer from 0 to 50,

[0049] z1 and z3 are independently integers from 0 to 100, and at least one of z1 or z3 is not 0,

[0050] z2 is an integer from 2 to 100,

[0051] z4 is an integer from 1 to 100,

[0052] z5 is an integer from 1 to 10.

[0053] In one aspect, a cell-permeable complex is provided that includes a nucleic acid non-covalently bound to a cationic amphiphilic polymer, and the cationic amphiphilic polymer has the following formula,

Chemical formula

[0054] R 1Ais, independently, hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and

[0055] R 2A is, independently, hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, independently, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, independently, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0056] L 1 and L 2 are, independently, a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene,

[0057] LP 1 and LP 2 are, independently, a lipophilic polymer domain, X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R 6 )-C(R 7 )(R 8 ),

[0058] X 2 is -O- or -S-,

[0059] R 1 、R 2 、R 5 、R 6 、R 7 、and R 8is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0060] L 4 is independently a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene,

[0061] R 40 R 41 and R 42 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,

[0062] Z is -S-, -S + R 13 -, -NR 13- or -N + (R 13 )(H)-,

[0063] R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0064] n1 is an integer from 0 to 50,

[0065] z1 and z3 are, independently, integers from 0 to 100, at least one of z1 or z3 is not 0, z2 is an integer from 2 to 100, z4 is an integer from 1 to 100, and z5 is an integer from 1 to 10.

[0066] In one aspect, a cell-permeable complex is provided that includes a nucleic acid non-covalently bound to a first cationic amphiphilic polymer and a second cationic amphiphilic polymer, the first cationic amphiphilic polymer having the following formula:

Chemical formula

[0067] R 1A is, independently, hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0068] R 2A is, independently, hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, Independently, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, Independently, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0069] L 1 and L 2 are independently a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene,

[0070] LP 1 and LP 2 are independently a lipophilic polymer domain,

[0071] X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 ), or -O-C(R 5 )(R 6 )-C(R 7 )(R8 )- and

[0072] X 2 is -O- or -S-,

[0073] R 1 R, 2 R, 5 R, 6 R, 7 and R 8 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0074] L 4 are independently a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene,

[0075] R 40 R, 41 and R 42 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,

[0076] Z is -S-, -S + R 13 -, -NR 13- or -N + (R 13 )(H)-,

[0077] R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl,

[0078] n1 is an integer from 0 to 50,

[0079] z1 and z3 are independently integers from 0 to 100, and at least one of z1 or z3 is not 0,

[0080] z2 is an integer from 2 to 100,

[0081] z4 is an integer from 1 to 100,

[0082] z5 is an integer from 1 to 10, and the first cationic amphiphilic polymer and the second amphiphilic polymer are different.

[0083] In another aspect, a nanoparticle composition is provided that includes a plurality of cell-permeable complexes as provided herein including embodiments thereof.

[0084] In another aspect, a pharmaceutical composition is provided that includes a cell-permeable complex as provided herein including embodiments thereof.

[0085] In another aspect, a method of transfecting a nucleic acid into a cell is provided. The method includes contacting the cell with a cell-permeable complex as provided herein including embodiments thereof.

[0086] In another aspect, a method of delivering a nucleic acid to the lung of a subject in need thereof is provided, the method including administering to the subject a cell-permeable complex as provided herein including embodiments thereof.

[0087] In another aspect, a method of treating a subject in need of treatment for a lung disease is provided. The method includes administering a therapeutically effective amount of a cell-permeable complex as provided herein, including embodiments thereof.

[0088] In another aspect, a method of delivering a nucleic acid to a plurality of tissues of a subject in need thereof is provided. The method includes administering to the subject a first cell-permeable complex and a second cell-permeable complex, wherein the first cell-permeable complex is a cell-permeable complex as provided herein, including embodiments thereof, and the first cell-permeable complex and the second cell-permeable complex are chemically different.

[0089] In another aspect, a method of delivering a nucleic acid to a plurality of tissues of a subject in need thereof is provided. The method includes administering to the subject a first amphiphilic polymer and a second amphiphilic polymer, wherein the first amphiphilic polymer is an amphiphilic polymer as provided herein, including embodiments thereof, and the first amphiphilic polymer and the second amphiphilic polymer are chemically different.

[0090] In one aspect, a method of transfecting a reticulocyte with a nucleic acid is provided, the method including contacting the cell with a cell-permeable complex as described herein, including embodiments thereof.

[0091] In one aspect, a method of transfecting a hematopoietic stem cell with a nucleic acid is provided, the method including contacting the cell with a cell-permeable complex as described herein, including embodiments thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0092]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Figure 3A

Figure 3B

Figure 3C

Figure 3D

Figure 3E

Figure 3F

Figure 4A

Figure 4B

Figure 5A

Figure 5B

Figure 6A

Figure 6B

Figure 7-1

Figure 7-2

Figure 7-3

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13-1

Figure 13-2

Figure 13-3

Figure 13-4

Figure 14-1

Figure 14-2

Figure 15-1

Figure 15-2

Figure 16

Figure 17A

Figure 17B

Figure 17C

Figure 18A

Figure 18B

Figure 18C

Figure 19

Figure 20A

Figure 20B

Figure 21A

Figure 21B

Figure 21C

Figure 21D

Figure 22

Mode for Carrying Out the Invention

[0093] Although various embodiments and aspects of the present disclosure are shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Those skilled in the art will envision many variations, modifications, and substitutions without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be used in practicing the present disclosure.

[0094] Unless otherwise indicated from the context, it is clearly intended that the various features of the present disclosure described herein can be used in any combination. Further, the present disclosure also contemplates that in some embodiments, any feature or combination of features described herein can be excluded or omitted. By way of illustration, if the present specification describes that a complex has components A, B, and C, it is specifically intended that any one of A, B, or C, or any combination thereof, can be omitted and excluded singly or in any combination.

[0095] It should be noted that as used in this specification and the appended claims, unless otherwise clearly indicated from the context, the singular forms "a", "an", and "the" include plural referents. Thus, for example, reference to "cancer cells" includes a plurality of cancer cells. In other examples, reference to "a nucleic acid" or "nucleic acid" includes a plurality of nucleic acid molecules, i.e., a plurality of nucleic acids.

[0096] The term "about" means a range of values that includes a particular value and would be considered by one of ordinary skill in the art to be reasonably similar to the particular value. In embodiments, about means within one standard deviation of the measurement value generally accepted in the art. In embodiments, about means a range extending from ±10% of the particular value. In embodiments, about means the specified value.

[0097] Also, as used herein, "and / or" refers to any and all possible combinations of one or more of the associated listed items, including combinations but excluding combinations when interpreted in the alternative sense of "or".

[0098] As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements but do not exclude other elements. As used herein, the transitional phrase "consisting essentially of" (and grammatical variations) should be interpreted to include the recited materials or steps and those that do not materially affect the "basic and novel characteristics" of the recited embodiments. Thus, the term "consisting essentially of" should not be interpreted as equivalent to "comprising" as used herein. "Consisting of" shall mean excluding other components in excess of trace elements and substantial method steps for administering the compositions disclosed herein. The aspects defined by each of these transitional terms are within the scope of this disclosure.

[0099] Definitions The abbreviations used herein have their conventional meanings within the chemical and biological arts. The chemical structures and chemical formulas described herein are constructed in accordance with standard rules of chemical valency known in the art.

[0100] When substituents are specified by their conventional chemical formulas written left to right, they equally encompass chemically identical substituents that would result from writing the structure right to left; for example, -CH2O- is equivalent to -OCH2-.

[0101] As used herein, the terms "oligomer" and "polymer" refer to compounds having multiple repeating subunits (e.g., polymerized monomers). The term "co-oligomer" or "copolymer" refers to an oligomer or polymer that contains two or more different residues (monomer units or monomers, used interchangeably herein). The number of monomers in an oligomer is generally less than the number of monomers in a polymer. Thus, in some examples, an oligomer can have a length of 1 to about 10 monomers, 1 to about 20 monomers, 1 to about 30 monomers, 1 to about 40 monomers, 1 to about 50 monomers, 1 to about 100 monomers, 1 to about 150 monomers, 1 to about 200 monomers, 1 to about 250 monomers, 1 to about 300 monomers, 1 to about 350 monomers, 1 to about 400 monomers, 1 to about 450 monomers, or 1 to about 500 monomers. In some examples, an oligomer can have a length of less than about 500 monomers, less than about 450 monomers, less than about 400 monomers, less than about 350 monomers, less than about 300 monomers, less than about 250 monomers, less than about 200 monomers, less than about 150 monomers, less than about 100 monomers, less than about 50 monomers, less than about 40 monomers, less than about 30 monomers, less than about 20 monomers, or less than about 10 monomers. In the context of a polymer, the number of monomers in the polymer is generally more than the number of monomers in an oligomer. Thus, in some examples, a polymer can have a length of about 500 to about 1000 monomers, about 500 to about 2000 monomers, about 500 to about 3000 monomers, about 500 to about 4000 monomers, about 500 to about 5000 monomers, about 500 to about 6000 monomers, about 500 to about 7000 monomers, about 500 to about 8000 monomers, about 500 to about 9000 monomers, about 500 to about 10000 monomers, or more than 10000 monomers.

[0102] The term "coincidence monomer" is used according to its meaning in the field of polymer chemistry and refers to a compound that can chemically covalently bond to other monomer molecules (such as the same or different other polymerizable monomers) to form a polymer.

[0103] The term "block copolymer" is used according to its ordinary meaning and refers to two or more portions (e.g., blocks) of polymerized monomers linked by covalent bonds. In embodiments, the block copolymer is a repeating pattern of the polymer. In embodiments, the block copolymer includes two or more monomers in a periodic (e.g., repeating pattern) arrangement. For example, a diblock copolymer has the formula: -B-B-B-B-B-B-A-A-A-A-A-, where "B" is the first subunit and "A" is the second subunit, and they are covalently bonded together. Thus, a triblock copolymer is a copolymer having three different blocks, two of which may be the same (e.g., -A-A-A-A-A-B-B-B-B-B-B-A-A-A-A-A-) or all three may be different (e.g., -A-A-A-A-A-B-B-B-B-B-B-C-C-C-C-C-), where "A" is the first subunit, "B" is the second subunit, and "C" is the third subunit, and they are covalently bonded together.

[0104] The term "alkyl", by itself or as part of another substituent, unless otherwise specified, means a straight-chain (i.e., unbranched) or branched carbon chain (or carbon), or a combination thereof, which can be fully saturated, monounsaturated or polyunsaturated, and can include monovalent, divalent, and polyvalent radicals. Alkyl can include a specified number of carbon atoms (e.g., C1~C 10(wherein "C1-C10" means from 1 to 10 carbons). Alkyl is an acyclic chain. Examples of saturated hydrocarbon functional groups include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, and homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, n-octyl, etc., but are not limited thereto. An unsaturated alkyl group has one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers, but are not limited thereto. Alkoxy is alkyl bonded to the remainder of the molecule via an oxygen linker (-O-). The alkyl portion can be an alkenyl portion. The alkyl portion can be an alkynyl portion. The alkyl portion can be fully saturated. Alkenyl can include more than one double bond and / or one or more triple bonds in addition to one or more double bonds. Alkynyl can include two or more triple bonds and / or one or more double bonds in addition to one or more triple bonds.

[0105] The term "alkylene", by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from alkyl, exemplified by -CH2CH2CH2CH2-, but not limited thereto. Generally, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, and groups having 10 or fewer carbon atoms are preferred herein. "Lower alkyl" or "lower alkylene" generally refers to a short-chain alkyl or alkylene group having 8 or fewer carbon atoms. The term "alkenylene", by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from alkene.

[0106] The term "heteroalkyl", by itself or in combination with another term, unless otherwise specified, means a stable straight or branched chain, or combinations thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), where the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. The heteroatom (e.g., N, S, Si, or P) can be located at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an acyclic chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. For example, up to two or three heteroatoms can be consecutive, such as in -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety can contain one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety can contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety can contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety can contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety can contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety can contain up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl", by itself or in combination with another term, unless otherwise specified, means a heteroalkyl containing at least one double bond. Heteroalkenyl can optionally contain, in addition to one or more double bonds, two or more double bonds and / or one or more triple bonds.The term "heteroalkynyl", by itself or in combination with another term, unless otherwise specified, means a heteroalkyl containing at least one triple bond. Heteroalkynyl may optionally contain two or more triple bonds and / or one or more double bonds in addition to one or more triple bonds.

[0107] Similarly, the term "heteroalkylene", by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from a heteroalkyl, exemplified by, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom may also occupy either or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, in the case of alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As noted above, heteroalkyl groups used herein include groups such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and / or -SO2R' that are attached to the remainder of the molecule through a heteroatom. When a specific heteroalkyl group, such as -NR'R'', etc., is listed after "heteroalkyl" is enumerated, it will be understood that the terms heteroalkyl and -NR'R'' are neither redundant nor mutually exclusive. Rather, the specific heteroalkyl group is listed for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, such as -NR'R'', etc.

[0108] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, unless otherwise specified, each mean the cyclic versions of "alkyl" and "heteroalkyl", respectively. Cycloalkyl and heteroalkyl are not aromatic. In addition, in the case of heterocycloalkyl, the heteroatom can occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, etc. "Cycloalkylene" and "heterocycloalkylene" mean, alone or as part of another substituent, divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively.

[0109] The term "halo" or "halogen", by itself or as part of another substituent, unless otherwise specified, means a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0110] Unless otherwise specified, the term "acyl" means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0111] Unless otherwise specified, the term "aryl" means a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring, or multiple rings fused together (i.e., fused-ring aryl) or covalently bonded (preferably 1 to 3 rings). Fused-ring aryl refers to multiple rings fused together where at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom such as N, O, or S, and the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together where at least one of the fused rings is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together where one ring has 5 members, the other ring has 6 members, and at least one of the rings is a heteroaryl ring. Similarly, 6,6-fused-ring heteroarylene refers to two rings fused together where one ring has 6 members, the other ring has 6 members, and at least one of the rings is a heteroaryl ring. Also, 6,5-fused-ring heteroarylene refers to two rings fused together where one ring has 6 members, the other ring has 5 members, and at least one of the rings is a heteroaryl ring. A heteroaryl group can be bonded to the rest of the molecule through a carbon atom or a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above aryl ring systems and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene" each mean a divalent radical derived from aryl and heteroaryl, respectively, alone or as part of another substituent. The heteroaryl group substituent may be -O-bonded to the ring heteroatom nitrogen.

[0112] For the sake of brevity, the term "aryl", when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl rings and heteroaryl rings as defined above. Thus, the term "arylalkyl" includes radicals in which an aryl group is bonded to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), and also includes alkyl groups in which a carbon atom (e.g., a methylene group) is replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.).

[0113] Symbol [Number] indicates the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0114] As used herein, the term "oxo" means an oxygen double-bonded to a carbon atom.

[0115] As used herein, the term "alkylsulfonyl" means a moiety having the formula -S(O2)-R', where R' is an alkyl group as defined above. R' may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0116] The term "alkylarylene" as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the following formula: [Chemistry]

[0117] The alkyl arylene moiety may be substituted with an alkylene moiety or an arylene linker (e.g., with 2, 3, 4, or 6 carbons), halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl. In an embodiment, the alkyl arylene is unsubstituted.

[0118] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for various types of functional groups are provided below.

[0119] Substituents for alkyl and heteroalkyl radicals (often including those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are in numbers in the range of 0 to (2m'+1), where m' is the total number of carbon atoms in such a radical, -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR’C(O)-OR’’, -NR’OR’’, or one or more of various groups selected from, but not limited to, these. R, R’, R’’, R’’’, and R’’’’ are each preferably independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy group, or arylalkyl group. When the compounds described herein contain more than one R group, for example, when more than one of these groups is present, the R groups are each independently selected as each R’, R’’, R’’, and R’’’’ group. When R’ and R’’ are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR’R’’ includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above considerations regarding substituents, one of ordinary skill in the art will understand that the term “alkyl” is intended to include groups containing carbon atoms bonded to groups other than hydrogen groups such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0120] Similar to the substituents described for alkyl radicals, the substituents for aryl and heteroaryl groups vary and, for example, in numbers ranging from 0 to the total number of open valences on the aromatic ring system, are -OR’, -NR’R’’, -SR’, -halogen, -SiR’R’’R’’’, -OC(O)R’, -C(O)R’, -CO2R’, -CONR’R’’, -OC(O)NR’R’’, -NR’’C(O)R’, -NR’-C(O)NR’’R’’’, -NR’’C(O)2R’, -NR-C(NR’R’’R’’’)=NR’’’’, -NR-C(NR’R’’)=NR’’’, -S(O)R’, -S(O)2R’, -S(O)2NR’R’’, -NRSO2R’, -NR’NR’’R’’’, -ONR’R’’, -NR’C(O)NR’’NR’’’R’’’’, -CN, -NO2, -R’, -N3, -CH(Ph)2, fluoro (C1-C4) alkoxy, and fluoro (C1-C4) alkyl, -NR’SO2R’’, -NR’C(O)R’’, -NR’C(O)-OR’’, -NROR’’, and are selected from the group consisting of, wherein R’, R’’, R’’’, and R’’’’ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds described herein contain two or more R groups, for example, each of the R groups is independently selected as each R’, R’’, R’’’, and R’’’’ group when there are two or more groups present.

[0121] Substituents of a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be shown as substituents on the ring (commonly referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (in accordance with the rules of chemical valence), and in the case of a fused ring or spirocyclic ring, a substituent shown as being associated with one member of the fused ring or spirocyclic ring (a floating substituent on a single ring) can be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on a polycycle). When the substituent is attached to the ring rather than a specific atom (a floating substituent) and the subscript of the substituent is an integer greater than 1, the multiple substituents can be on the same atom, the same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent can optionally be different. When the point of attachment of the ring to the remainder of the molecule is not limited to a single atom (a floating substituent), the point of attachment can be any atom of that ring, and in the case of a fused ring or spirocyclic ring, can be any atom of either the fused ring or spirocyclic ring in accordance with the rules of chemical valence. When the ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is shown together with another floating substituent (including, but not limited to, the point of attachment to the remainder of the molecule), the floating substituent can be attached to the heteroatom. When it is shown that a ring heteroatom is attached to one or more hydrogens in a structure or formula having a floating substituent (e.g., a ring nitrogen having two bonds to ring atoms and a third bond to a hydrogen), it will be understood that when the heteroatom is attached to the floating substituent, the substituent replaces the hydrogen while following the rules of chemical valence.

[0122] Two or more substituents may optionally combine to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found to be attached to the cyclic backbone structure. In embodiments, the ring-forming substituents are attached to adjacent members of the backbone structure. For example, two ring-forming substituents attached to adjacent members of a cyclic backbone structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0123] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be of the formula -T-C(O)-(CRR’) q -U- (wherein T and U are independently -NR-, -O-, -CRR’-, or a single bond, and q is an integer from 0 to 3) to form a ring. Alternatively, two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be of the formula -A-(CH2) r -B- (wherein A and B are independently -CRR’-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR’-, or a single bond, and r is an integer from 1 to 4) and may be substituted with such substituents. One of the single bonds of the newly formed ring may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of an aryl ring or heteroaryl ring are of the formula -(CRR’) s -X’-(C’’R’’R’’’) d- can be optionally replaced by substituents, wherein s and d are, independently, integers from 0 to 3, and X’ is -O-, -NR’-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR’-. The substituents R, R’, R’’, and R’’’ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0124] As used herein, the terms “heteroatom” or “ring heteroatom” are intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0125] As used herein, “substituent” means a group selected from the following moieties. (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), which is substituted with at least one substituent selected from the following, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl. (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, Unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (ii) Alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 aryl, C 10Aryl, or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, which is substituted with at least one substituent selected from the following. (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, Unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), provided that: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl, C 10Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, substituted with at least one substituent selected from aryl (e.g., phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0126] As used herein, "size-limited substituent" or "size-limited substituent group" means a group selected from all of the substituents described above for "substituent", and each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C 20 alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C6-C 10 aryl, and each substituted or unsubstituted heteroaryl is substituted or unsubstituted 5- to 10-membered heteroaryl.

[0127] As used herein, "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent", and each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3- to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C6-C 10Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0128] In some embodiments, each substituent described for the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described for the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limiting substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0129] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl can be a substituted or unsubstituted C1-C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl. In embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C 20is an alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0130] In an embodiment, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In an embodiment, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In an embodiment, the compound is a chemical species described herein.

[0131] In an embodiment, the substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In an embodiment, the substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0132] In embodiments, the substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, and when the substituted moiety is substituted with a plurality of substituents, each substituent may optionally be different. In embodiments, when the substituted moiety is substituted with a plurality of substituents, each substituent is different.

[0133] In embodiments, the substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limiting substituent, and when the substituted moiety is substituted with a plurality of substituents, each size-limiting substituent may optionally be different. In embodiments, when the substituted moiety is substituted with a plurality of size-limiting substituents, each size-limiting substituent is different.

[0134] In embodiments, the substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, and when the substituted moiety is substituted with a plurality of lower substituents, each lower substituent may optionally be different. In embodiments, when the substituted moiety is substituted with a plurality of lower substituents, each lower substituent is different.

[0135] In embodiments, the substituent moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituent moiety is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, when the substituent moiety is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent is different.

[0136] Certain compounds of the present disclosure have an asymmetric carbon atom (optical center or chiral center) or a double bond, and enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers that can be defined as (R)- or (S)- from the perspective of absolute stereochemistry or (D)- or (L)- with respect to amino acids are included within the scope of the present disclosure. The present disclosure does not include compounds that are known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E geometric isomers and Z geometric isomers.

[0137] As used herein, the term "isomer" refers to compounds that have the same number and types of atoms and thus the same molecular weight, but differ with respect to the structural or spatial arrangement of the atoms.

[0138] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another.

[0139] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and that all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0140] Unless otherwise specified, the structures shown herein are also intended to include all stereochemical forms of that structure, i.e., the R and S configurations for each asymmetric center. Accordingly, single stereoisomers of the compounds, as well as mixtures of enantiomers and diastereomers, are within the scope of the present disclosure.

[0141] Unless otherwise specified, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, substitution of hydrogen with deuterium or tritium, or substitution of carbon with 13 C or 14 C enriched carbon, compounds having the present structure are within the scope of the present disclosure.

[0142] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes in one or more of the atoms that make up such compounds. For example, the compounds may be radioactively labeled with radioactive isotopes such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variants of the compounds of the present disclosure are included within the scope of the present disclosure, whether radioactive or not.

[0143] It should be noted that through this application, each amino acid position containing alternatives, e.g., more than one possible amino acid, is described in the Markush group. Each member of the Markush group should be considered separately and thus is specifically contemplated to include another embodiment and should not be read as a single unit for the Markush group.

[0144] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to an association resulting from an intermolecular or intramolecular association of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, conjugates between a first bioconjugate reactive group (e.g., -NH2, -COOH, -N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amino acid containing an amine side chain, or carboxylate) provided herein can be direct, e.g., by a covalent bond or linker (e.g., a first linker to a second linker), or indirect, e.g., by non-covalent interactions (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions, etc.). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups), including but not limited to nucleophilic substitution (e.g., reaction of amines and alcohols with acyl halides, active esters), electrophilic substitution (e.g., enamine reactions), and addition to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reactions, Diels-Alder additions). These and other useful reactions are discussed, for example, in March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985, Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996, and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D.C., 1982.In embodiments, the first bioconjugate reactive group (e.g., a maleimide moiety) is covalently bonded to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently bonded to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently bonded to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., an -N-hydroxysuccinimide moiety) is covalently bonded to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., a maleimide moiety) is covalently bonded to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., a -sulfonato-N-hydroxysuccinimide moiety) is covalently bonded to the second bioconjugate reactive group (e.g., an amine).

[0145] Useful bioconjugate reactive moieties for use in the bioconjugate chemistry of this specification include, for example, the following. (a) Carboxyl groups and various derivatives thereof, including but not limited to N-hydroxysuccinimide esters, N-hydroxybenzotriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl, and aromatic esters; (b) Hydroxyl groups that can be converted to esters, ethers, aldehydes, etc.; (c) Haloalkyl groups where the halide can be subsequently substituted with a nucleophilic group such as, for example, an amine, carboxylate anion, thiolate anion, carbanion, or alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) Dienophile groups that can participate in a Diels-Alder reaction, such as, for example, maleimide or maleimide groups; (e) An aldehyde or ketone group such that subsequent derivatization is possible, for example, via formation of a carbonyl derivative such as an imine, hydrazone, semicarbazone, or oxime, or via a mechanism such as Grignard addition or alkyllithium addition; (f) A sulfonyl halide group for subsequent reaction with an amine to form, for example, a sulfonamide; (g) A thiol group that can be converted to a disulfide, reacted with an acyl halide, bound to a metal such as gold, or reacted with a maleimide; (h) An amine or sulfhydryl group (e.g., present in cysteine) that can be, for example, acylated, alkylated, or oxidized; (i) An alkene that can undergo, for example, a cycloaddition, acylation, Michael addition, etc.; (j) An epoxide that can react with, for example, an amine and a hydroxyl compound; (k) Phosphoramidites and other standard functional groups useful for nucleic acid synthesis; (l) A metal - silicon oxide bond; (m) A metal bound to a reactive phosphorus group (e.g., phosphine) to form, for example, a phosphodiester bond; (n) An azide bound to an alkyne using copper - catalyzed cycloaddition click chemistry; and (o) A biotin conjugate can react with avidin or streptavidin to form an avidin - biotin complex or a streptavidin - biotin complex.

[0146] The bioconjugate reactive groups can be selected such that they do not participate in or interfere with the chemical stability of the conjugates described herein. Alternatively, the reactive functional groups can be protected by the presence of a protecting group from participating in the cross - linking reaction. In embodiments, the bioconjugate includes a molecular entity obtained from the reaction of an unsaturated bond such as maleimide and a sulfhydryl group.

[0147] "Analog", "analogue", or "derivative" are used according to their plain and ordinary meaning in Chemistry and Biology and refer to a compound that is structurally similar to another compound (i.e., the so-called "reference" compound), but has a different composition, e.g., substitution of one atom by an atom of a different element, or the presence of a particular functional group, or substitution of one functional group by another functional group, or a different absolute stereochemistry at one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent to the reference compound in terms of function and indication, but is different in terms of structure or origin.

[0148] As used herein, the terms "a" or "an" mean one or more. In addition, as used herein, the phrase "substituted with a[n]" means that a particular group can be substituted with one or more of any or all of the designated substituents. For example, when a group such as an alkyl group or a heteroaryl group is "substituted with unsubstituted C1-C 20 alkyl or unsubstituted 2- to 20-membered heteroalkyl", the group can contain one or more unsubstituted C1-C 20 alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl.

[0149] Furthermore, when a moiety is substituted with an R substituent, the group can be referred to as "R-substituted". When a moiety is substituted with R, the moiety is substituted with at least one R substituent, and each R substituent can optionally be different. When a particular R group is present in the description of a chemical species (such as formula (I)), Roman alphabet symbols can be used to distinguish each representation of that particular R group. For example, when multiple R 13 substituents are present, each R 13 substituent can be distinguished as R 13A , R 13B , R 13C , R 13D , etc., and R 13A , R 13B , R 13C , R 13D , etc. can each be distinguished from R 13Defined within the scope of the definition and arbitrarily different.

[0150] Furthermore, when a moiety is substituted with an R substituent, the group may be referred to as "R substitution". When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is arbitrarily different. When a specific R group is present in the description of a chemical species (such as formula (I)), Roman alphabet symbols may be used to distinguish each representation of the specific R group. For example, when multiple R 201 substituents are present, each R 201 substituent is 201A R 201B R 201C R 201D etc., and each of R 201A R 201B R 201C R 201D etc. is defined within the scope of the definition of R 201 and arbitrarily different.

[0151] The term "nucleophilic moiety" refers to a chemical species or functional group that can donate one or more electrons (e.g., two) to an electrophilic reagent. In embodiments, the nucleophilic moiety refers to a chemical species or functional group that can donate electrons to an electrophilic reagent to form a bond in a chemical reaction.

[0152] The term "electrophilic moiety" refers to a chemical species or functional group that can accept one or more electrons (e.g., two). In embodiments, the electrophilic moiety refers to a chemical species or functional group that has an empty orbital and can thus accept electrons to form a bond in a chemical reaction.

[0153] The term "oligoglycol moiety" refers to a chemical component having the general formula: R 400 -O-(CH2-CH2-O)n 300 -

Number

[0154] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art. Thus, when a group can be substituted with one or more of several substituents, such substitution is made so as to conform to the principles of chemical bonding and not be inherently unstable and / or to result in compounds known to those skilled in the art to be likely unstable under ambient conditions such as aqueous, neutral, and some known physiological conditions. For example, heterocycloalkyl or heteroaryl is bonded to the remainder of the molecule through a ring heteroatom in accordance with the principles of chemical bonding known to those skilled in the art, thereby avoiding compounds that are inherently unstable.

[0155] The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds, either neat or in a suitable inert solvent, with a sufficient amount of the desired base. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, and the like. Also included are amino acid salts, such as arginine salts, and organic acid salts, such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acidic functional groups that allow the compound to be converted into either a base addition salt or an acid addition salt.

[0156] Accordingly, the compounds of the present disclosure may exist as salts with pharmaceutically acceptable acids and the like. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid, as well as quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0157] The neutral form of the compound is preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in terms of certain physical properties such as solubility in polar solvents.

[0158] In addition to the salt forms, the present disclosure provides prodrug forms of the compounds. The prodrugs of the compounds described herein are compounds that are readily chemically transformed under physiological conditions to yield the compounds of the present disclosure. The prodrugs of the compounds described herein can be converted in vivo after administration. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, for example, when contacted with a suitable enzyme or chemical reagent.

[0159] Certain compounds of the present disclosure may exist in unsolvated forms, as well as solvated forms including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline forms or amorphous forms. Generally, all physical forms are equivalent for the intended uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0160] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, see Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd ed., J. Wiley & Sons (New York, NY 1994), Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice of the present disclosure. The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of the present disclosure.

[0161] "Nucleic acid" refers to deoxyribonucleotides or ribonucleotides in any of single-stranded, double-stranded, or multi-stranded forms and their polymers, or their complements. Terms such as "polynucleotide", "oligonucleotide", "oligo" refer to the linear sequence of nucleotides in their ordinary and customary meanings. The term "nucleotide" refers to a single polynucleotide unit, i.e., a monomer, in its ordinary and customary meanings. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified forms thereof. Examples of polynucleotides contemplated herein include single-stranded and double-stranded DNA, single-stranded and double-stranded RNA, and hybrid molecules having mixtures of single-stranded and double-stranded DNA and RNA. Examples of nucleic acids, such as polynucleotides, contemplated herein include any type of RNA, such as messenger RNA (mRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), CRISPR RNA (crRNA), trans-activating RNA (tracrRNA), plasmid DNA (pDNA), minicircle DNA, genomic DNA (gNDA), and any fragments thereof. The term "double-stranded" in the context of polynucleotides refers to double-strandedness in its ordinary and customary meanings. Nucleic acids can be linear or branched. For example, a nucleic acid can be a linear chain of nucleotides, or a nucleic acid can be branched, for example, such that the nucleic acid has one or more arms or branches of nucleotides. Optionally, the branched nucleic acid can branch repeatedly to form higher-order structures such as dendrimers.

[0162] For example, a nucleic acid containing a nucleic acid having a phosphorothioate backbone can contain one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, such as a nucleic acid or polypeptide, via a covalent bond, non-covalent bond, or other interaction. By way of example, a nucleic acid can contain an amino acid-reactive moiety that reacts with an amino acid on a protein or polypeptide via a covalent bond, non-covalent bond, or other interaction.

[0163] This term also encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, or non-naturally occurring, have binding properties similar to a reference nucleic acid, and are metabolized in a manner similar to reference nucleotides. Examples of such analogs include, for example, phosphoramidates, phosphorodiamidates, phosphorothioates (also known as phosphorothioates where the oxygen of the phosphate is replaced by double-bonded sulfur), phosphorodithioates, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoglycolic acid, methylphosphonates, boronophosphates, or phosphodiester derivatives containing an O-methylphosphoramidite linkage (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press), as well as modifications to nucleotide bases such as in the case of 5-methylcytidine or pseudouridine, and peptide nucleic acid backbones and linkages, but are not limited thereto. Other analog nucleic acids include those having a positive backbone, a non-ionic backbone, modified sugars, and non-ribose backbones (e.g., phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) known in the art), as described in U.S. Pat. Nos. 5,235,033 and 5,034,506, as well as Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications to the ribose-phosphate backbone can be made for various reasons, such as to increase the stability and half-life of such molecules in a physiological environment or as probes on biochips. Mixtures of naturally occurring nucleic acids and analogs can be made, or mixtures of different nucleic acid analogs and mixtures of naturally occurring nucleic acids and analogs can be made. In some embodiments, the internucleotide linkages in DNA are phosphodiesters, phosphodiester derivatives, or a combination of both.

[0164] Nucleic acids can contain non-specific sequences. As used herein, the term "non-specific sequence" refers to a nucleic acid sequence containing a series of residues that are not designed to be complementary, or only partially complementary, to any other nucleic acid sequence. By way of example, a non-specific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism. An "inhibitory nucleic acid" is a nucleic acid (e.g., DNA, RNA, polymer of nucleotide analogs) that can bind to a target nucleic acid (e.g., mRNA that can be translated into protein) and reduce the transcription of the target nucleic acid (e.g., from DNA to mRNA), reduce the translation of the target nucleic acid (e.g., mRNA), or alter the splicing of the transcript (e.g., single-stranded morpholino oligo). In embodiments, the nucleic acid is RNA (e.g., mRNA). In embodiments, the nucleic acid is from 10 to 100,000 bases in length. In embodiments, the nucleic acid is from 50 to 10,000 bases in length. In embodiments, the nucleic acid is from 50 to 5,000 bases in length. In embodiments, the nucleic acid is from 50 to 1,000 bases in length.

[0165] The terms "polypeptide", "peptide", and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, and the polymer can be attached to moieties that are not composed of amino acids. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of the corresponding naturally occurring amino acids, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. These terms also apply to cyclic peptides, peptides modified with non-peptide functional groups, peptidomimetics, polyamides, and macrolactams. A "fusion protein" refers to a chimeric protein that encodes two or more distinct protein sequences that are recombinantly expressed as a single moiety.

[0166] The terms "peptidyl" and "peptidyl moiety" mean a monovalent peptide.

[0167] The term "amino acid" refers to naturally occurring amino acids and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids include those encoded by the genetic code, as well as amino acids that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids, i.e., compounds having an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methyl sulfonium. Such analogs have a modified R group (e.g., norleucine) or a modified peptide backbone, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics refer to compounds that have a structure different from the general chemical structure of amino acids but function in a manner similar to naturally occurring amino acids. The terms "non-naturally occurring amino acids" and "unnatural amino acids" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that are not found in nature.

[0168] Amino acids can be referred to herein by either their generally known three-letter symbols or the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Similarly, nucleotides can be referred to by their generally recognized one-letter codes.

[0169] "Contacting" is used in its ordinary and customary sense and refers to a process that enables at least two different species (e.g., chemical compounds including biomolecules or cells) to be brought into proximity sufficient for them to react, interact, or physically touch. However, it should be understood that the resulting reaction product can be generated directly from the reaction between the added reagents or from intermediates derived from one or more of the added reagents generated in the reaction mixture. In embodiments, contacting includes, for example, interacting a nucleic acid with an endonuclease.

[0170] A "control" sample or value refers to a sample that serves as a reference for comparison with a test sample, usually a known reference. For example, a test sample can be taken from test conditions in the presence of, for example, a test compound and can be compared to a sample from known conditions in the absence of, for example, the test compound (negative control) or in the presence of a known compound (positive control). A control can also represent an average value collected from several tests or results. One of ordinary skill in the art will recognize that a control can be designed for the evaluation of any number of parameters. For example, a control can be devised for comparing treatment effects based on pharmacological data (e.g., half-life) or treatment means (e.g., comparison of side effects). One of ordinary skill in the art will understand which standard control is most appropriate in a given situation and will be able to analyze data based on comparison to the standard control value. Standard controls are also useful for determining the significance of data (e.g., statistical superiority). For example, if the value of a given parameter varies widely in the standard control, the variation in the test sample is not considered significant.

[0171] A "label" or "detectable moiety" is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include 32 P, fluorescent dyes, high electron density reagents, enzymes (such as those commonly used in ELISA), biotin, digoxigenin, or haptens, and proteins or other substances that can be made detectable by introducing a radioactive label into a peptide or antibody having specific reactivity with, for example, a target peptide. Any suitable method known in the art for conjugating an antibody to a label (e.g., using the methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego) can be used.

[0172] As used herein, the term "biological sample" or "sample" refers to a material obtained from or derived from a subject or patient. Biological samples include tissue sections such as biopsy samples and autopsy samples, and frozen sections taken for histological purposes. Such samples include blood, blood fractions, or blood products (e.g., serum, plasma, platelets, red blood cells, etc.), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells), feces, urine, synovial fluid, joint tissue, synovial tissue, synovial cells, fibroblast-like synovial cells, macrophage-like synovial cells, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, and the like. Biological samples are typically obtained from eukaryotes such as mammals (primates, e.g., chimpanzees or humans; cattle; dogs; cats; rodents, e.g., guinea pigs, rats, mice; rabbits, etc.), or birds, reptiles, or fish.

[0173] As used herein, the term "cell" refers to a cell that performs sufficient metabolism or other functions to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with specific dyes, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. Cells can include prokaryotic cells and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian cells, insect cells (e.g., Spodoptera), and human cells.

[0174] The term "stem cell" or "stem cells" refers to a clonal, self-renewing population of cells that are pluripotent and can thus give rise to several differentiated cell types.

[0175] The term "gene" means a segment of DNA involved in the production of a protein, which includes regions before and after the coding region (leader and trailer), and intervening sequences (introns) between individual coding segments (exons). The leader, trailer, and introns contain regulatory elements necessary during gene transcription and translation. Further, a "protein gene product" is a protein expressed from a specific gene.

[0176] As used herein in reference to a gene, the terms "expression" or "expressed" mean the transcription and / or translation products of that gene. The expression level of a DNA molecule in a cell can be determined based on either the amount of the corresponding mRNA present in the cell or the amount of the protein encoded by the DNA produced by that cell (Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, 18.1-18.88).

[0177] Expression of a transfected gene can occur transiently or stably in a cell. During "transient expression", the transfected gene is not passed on to daughter cells during cell division. Since its expression is limited to the transfected cell, the expression of the gene is lost over time. In contrast, co-transfection of a transfected cell with another gene conferring a convenience at the time of selection and the transfected gene can result in stable expression of the transfected gene. The advantage of such a selection can be resistance to a specific toxin presented to the cell.

[0178] The term "plasmid" refers to a nucleic acid molecule encoding a gene and / or regulatory elements necessary for the expression of the gene. Expression of a gene from a plasmid can occur in cis or in trans. When a gene is expressed in cis, the gene and regulatory elements are encoded by the same plasmid. Expression in trans refers to the case where the gene and regulatory elements are encoded by separate plasmids.

[0179] The term "exogenous" refers to a molecule or substance (e.g., a nucleic acid or protein) that is derived from outside of a given cell or organism. Conversely, the term "endogenous" refers to a molecule or substance that is naturally present in, or is derived from within, a given cell or organism.

[0180] A "vector" is a nucleic acid that is capable of transporting another nucleic acid into a cell. A vector can, when present in an appropriate environment, induce the expression of one or more proteins encoded by one or more genes carried by the vector.

[0181] The term "codon optimization" refers to modifying the codons in the gene or coding region of a nucleic acid molecule for transformation into various hosts so as to reflect the typical codon usage frequency of the host organism without modifying the polypeptide encoded by the DNA. Such optimization can include replacing at least one, two or more, or a significant number of codons with one or more codons that are more frequently used in the genes of the host organism. Given the large number of gene sequences available for a wide range of animal, plant, and microbial species, the relative codon usage frequency can be calculated. Codon usage tables are readily available, for example, in the "Codon Usage Database" available at www.kazusa.or.jp / codon / . A person skilled in the art can apply the knowledge regarding codon usage frequency or codon preference in each organism to any given polypeptide sequence and create a nucleic acid fragment of a codon-optimized coding region that encodes the polypeptide but uses codons that are optimal for a given species. The codon-optimized coding region can be designed by various methods known to those skilled in the art.

[0182] A "cell culture" is an in vitro population of cells existing outside the body. A cell culture can be established from primary cells isolated from a cell bank or an animal, or from one of its cell sources, and from secondary cells that have been immortalized for long-term in vitro culture.

[0183] The terms "transfection", "transduction", "transfect" or "transduce" can be used interchangeably and are defined as the process of introducing nucleic acid molecules and / or proteins into cells. Nucleic acids can be introduced into cells using non-viral or virus-based methods. A nucleic acid molecule can be a sequence encoding a complete protein or a functional portion thereof. Typically, it is a nucleic acid vector having elements necessary for protein expression (e.g., promoter, transcription start site, etc.). Non-viral methods of transfection include any suitable method that does not use viral DNA or viral particles as a delivery system for introducing nucleic acid molecules into cells. Exemplary non-viral transfection methods include calcium phosphate transfection, liposome transfection, nucleofection, sonoporation, transfection through heat shock, magnetofection, and electroporation. In the case of virus-based methods, any useful viral vector can be used in the methods described herein. Examples of viral vectors include, but are not limited to, retroviral vectors, adenoviral vectors, lentiviral vectors, and adeno-associated viral vectors. In some embodiments, the nucleic acid molecule is introduced into cells using a retroviral vector according to standard procedures well known in the art. The terms "transfection" or "transduction" also refer to the introduction of proteins into cells from the external environment. Typically, protein transduction or transfection relies on the attachment of a peptide or protein capable of crossing the cell membrane to the protein of interest. See, for example, Ford et al. (2001) Gene Therapy 8:1-4 and Prochiantz (2007) Nat. Methods 4:119-20.

[0184] As used herein, the terms "specific binding" or "binds specifically" refer to two molecules that form a relatively stable complex (e.g., ribonucleoprotein and transfection peptide) under physiological conditions.

[0185] Methods for determining whether a ligand binds to another species (e.g., a protein or nucleic acid) and / or for determining the affinity of such ligand-species interactions are known in the art. For example, binding of a ligand to a protein can be detected and / or quantified using a variety of techniques including, but not limited to, Western blot, dot blot, surface plasmon resonance (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), isothermal titration calorimetry (ITC), or enzyme-linked immunosorbent assay (ELISA).

[0186] Immunoassays that can be used to analyze the immunospecific binding and cross-reactivity of a ligand include, but are not limited to, competitive and non-competitive assay systems using techniques such as Western blot, RIA, ELISA (enzyme-linked immunosorbent assay), "sandwich" immunoassay, immunoprecipitation assay, immunodiffusion assay, agglutination assay, complement fixation assay, immunoradiometric assay, and fluorescence immunoassay. Such assays are conventional and well known in the art.

[0187] The term "antibody" refers to a polypeptide encoded by an immunoglobulin gene or a functional fragment thereof that specifically binds to and recognizes an antigen. The immunoglobulin genes recognized include kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as numerous immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which similarly define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively.

[0188] The terms "antigen" and "epitope" are used interchangeably to refer to a portion of a molecule (e.g., a polypeptide) that is specifically recognized by a component of the immune system, such as an antibody, a T cell receptor, or another immune receptor, such as a receptor on a natural killer (NK) cell. As used herein, the term "antigen" encompasses antigenic epitopes and antigenic fragments thereof.

[0189] An exemplary immunoglobulin (antibody) structural unit can have a tetramer. Each tetramer consists of two identical pairs of polypeptide chains, each pair having one "light" chain (about 25 kDa) and one "heavy" chain (about 50 - 70 kDa). The N-terminus of each chain defines a variable region of about 100 - 110 or more amino acids that is primarily involved in antigen recognition. The term "variable heavy chain", "V H ", or "VH" refers to the variable region of an immunoglobulin heavy chain, including Fv, scFv, dsFv, or Fab, while the term "variable light chain", "V L ", or "VL" refers to the variable region of an immunoglobulin light chain, including Fv, scFv, dsFv, or Fab.

[0190] Examples of antibody functional fragments include intact antibody molecules, antibody fragments such as Fv, single-chain Fv (scFv), complementarity-determining regions (CDRs), VL (light-chain variable region), VH (heavy-chain variable region), Fab, F(ab)2’, and any other functional portion of an immunoglobulin peptide capable of binding to a target antigen (see, e.g., FUNDAMENTAL IMMUNOLOGY (Paul ed., 4th ed. 2001)), but are not limited thereto. As will be understood by those skilled in the art, various antibody fragments can be obtained by various methods, such as digestion of intact antibodies with enzymes such as pepsin, or de novo synthesis. Antibody fragments are often de novo synthesized by using chemical or recombinant DNA methodologies. Thus, as used herein, the term antibody includes any antibody fragment that is produced by modification of a whole antibody, or is de novo synthesized using recombinant DNA methodologies (e.g., single-chain Fv), or is identified using a phage display library (see, e.g., McCafferty et al., (1990) Nature 348:552). The term “antibody” also includes bivalent or bispecific molecules, diabodies, triabodies, and tetra-bodies. Bivalent and bispecific molecules are described, for example, in Kostelny et al. (1992) J. Immunol. 148:1547, Pack and Pluckthun (1992) Biochemistry 31:1579, Hollinger et al. (1993), PNAS USA 90:6444, Gruber et al. (1994) J Immunol. 152:5368, Zhu et al. (1997) Protein Sci. 6:781, Hu et al. (1996) Cancer Res. 56:3055, Adams et al. (1993) Cancer Res. 53:4026, and McCartney, et al. (1995) Protein Eng. 8:301.

[0191] As used herein, terms such as "sacrifice", "self-sacrifice", "self-sacrifice mechanism", "sacrificial moiety", "sacrificial domain" refer to the ability of a chemical group to undergo an intramolecular reaction, thereby causing the chemical group to undergo a chemical rearrangement and the rearranged chemical group to be released from the remaining portion of the compound to which it was attached. A "pH-sensitive" sacrificial domain refers to a chemical group that undergoes a sacrificial reaction within a lower pH range and substantially does not undergo a sacrificial reaction outside of that lower pH range (e.g., pH of about 1-5, pH of about 5-7, or pH of about 7-10). In embodiments, the lower pH range is pH 1-3, pH 2-4, pH 3-5, pH 4-6, pH 5-7, pH 6-8, pH 7-9, or pH 8-10. In embodiments, the pH-sensitive sacrificial region comprises a cationic alpha amino ester (oligo(α-amino ester)). In embodiments, the cationic component of the cationic alpha amino ester is a positively charged nitrogen atom (e.g., a cationic amine). In embodiments, the cationic component of the cationic alpha amino ester is not a guanidinium group. In embodiments, the cationic component of the cationic alpha amino ester is not a piperidinium group.

[0192] Terms such as "cell-permeable complex" refer, in their ordinary and customary meaning, to chemical complexes (e.g., complexes or compositions disclosed herein and embodiments thereof) that can permeate cells (living cells such as eukaryotic or prokaryotic cells). In embodiments, the cell-permeable complex comprises a nucleic acid ionically bound to a cationic amphiphilic polymer. In embodiments, the nucleic acid cannot substantially permeate cells in the absence of the cationic amphiphilic polymer. Thus, in embodiments, the cationic amphiphilic polymer facilitates the transport of the nucleic acid into the cell. As used herein, terms such as "cationic charge-variable releasable transporter", "CART", etc. refer to the cell-permeable complexes disclosed herein. The CART compound can release the nucleic acid component intracellularly through the action of a pH-sensitive sacrificial domain within the cationic amphiphilic polymer component (the action of releasing the nucleic acid intracellularly by reacting in response to the intracellular pH). In embodiments, the cationic amphiphilic polymer rapidly degrades intracellularly (e.g., T1 / 2 less than 6 hours at pH 7.4). In at least some embodiments, polyplexes, complexes, electrostatic complexes, CART / mRNA complexes, CART / oligonucleotide complexes, and nanoparticles can be used interchangeably to refer to the cell-permeable complex.

[0193] As used herein, the term "amphiphilic polymer" refers to a polymer that contains both a hydrophilic portion and a hydrophobic portion. In embodiments, the hydrophilic portion to hydrophobic portion is present in a 1:1 mass ratio. In embodiments, the hydrophilic portion to hydrophobic portion is present in a 1:2 mass ratio. In embodiments, the hydrophilic to hydrophobic portion is present in a 1:5 mass ratio. In embodiments, the hydrophilic to hydrophobic portion is present in a 2:1 mass ratio. In embodiments, the hydrophilic portion to hydrophobic portion is present in a 5:1 mass ratio. The amphiphilic polymer can be a diblock or triblock copolymer. In embodiments, the amphiphilic polymer can comprise two hydrophilic portions (e.g., blocks) and one hydrophobic portion (e.g., block).

[0194] Terms such as "lipophilic polymer domain", often referred to as a "lipid block", refer to regions of a cationic amphiphilic polymer that are not hydrophilic (e.g., insoluble in water alone). In embodiments, the lipophilic polymer domain has low solubility in water. For example, low solubility in water refers to a solubility of the lipophilic polymer domain of from about 0.0005 mg / mL to about 10 mg / mL that dissolves in water.

[0195] The term "initiator" refers to a compound involved in a reaction to synthesize a cationic amphiphilic polymer for the purpose of initiating a polymerization reaction. Thus, an initiator is typically incorporated at the end of the synthesized polymer. For example, a plurality of molecules of one type (formula) of monomer or two or more monomers (e.g., two different types of monomers) can be reacted with an initiator to provide a cationic amphiphilic polymer. The initiator can be present at at least one end of the resulting polymer and cannot constitute the repeating (or polymerized) units present in the polymer.

[0196] The term "disease" or "condition" refers to the existing or health state of a subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. The disease can be an autoimmune disease, an inflammatory disease, a cancer disease, an infectious disease, a metabolic disease, a developmental disease, a cardiovascular disease, a liver disease, an intestinal disease, an endocrine disease, a neurological disease, or other diseases. In some examples, the disease is cancer (e.g., breast cancer, ovarian cancer, sarcoma, osteosarcoma, lung cancer, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, neuroblastoma).

[0197] The term "infection" or "infectious disease" refers to a disease or condition that can be caused by an organism such as a bacterium, virus, fungus, or any other pathogenic microbial agent.

[0198] As used herein, the term "cancer" refers to all types of cancers, neoplasms, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, melanoma, neuroendocrine tumors, carcinomas, and sarcomas. Exemplary cancers that can be treated by the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma. Additional examples include thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, Waldenström's macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, pre-malignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, malignant hypercalcemia, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic neoplasms, medullary thyroid carcinoma, medullary thyroid carcinoma tumor, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, or prostate cancer.

[0199] As defined herein, terms such as "inhibit", "inhibiting", "inhibition" mean, with respect to the activity and / or functionality of a molecule (e.g., a polynucleotide or protein), having a negative effect on the activity or function of the molecule (e.g., reducing or decreasing the activity or function of the molecule) as compared to the activity or function of the protein in the absence of such inhibition. Thus, inhibition includes, at least in part, partially or completely blocking a stimulus, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or enzyme activity or the amount of a protein or polynucleotide. Similarly, an "inhibitor" is, for example, a compound that inhibits a target biomolecule (i.e., a nucleic acid, peptide, carbohydrate, lipid, or any other molecule found in nature) by, for example, binding, partially or completely blocking, decreasing, preventing, delaying, inactivating, desensitizing, or downregulating the activity of the target biomolecule. In the context of disease prevention and treatment, an inhibitor refers to reducing a disease or a symptom of a disease.

[0200] "Treatment", "treating", and "treat" are defined as the action of an agent on a disease, disorder, or condition to reduce or ameliorate the disease, disorder, or condition and / or any adverse or other unwanted effects of the symptoms thereof. "Treating" or "treatment" of a condition or subject in need thereof means taking steps to obtain a beneficial or desired result, including clinical results such as reducing symptoms, (2) inhibiting a disease, e.g., arresting or reducing the development of the disease or its clinical symptoms, (3) alleviating a disease, e.g., causing regression of the disease or its clinical symptoms, or (4) delaying a disease. For example, beneficial or desired clinical results include, but are not limited to, reduction and / or elimination of cancer cells and prevention and / or reduction of metastasis of cancer cells.

[0201] In the context of a disease, the terms "prevent", "prevention", or "preventing" refer to the non-occurrence of the clinical symptoms of a disease in a subject who has not yet experienced or manifested the symptoms of the disease. In some examples, such prevention can be applied to subjects who can be considered to have a predisposition to the disease, while in some other examples, the subject may not necessarily be considered to have a predisposition to the disease.

[0202] As used herein, "administering" refers to physically introducing a composition into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Preferred routes of administration of the compositions described herein include, for example, intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration by injection or infusion. As used herein, the phrase "parenteral administration" means a route of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracardiac injection and infusion, and in vivo electroporation. Alternatively, the compositions described herein can be administered via local, epidermal or mucosal routes of administration, for example, non-parenteral routes such as intranasal, oral, vaginal, rectal, sublingual or topical. Administration can also be carried out, for example, once, a plurality of times, and / or over one or more extended periods of time.

[0203] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, such as cancer, from one organ or from another non-adjacent organ or part of the body. Cancer arises at a primary tumor, for example, at a site of origin such as the breast, which is referred to as primary breast cancer. Some cancer cells at the primary tumor or site of origin acquire the ability to penetrate and invade the surrounding normal tissue in the local area and / or to penetrate the walls of the lymphatic or vascular system and circulate through the system to other sites and tissues in the body. Clinically detectable secondary tumors formed from the cancer cells of the primary tumor are called metastatic or secondary tumors. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be the same as those of the original tumor. Thus, when lung cancer metastasizes to the breast, the secondary tumor at the breast site consists of abnormal lung cells and not abnormal breast cells. The secondary tumor at the breast is called metastatic lung cancer. Thus, the phrase "metastatic cancer" refers to a disease in which a subject has one or more secondary tumors that had or have a primary tumor. The phrase "subject having non-metastatic cancer or cancer that is not metastatic" refers to a disease in which a subject has a primary tumor but does not have one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject having a history of a primary lung tumor and having one or more secondary tumors at a second site or multiple sites, such as the breast.

[0204] An "anticancer agent" is a therapeutic agent having anticancer activity that can be used in the treatment or prevention of cancer. An anticancer agent can be a macromolecule or a small molecule. Examples of anticancer agents include antibodies, small molecules, and macromolecules or combinations thereof. Examples of anticancer activity include, but are not limited to, reduction in the number of cancer cells, shrinkage of the size of the cancer, killing of cancer cells, reduction and / or inhibition of metastasis, and reduction of growth and / or proliferation of cancer cells.

[0205] In the context of a substance associated with a disease or the activity or function of a substance, the terms "associated with" or "relating to" mean that the disease is (wholly or in part) caused by, or the symptoms of the disease are (wholly or in part) caused by, the substance or the activity or function of the substance. When this term is used in the context of a symptom, for example, a symptom associated with a disease or condition, this term means that the symptom may indicate a disease or condition that is present in the subject exhibiting the symptom.

[0206] The terms "subject", "individual", "host", or "subject in need thereof" refer to an organism that has a disease or condition or that may have a disease or condition in the future. The term "patient" refers to an organism that already has a disease or condition, for example, a patient diagnosed with a disease or condition or having one or more symptoms associated with a disease or condition. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human.

[0207] The term "vaccine" refers to a composition that can provide active acquired immunity and / or a therapeutic effect (e.g., treatment) against a specific disease or pathogen. A vaccine typically contains one or more agents that can induce an immune response in a subject against the pathogen or disease, i.e., the target pathogen or target disease. The immunogenic agent stimulates the body's immune system to recognize the agent as a threat or indicator of the presence of the target pathogen or target disease, such that the immune system can more readily recognize and destroy any of those pathogens upon subsequent exposure to them, thereby inducing immune memory. A vaccine can be prophylactic (e.g., preventing or ameliorating the effects of any future natural or pathogen-caused infection, or preventing or ameliorating the onset of cancer expected in a subject having a predisposition) or therapeutic (e.g., treating cancer in a subject diagnosed with cancer). Administration of a vaccine is called vaccination. In some embodiments, a vaccine composition can provide a nucleic acid, e.g., mRNA encoding an antigenic molecule (e.g., a peptide), to a subject. In the subject, the nucleic acid delivered via the vaccine composition can be expressed into an antigen molecule, enabling the subject to acquire immunity against the antigen molecule. In the context of vaccination against an infectious disease, the vaccine composition can provide mRNA encoding an antigenic molecule associated with a specific pathogen, e.g., one or more peptides known to be expressed by the pathogen (e.g., a pathogenic bacterium or a pathogenic virus). In the context of a cancer vaccine, the vaccine composition can provide mRNA encoding a specific peptide associated with cancer, e.g., a peptide that is expressed substantially only in cancer cells or is expressed at a higher level in cancer cells than in normal cells. A subject can have immunity against a peptide associated with cancer and can specifically kill cancer cells after vaccination with the cancer vaccine composition.

[0208] As used herein, the term "immune response" includes, but is not limited to, an "adaptive immune response," also known as an "acquired immune response," which elicits immunological memory after an initial response to a specific pathogen or a specific type of cell targeted by the immune response, and thereafter, upon encounter with the target, elicits an enhanced response against the target. Induction of immunological memory can provide the basis for vaccination.

[0209] The terms "immunogenic" or "antigenic" refer to a compound or composition that, when administered to an immunocompetent subject, induces an immune response, such as a cytotoxic T lymphocyte (CTL) response, a B cell response (e.g., production of antibodies that specifically bind to an epitope), an NK cell response, or any combination thereof. Thus, an immunogenic composition or an antigenic composition is a composition that can elicit an immune response in an immunocompetent subject. For example, an immunogenic composition or an antigenic composition can comprise one or more immunogenic epitopes associated with a pathogen or a specific type of cell that is the target of the immune response. In addition, an immunogenic composition can comprise an isolated nucleic acid construct (DNA or RNA) that encodes one or more immunogenic epitopes of an antigenic polypeptide and that can be used to express the epitope (and thus can be used to elicit an immune response against the polypeptide or a related polypeptide associated with the target pathogen or cell type).

[0210] According to the method provided by the present invention, an effective amount of one or more agents, compositions or complexes (e.g., cell-permeable complexes or vaccine compositions) used interchangeably herein can be administered to a subject. The terms "effective amount" and "effective dosage" are used interchangeably. The term "effective amount" is defined as any amount necessary to produce a desired effect (e.g., transfection of nucleic acid into cells and exhibit the intended results of the transfected nucleic acid). An effective amount and schedule for administering the agent can be determined experimentally by those skilled in the art. The dosage range of administration is in a range large enough to produce the desired effect, such as transfection of nucleic acid, regulation of gene expression, gene editing, induction of stem cells, induction of immune response, etc. The dosage should not be so much as to cause substantial adverse side effects such as unwanted cross-reactions, anaphylactic reactions, etc. Generally, the dosage may vary depending on age, condition, gender, type of disease, degree of disease or disorder, route of administration, or whether other drugs are included in the regimen, and can be determined by those skilled in the art. In case any contraindication occurs, an individual physician can adjust the dosage. The dosage may vary and can be administered once or more per day for one day or several days. Guidelines can be found in the literature regarding the appropriate dosage of a given class of pharmaceuticals. For example, for a given parameter, the therapeutically effective amount can show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. The effectiveness can also be expressed as an increase or decrease in "fold". For example, the therapeutically effective amount can be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effective than the control.The correct dosage and formulation may depend on the treatment objective, and one of ordinary skill in the art can determine the correct dosage and formulation using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992), Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999), Remington: The Science and Practice of Pharmacy, 20th Edition, Gennaro, Editor (2003) and Pickar, Dosage Calculations (1999)).

[0211] The term "kill" with respect to cancer treatment is intended to include any type of manipulation that will cause at least a portion of the cancer cells or cancer cell population to die.

[0212] Cell-permeable complex The cell-permeable complexes provided herein, including that embodiment, comprise a nucleic acid non-covalently bound to a cationic amphiphilic polymer (e.g., having Formulas (XII), (XIII), (XIV), and (XV)). The cationic amphiphilic polymer(s) can deliver the nucleic acid(s) to which they are bound (e.g., RNA or DNA) to various cells in vitro and in vivo. Depending on the chemical composition of the cationic amphiphilic polymer, the cells, tissues, or organs to which the nucleic acid is delivered can vary. For example, in an embodiment, the cationic amphiphilic polymer delivers the nucleic acid to the lung. In an embodiment, the cationic amphiphilic polymer delivers the nucleic acid systemically. In yet other embodiments, the cationic amphiphilic polymer delivers the nucleic acid to reticulocytes. In yet other embodiments, the cationic amphiphilic polymer delivers the nucleic acid to hematopoietic progenitor cells (HPC). The cell-permeable complexes provided herein, including that embodiment, can further comprise multiple (two or more, e.g., two) cationic amphiphilic polymer types (e.g., a mixture of a first cationic amphiphilic polymer and a second amphiphilic polymer), and each of the cationic amphiphilic polymer types is chemically different.

[0213] In one aspect, a complex is provided that comprises a nucleic acid non-covalently bound to a cationic amphiphilic polymer of Formula (XII) as provided herein, including that embodiment. In one aspect, a complex is provided that comprises a nucleic acid non-covalently bound to a cationic amphiphilic polymer of Formula (XIII) as provided herein, including that embodiment. In one aspect, a complex is provided that comprises a nucleic acid non-covalently bound to a cationic amphiphilic polymer of Formula (XIV) as provided herein, including that embodiment. In one aspect, a complex is provided that comprises a nucleic acid non-covalently bound to a cationic amphiphilic polymer of Formula (XV) as provided herein, including that embodiment.

[0214] In one aspect, there is provided a cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer as provided herein including its embodiments, of formula (XII). In one aspect, there is provided a cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer as provided herein including its embodiments, of formula (XIII). In one aspect, there is provided a cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer as provided herein including its embodiments, of formula (XIV). In one aspect, there is provided a cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer as provided herein including its embodiments, of formula (XV).

[0215] In a first aspect, there is provided a cell-permeable complex (e.g., having formula (XII), (ΧIII), (XIV), and (XV)) comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer, the cationic amphiphilic polymer comprising a pH-sensitive sacrificial domain (e.g., having formula (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI)). In embodiments, one or more counterions (e.g., anions) may also be present as a countercharge to the positive charge of the cationic amphiphilic polymer. In embodiments, the nucleic acid is non-covalently bound to the cationic amphiphilic polymer. In embodiments, the nucleic acid is ionically bound to the cationic amphiphilic polymer. In embodiments, the cell-permeable complex comprises a plurality of optionally different nucleic acids (e.g., 1 to 10 additional nucleic acids, 1 to 5 additional nucleic acids, 1 to 5 additional nucleic acids, 2 additional nucleic acids, or 1 additional nucleic acid). In embodiments, the nucleic acid is DNA. In embodiments, the nucleic acid is RNA. In embodiments, the nucleic acid is mRNA.

[0216] In embodiments, the ratio of the number of cations in the cationic amphiphilic polymer molecule to the number of anions on the nucleic acid molecule present in the cell-permeable complex is about 1:1, about 5:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 10 2 :1, about 10 3 :1, about 104 : 1. Approximately 10 5 : 1. Approximately 10 6 : 1. Approximately 10 7 : 1. Approximately 10 8 : 1. Approximately 10 9 : 1. Approximately 10 10 : 1 or a greater ratio, or any range between the aforementioned values. In other embodiments, the ratio of the number of anions on the nucleic acid molecule to the number of cations on the cationic amphiphilic polymer molecule present in the cell-permeable complex is approximately 1:1, approximately 5:1, approximately 10:1, approximately 20:1, approximately 30:1, approximately 40:1, approximately 50:1, approximately 60:1, approximately 70:1, approximately 80:1, approximately 90:1, approximately 10 2 : 1. Approximately 10 3 : 1. Approximately 10 4 : 1. Approximately 10 5 : 1. Approximately 10 6 : 1. Approximately 10 7 : 1. Approximately 10 8 : 1. Approximately 10 9 : 1. Approximately 10 10 : 1 or a greater ratio, or any range between the aforementioned values. In some preferred embodiments, this ratio is approximately 10 cationic charges on the amphiphilic polymer molecule per 1 negative charge on the nucleic acid. Other embodiments can have 1 negative charge on the nucleic acid from 5 cationic charges of the amphiphilic polymer molecule, or 1 negative charge on the nucleic acid from 20 cationic charges of the amphiphilic polymer molecule.

[0217] In embodiments, the ratio of the number of cations in the cationic amphiphilic polymer molecule to the number of anions on the nucleic acid molecule present in the cell-permeable complex is 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 10 2 : 1. 10 3 : 1. 10 4 : 1. 10 5 : 1. 10 6 : 1. 10 7 : 1. 10 8 : 1. 10 9 : 1. 10 10: 1. Or a ratio greater than this, or any range between the aforementioned values. In other embodiments, the ratio of the number of anions on the nucleic acid molecule to the number of cations on the cationic amphiphilic polymer molecule present in the cell-permeable complex can be 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 10:1, 10 2 : 1, 10 3 : 1, 10 4 : 1, 10 5 : 1, 10 6 : 1, 10 7 : 1, 10 8 : 1, 10 9 : 1, 10 10 : 1. Or a ratio greater than this, or any range between the aforementioned values. In some preferred embodiments, this ratio is approximately 10 cationic charges on the amphiphilic polymer molecule per 1 negative charge on the nucleic acid. Other embodiments can have 1 negative charge on the nucleic acid from 5 cationic charges of the amphiphilic polymer molecule, or 1 negative charge on the nucleic acid from 20 cationic charges of the amphiphilic polymer molecule.

[0218] In embodiments, the ratio of the number of nucleic acid molecules to the number of cationic amphiphilic polymer molecules present in the cell-permeable complex is about 1:1, about 10:1, about 10 2 : 1, about 10 3 : 1, about 10 4 : 1, about 10 5 : 1, about 10 6 : 1, about 10 7 : 1, about 10 8 : 1, about 10 9 : 1, about 10 10 : 1. Or a ratio greater than this, or any range between the aforementioned values. In other embodiments, the ratio of the number of cationic amphiphilic polymer molecules to the number of nucleic acid molecules present in the cell-permeable complex is about 1:1, about 10:1, about 10 2 : 1, about 10 3 : 1, about 10 4 : 1, about 10 5 : 1, about 10 6 : 1, about 10 7:1. Approximately 10 8 :1. Approximately 10 9 :1. Approximately 10 10 :1, or a ratio greater than this, or any range between the aforementioned values may be possible.

[0219] In embodiments, the ratio of the number of nucleic acid molecules to the number of cationic amphiphilic polymer molecules present in the cell-permeable complex is 1:1, 10:1, 10 2 :1, 10 3 :1, 10 4 :1, 10 5 :1, 10 6 :1, 10 7 :1, 10 8 :1, 10 9 :1, 10 10 :1, or a ratio greater than this, or any range between the aforementioned values may be possible. In other embodiments, the ratio of the number of cationic amphiphilic polymer molecules to the number of nucleic acid molecules present in the cell-permeable complex is 1:1, 10:1, 10 2 :1, 10 3 :1, 10 4 :1, 10 5 :1, 10 6 :1, 10 7 :1, 10 8 :1, 10 9 :1, 10 10 :1, or a ratio greater than this, or any range between the aforementioned values may be possible.

[0220] In embodiments, the cationic amphiphilic polymer can be a cationic charge-variable releasable transporter (CART). In embodiments, CART can include an oligomeric chain containing a series of cationic sequences that undergo a pH-sensitive change in charge from cationic to neutral or from cationic to anionic.

[0221] In embodiments, the cationic amphiphilic polymer has a pH-sensitive sacrificial domain (e.g., of formulas (XVI), (XVII), (XVIII), (XIX), (XX), and (XXI)) and a lipophilic polymer domain (e.g., LP 1 、LP 2, LP 3 ) It has. In embodiments, the lipophilic polymer domain can promote cell permeation, cell delivery, and / or transport through the cell membrane. In embodiments, the lipophilic polymer domain can be substantially insoluble in water (e.g., dissolve in water at less than about 0.0005 mg / mL to about 10 mg / mL). In embodiments, the lipophilic polymer domain can promote the aggregation of the cationic amphiphilic polymer into nanoparticles. In embodiments, such nanoparticles can have an average longest dimension of about 50 nm to about 500 nm. In embodiments, the lipophilic polymer domain can promote the endosomal fusion of the remains of the cationic amphiphilic polymer following entry and sacrifice into the endosome. In embodiments, the cell-permeable complex of the present disclosure protects the nucleic acid cargo from degradation. Terms such as "nucleic acid cargo" refer to species for which transport into cells by the cell-permeable complexes and embodiments thereof disclosed herein is desired in the ordinary and customary sense.

[0222] In embodiments, the cationic amphiphilic polymer has the following formula, [Chemical formula] wherein ring A is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, CART has the formula: -L 1 -[(LP 1 ) z1 -(LP 2 ) z3 -(IM) z2 ) z4 -L 2 -R 2A and has, wherein R 2A is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, where L 1 and L 2 are, independently, a bond, -C(O)O-, -O-, -S-, -NH-, - C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, where LP 1 and LP 2 are, independently, a lipophilic polymer domain, LP 1 or LP 2 at least one of which is a lipophilic polymer domain, and IM has the following formula,

Chemical formula

[0223] In formulas (XVI) and (XVII), X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R 6 )-C(R 7 )(R 8 ). X 2 is -O- or -S-. R 1 and R 2 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L 4 is a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. R 40 , R 41 , and R 42 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. Z is -S-, -S + R 13 (R 13- , or -NR + (R 13 )(H)-. R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. n1 is an integer from 0 to 50. z2 is an integer from 2 to 100, and z5 is an integer from 1 to 10.

[0224] In an embodiment, ring A is a substituted or unsubstituted aryl. In an embodiment, ring A is a substituted or unsubstituted phenyl. In an embodiment, ring A is a substituted or unsubstituted aryl. In an embodiment, ring A is a substituted or unsubstituted phenyl or naphthalenyl.

[0225] In an embodiment, the cationic amphiphilic polymer has the following formula:

Chemical formula

Chemical formula

[0226] In an embodiment, the cationic amphiphilic polymer has the following formula:

Chemical formula

Chemical formula

[0227] In an embodiment, the cationic amphiphilic polymer has the following formula:

Chemical formula

[0228] In an embodiment, z5 is an integer from 1 to 3. In an embodiment, z5 is 1 or 3. In an embodiment, z5 is 1. In an embodiment, z5 is 3. In an embodiment, R 2A is hydrogen. In an embodiment, L 2 is a bond.

[0229] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical Formula] wherein ring A is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, and CART has the formula: -L 1 -[(LP 1 ) z1 -(IM) z2 -(LP 2 ) Z3 z4 -L 2 -R 2A wherein R 2A is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, and L 1 and L 2 are independently a bond, -C(O)O-, -O-, -S-, -NH-, - C(O)NH- ​-NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, and LP 1 and LP 2 are, independently, a bond or a lipophilic polymer domain, and LP 1 or LP 2 at least one of which is a lipophilic polymer domain, IM has the following formula, [Chemical formula] z5 is an integer from 1 to 10, z1 and z3 are, independently, integers from 0 to 100, at least one of z1 or z3 is not 0, z4 is an integer from 1 to 100, and z2 is an integer from 2 to 100.

[0230] In formulas (XVI) and (XVII), X1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R 6 )-C(R 7 )(R 8 ). X 2 is -O- or -S-. R 1 and R 2 are, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L 4is a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, a substituted or unsubstituted alkylene, or a substituted or unsubstituted heteroalkylene. R 40 , R 41 , and R 42 are, independently, hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl. Z is -S-, -S + R 13 -, -NR 13- , or -N + (R 13 )(H)-. R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, n1 is an integer from 0 to 50. z2 is an integer from 2 to 100, and z5 is an integer from 1 to 10.

[0231] In an embodiment, ring A is a substituted or unsubstituted aryl. In an embodiment, ring A is a substituted or unsubstituted phenyl. In an embodiment, ring A is a substituted or unsubstituted aryl. In an embodiment, ring A is a substituted or unsubstituted phenyl or naphthalenyl.

[0232] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

Chemical formula

[0233] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

Chemical formula

Chemical formula

[0234] In an embodiment, ring A is a substituted or unsubstituted aryl. In some other embodiments, ring A is a substituted or unsubstituted phenyl. In still some other embodiments, ring A is a substituted or unsubstituted aryl. In still some other embodiments, ring A is a substituted or unsubstituted phenyl or naphthalenyl.

[0235] In an embodiment, ring A is an unsubstituted aryl (i.e., unsubstituted except for the CART moiety). In an embodiment, ring A is an unsubstituted phenyl (i.e., unsubstituted except for the CART moiety). In an embodiment, ring A is an unsubstituted phenyl or naphthalenyl (i.e., unsubstituted except for the CART moiety). In an embodiment, ring A is a substituted aryl (i.e., substituted in addition to the CART moiety). In an embodiment, ring A is a substituted phenyl (i.e., substituted in addition to the CART moiety). In an embodiment, ring A is a substituted phenyl or naphthalenyl (i.e., substituted in addition to the CART moiety).

[0236] In an embodiment, the cell-permeable complex has a detectable agent (e.g., a fluorophore).

[0237] In an embodiment, R 1Ais an aryl substituted with a methoxy linker. In embodiments, R 1A is an aryl substituted with a linker (e.g., -CH2-O-). R 1A being an aryl substituted with a methoxy linker has the following non-limiting examples of the formula:

Chemical formula

[0238] In embodiments, the cationic amphiphilic polymer has the following formula (IX):

Chemical formula

[0239] In embodiments, the cationic amphiphilic polymer has the following formula (X):

Chemical formula

[0240] In embodiments, the cationic amphiphilic polymer has the following formula (XI),

Chemical formula

[0241] In an embodiment, L 1 is -CH2-O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0242] In one aspect, a cell-permeable complex is provided that includes a nucleic acid non-covalently bound to a cationic amphiphilic polymer, the cationic amphiphilic polymer includes a pH-sensitive sacrificial domain and a lipophilic polymer domain, and the cationic amphiphilic polymer has the following formula.

Chemical formula

[0243] In Formulas (XII) and (XIII), R 1A is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, ​-CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0244] R 2A is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0245] L 1 and L 2is independently a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene.

[0246] LP 1 and LP 2 are independently lipophilic polymer domains.

[0247] X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R 6 )-C(R 7 )(R 8 ).

[0248] X 2 is -O- or -S-.

[0249] R 1 R 2 R 5 R 6 R 7 and R 8 are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0250] L 4 is a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0251] R 40 、R 41 、and R 42 are, independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0252] Z is -S-, -S + R 13 -, -NR 13- -, or -N + (R 13 )(H)-.

[0253] R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0254] n1 is an integer from 0 to 50.

[0255] z1 and z3 are, independently, integers from 0 to 100, and at least one of z1 or z3 is not 0.

[0256] z4 is an integer from 1 to 100.

[0257] z2 is an integer from 2 to 100, and z5 is an integer from 1 to 10.

[0258] In one aspect, there is provided a cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer, the cationic amphiphilic polymer comprising a pH-sensitive sacrificial domain and a lipophilic polymer domain, and the cationic amphiphilic polymer has the following formula. [Chemical formula]

[0259] In formulas (XIV) and (XV), R 1A is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0260] R 2Ais hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0261] L 1 and L 2 are independently a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0262] LP 1 and LP 2 are independently a lipophilic polymer domain,

[0263] X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5)(R 6 )-C(R 7 )(R 8 )- is.

[0264] X 2 is -O- or -S-.

[0265] R 1 、R 2 、R 5 、R 6 、R 7 、 and R 8 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0266] L 4 is a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0267] R 40 and R 41 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0268] Z is -S-, -S + R 13 -, -NR 13- 、 or -N + (R 13 )(H)-.

[0269] R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0270] n1 is an integer from 0 to 50.

[0271] z1 and z3 are independently integers from 0 to 100, and at least one of z1 or z3 is not 0. z4 is an integer from 1 to 100. z2 is an integer from 2 to 100. z5 is an integer from 1 to 10.

[0272] In one aspect, a complex is provided that includes a nucleic acid non-covalently bound to a cationic amphiphilic polymer, and the cationic amphiphilic polymer has the following formula: [Chemical formula] In the formula,

[0273] R 1A is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0274] R 2A is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, independently, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, independently, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0275] L 1 and L 2 are independently a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene,

[0276] LP 1 and LP 2 are, independently, lipophilic polymer domains,

[0277] X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R 6 )-C(R 7 )(R 8 )-,

[0278] X 2 is -O- or -S-,

[0279] R 1 、R 2 、R 5 、R 6 、R 7 、and R 8 are, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0280] L 4 are, independently, a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene,

[0281] R 40 、R 41 、and R 42 are, independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,

[0282] Z is -S-, -S + R 13 -, -NR 13- or -N + (R 13 )(H)- and

[0283] R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0284] n1 is an integer from 0 to 50,

[0285] z1 and z3 are independently integers from 0 to 100, and at least one of z1 or z3 is not 0,

[0286] z2 is an integer from 2 to 100,

[0287] z4 is an integer from 1 to 100,

[0288] z5 is an integer from 1 to 10.

[0289] In one aspect, there is provided a cell - permeable complex comprising a nucleic acid non - covalently bound to a cationic amphiphilic polymer, and the cationic amphiphilic polymer has the following formula,

Chemical formula

[0290] R 1Ais, independently, hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0291] R 2A is, independently, hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, independently, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, independently, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0292] L 1 and L 2 are each independently a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene,

[0293] LP 1 and LP 2 are each independently a lipophilic polymer domain,

[0294] X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R 6 )-C(R 7 )(R 8 )(R

[0295] X 2 is -O- or -S-,

[0296] R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl,

[0297] L 4is, independently, a bond, -C(O)O-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene,

[0298] R 40 、R 41 、and R 42 are, independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,

[0299] Z is -S-, -S + R 13 -, -NR 13- 、or -N + (R 13 )(H)-,

[0300] R 13 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, =O, -NH2, -COOH, -CONH2, -SH, -SO3H, SO2NH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0301] n1 is an integer from 0 to 50,

[0302] z1 and z3 are, independently, integers from 0 to 100, at least one of z1 or z3 is not 0, z2 is an integer from 2 to 100, z4 is an integer from 1 to 100, and z5 is an integer from 1 to 10.

[0303] In an embodiment, X1 is CH2.

[0304] In an embodiment, L4 is a substituted or unsubstituted C2-C8 alkylene. In an embodiment, L 4 is a substituted or unsubstituted C8 alkylene. In an embodiment, L 4 is a substituted or unsubstituted C7 alkylene. In an embodiment, L 4 is a substituted or unsubstituted C6 alkylene. In an embodiment, L 4 is a substituted or unsubstituted C5 alkylene. In an embodiment, L 4 is a substituted or unsubstituted C4 alkylene. In an embodiment, L 4 is a substituted or unsubstituted C3 alkylene. In an embodiment, L 4 is a substituted or unsubstituted C2 alkylene. In an embodiment, L 4 is an unsubstituted C2-C8 alkylene. In an embodiment, L 4 is an unsubstituted C8 alkylene. In an embodiment, L 4 is an unsubstituted C7 alkylene. In an embodiment, L 4 is an unsubstituted C6 alkylene. In an embodiment, L 4 is an unsubstituted C5 alkylene. In an embodiment, L 4 is an unsubstituted C4 alkylene. In an embodiment, L 4 is an unsubstituted C3 alkylene. In an embodiment, L 4 is an unsubstituted C2 alkylene. In an embodiment, L 4 is an unsubstituted C2 alkylene, an unsubstituted C3 alkylene, or an unsubstituted C4 alkylene.

[0305] In an embodiment, L 4 is a substituted (e.g., substituted with at least one substituent, a size-limiting substituent, or a lower substituent) or unsubstituted C2-C8 alkylene (e.g., C2-C8, C2-C6, C2-C4, or C2). In an embodiment, L 4 is an unsubstituted C2-C8 alkylene (e.g., C2-C8, C2-C6, C2-C4, or C2). In an embodiment, L 4 is an unsubstituted C2 alkylene, an unsubstituted C3 alkylene, or an unsubstituted C4 alkylene.

[0306] In an embodiment, substituted L 4 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and substituted L 4 When is substituted with a plurality of groups selected from a substituent, a size-limiting substituent, and a lower substituent, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In an embodiment, L 4 When substituted, is substituted with at least one substituent. In an embodiment, L 4 When substituted, is substituted with at least one size-limiting substituent. In an embodiment, L 4 When substituted, is substituted with at least one lower substituent.

[0307] In an embodiment, R 40 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In an embodiment, R 40 is independently hydrogen, substituted (e.g., substituted with at least one of a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted (e.g., substituted with at least one of a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered).

[0308] In an embodiment, substituted R 40 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkylene, substituted heterocycloalkylene, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and substituted R 40When it is substituted with a plurality of groups selected from substituents, size-limited substituents, and lower substituents, each substituent, size-limited substituent, and / or lower substituent may optionally be different. In an embodiment, R 40 when substituted, is substituted with at least one substituent. In an embodiment, R 40 when substituted, is substituted with at least one size-limited substituent. In an embodiment, R 40 when substituted, is substituted with at least one lower substituent.

[0309] In an embodiment, R 41 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In an embodiment, R 41 is independently hydrogen, substituted (e.g., substituted with at least one of a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted (e.g., substituted with at least one of a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered).

[0310] In an embodiment, substituted R 41 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and when substituted R 41 is substituted with a plurality of groups selected from substituents, size-limited substituents, and lower substituents, each substituent, size-limited substituent, and / or lower substituent may optionally be different. In an embodiment, R 41 when substituted, is substituted with at least one substituent. In an embodiment, R 41 when substituted, is substituted with at least one size-limited substituent. In an embodiment, R 41When substituted, it is substituted with at least one lower substituent.

[0311] In embodiments, R 42 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R 42 is independently hydrogen, substituted (e.g., substituted with at least one of a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted (e.g., substituted with at least one of a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered).

[0312] In embodiments, substituted R 42 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when substituted R 42 is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, R 42 when substituted, is substituted with at least one substituent. In embodiments, R 42 when substituted, is substituted with at least one size-limiting substituent. In embodiments, R 42 when substituted, is substituted with at least one lower substituent.

[0313] In embodiments, R 40 , R 41 , and R 42 are independently hydrogen or substituted heteroalkyl. In embodiments, R 40 , R 41 , and R 42 are independently hydrogen or -C(NH)NH2. In embodiments, R40 , R 41 , and R 42 Of these, at least two are hydrogen and one is -C(NH)NH2.

[0314] In an embodiment, R 1A is independently a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), a substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In an embodiment, R 1A is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In an embodiment, R 1A is an unsubstituted alkyl, an unsubstituted heteroalkyl, an unsubstituted cycloalkyl, an unsubstituted heterocycloalkyl, an unsubstituted aryl, or an unsubstituted heteroaryl.

[0315] In an embodiment, R 1Ais hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl.

[0316] In an embodiment, R 1A is substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 1A is substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 1A is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 1A is substituted or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl). In an embodiment, R 1A is substituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl). In an embodiment, R 1A is unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl). In an embodiment, R 1A is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 1A is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 1A is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 1A is substituted or unsubstituted heterocycloalkyl (e.g., 2-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl). In an embodiment, R1A is a substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In an embodiment, R 1A is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In an embodiment, R 1A is a substituted or unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl). In an embodiment, R 1A is a substituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl). In an embodiment, R 1A is an unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl). In an embodiment, R 1A is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 1A is a substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 1A is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0317] In an embodiment, R 1A is a substituted or unsubstituted aryl. In some other embodiments, R 1A is a substituted or unsubstituted phenyl. In still some other embodiments, R 1A is a substituted or unsubstituted aryl. In still some other embodiments, R 1A is a substituted or unsubstituted phenyl or naphthalenyl.

[0318] In an embodiment, R 2Ais, independently, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, R 2A is substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl. In embodiments, R 2A is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0319] In embodiments, R 2A is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.

[0320] In embodiments, R 2Ais a substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 2A is a substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 2A is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 2A is a substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In an embodiment, R 2A is a substituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In an embodiment, R 2A is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In an embodiment, R 2A is a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 2A is a substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 2A is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 2A is a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In an embodiment, R 2A is a substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In an embodiment, R 2A is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In an embodiment, R2A is a substituted or unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 2A is a substituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 2A is an unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl). In embodiments, R 2A is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R 2A is a substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R 2A is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0321] In embodiments, R 3A is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R 3A is independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, R 3A is substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl. In embodiments, R 3A is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0322] In embodiments, R 3Ais hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl.

[0323] In an embodiment, R 3A is substituted or unsubstituted aryl. In some other embodiments, R 3A is substituted or unsubstituted phenyl. In still some other embodiments, R 3A is substituted or unsubstituted aryl. In still some other embodiments, R 3A is substituted or unsubstituted phenyl or naphthalenyl.

[0324] In an embodiment, R 3A is substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 3A is substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 3A is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 3A is substituted or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl). In an embodiment, R 3A is substituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl). In an embodiment, R 3A is unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl). In an embodiment, R 3A is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 3Ais a substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 3A is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 3A is a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In an embodiment, R 3A is a substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In an embodiment, R 3A is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In an embodiment, R 3A is a substituted or unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl). In an embodiment, R 3A is a substituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl). In an embodiment, R 3A is an unsubstituted aryl (e.g., C6-C 10 aryl, C 10 aryl, or phenyl). In an embodiment, R 3A is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 3A is a substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 3A is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0325] In Formulas XII, XIII, XIV, and XV as provided herein including that embodiment, L 1 can be substituted or unsubstituted C1-C3 alkylene. In an embodiment, L 1 is substituted or unsubstituted methylene. In an embodiment, L 1 is substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2-6 membered heteroalkylene. In an embodiment, L 1 is substituted or unsubstituted C1-C3 alkylene, or substituted or unsubstituted 2-3 membered heteroalkylene.

[0326] In an embodiment, L 1 is substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). In an embodiment, L 1 is substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkylene, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted arylene, or substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroarylene. In an embodiment, L 1is unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, or unsubstituted heteroarylene. In an embodiment, L 1 is unsubstituted alkylene (e.g., C1-C6 alkylene). In an embodiment, L 1 is a bond.

[0327] In an embodiment, L 1 is -CH2-O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In an embodiment, L 1 is -CH2-O-.

[0328] In an embodiment, L 1 is -CH2-O-,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0329] In formulas XII, XIII, XIV, and XV as provided herein including that embodiment, L 2 can be substituted or unsubstituted C1-C3 alkylene. In an embodiment, L 2is a substituted or unsubstituted methylene. In an embodiment, L 2 is a substituted or unsubstituted C1-C6 alkylene, or a substituted or unsubstituted 2-6 membered heteroalkylene. In an embodiment, L 2 is a substituted or unsubstituted C1-C3 alkylene, or a substituted or unsubstituted 2-3 membered heteroalkylene.

[0330] In an embodiment, L 2 is a substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), a substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), a substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), a substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), a substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or a substituted or unsubstituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). In an embodiment, L 2 is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkylene, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkylene, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkylene, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkylene, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted arylene, or a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroarylene. In an embodiment, L 2 is an unsubstituted alkylene, an unsubstituted heteroalkylene, an unsubstituted cycloalkylene, an unsubstituted heterocycloalkylene, an unsubstituted arylene, or an unsubstituted heteroarylene. In an embodiment, L 2is unsubstituted alkylene (e.g., C1-C6 alkylene). In an embodiment, L 2 is a bond.

[0331] In Formulas XII, XIII, XIV, and XV as provided herein including that embodiment, L 4 can be substituted or unsubstituted C1-C3 alkylene. In an embodiment, L 4 is substituted or unsubstituted methylene. In an embodiment, L 4 is substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2-6 membered heteroalkylene. In an embodiment, L 4 is substituted or unsubstituted C1-C3 alkylene, or substituted or unsubstituted 2-3 membered heteroalkylene.

[0332] L provided herein 4 can be an aliphatic linker, a peptide linker, or a pegylated linker. In an embodiment, L 4 is substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). In an embodiment, L 4is substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkylene, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted arylene, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroarylene. In an embodiment, L 4 is unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, or unsubstituted heteroarylene. In an embodiment, L 4 is unsubstituted alkylene (e.g., C1-C6 alkylene). In an embodiment, L 4 is a bond.

[0333] In Formulas XII, XIII, XIV, and XV as provided herein including that embodiment, z2 can be an integer from 2 to 90 (e.g., 5 to 90, 10 to 90, or 20 to 90), 2 to 80 (e.g., 5 to 80, 10 to 80, or 20 to 80), 2 to 70 (e.g., 5 to 70, 10 to 70, or 20 to 70), 2 to 50 (e.g., 5 to 50, 10 to 50, or 20 to 50), or 2 to 25. In an embodiment, z1 and z3 are independently integers from 0 to 90 (e.g., 5 to 90, 10 to 90, or 20 to 90), 0 to 80 (e.g., 5 to 80, 10 to 80, or 20 to 80), 0 to 70 (e.g., 5 to 70, 10 to 70, or 20 to 70), 0 to 50 (e.g., 5 to 50, 10 to 50, or 20 to 50), or 2 to 25. In an embodiment, z1 and z3 are independently integers from 2 to 90 (e.g., 5 to 90, 10 to 90, or 20 to 90), 2 to 80 (e.g., 5 to 80, 10 to 80, or 20 to 80), 2 to 70 (e.g., 5 to 70, 10 to 70, or 20 to 70), 2 to 50 (e.g., 5 to 50, 10 to 50, or 20 to 50), or 2 to 25. In an embodiment, z4 is independently an integer from 1 to 90 (e.g., 5 to 90, 10 to 90, or 20 to 90), 1 to 80 (e.g., 5 to 80, 10 to 80, or 20 to 80), 1 to 70 (e.g., 5 to 70, 10 to 70, or 20 to 70), 1 to 50 (e.g., 5 to 50, 10 to 50, or 20 to 50), or 2 to 25. In an embodiment, z4 is independently an integer from 2 to 90 (e.g., 5 to 90, 10 to 90, or 20 to 90), 2 to 80 (e.g., 5 to 80, 10 to 80, or 20 to 80), 2 to 70 (e.g., 5 to 70, 10 to 70, or 20 to 70), 2 to 50 (e.g., 5 to 50, 10 to 50, or 20 to 50), or 2 to 25.

[0334] In embodiments of the cell-permeable complex, the pH-sensitive sacrificial domain comprises a first nucleophilic moiety (e.g., Z) and a first electrophilic moiety, wherein the first nucleophilic moiety is reactive with the first electrophilic moiety within a pH range and is substantially non-reactive with electrophilic moieties outside of that pH range (e.g., pH of about 1-5, pH of about 5-7, or pH of about 7-10). In embodiments, the pH range in which the first nucleophilic moiety is most reactive with the first electrophilic moiety is pH 1-3, pH 2-4, pH 3-5, pH 4-6, pH 5-7, pH 6-8, pH 7-9, or pH 8-10. The nucleophilic moiety is used according to its plain ordinary meaning in chemistry and refers to a moiety (e.g., a functional group) that can donate electrons.

[0335] In the embodiment, the pH range in which the first nucleophilic moiety is most reactive with the first electrophilic moiety is pH 1 to 3. In the embodiment, the pH range in which the first nucleophilic moiety is most reactive with the first electrophilic moiety is pH 2 to 4. In the embodiment, the pH range in which the first nucleophilic moiety is most reactive with the first electrophilic moiety is pH 3 to 5. In the embodiment, the pH range in which the first nucleophilic moiety is most reactive with the first electrophilic moiety is pH 4 to 6. In the embodiment, the pH range in which the first nucleophilic moiety is most reactive with the first electrophilic moiety is pH 5 to 7. In the embodiment, the pH range in which the first nucleophilic moiety is most reactive with the first electrophilic moiety is pH 6 to 8. In the embodiment, the pH range in which the first nucleophilic moiety is most reactive with the first electrophilic moiety is pH 7 to 9. In the embodiment, the pH range in which the first nucleophilic moiety is most reactive with the first electrophilic moiety is pH 8 to 10. In the embodiment, the pH is 1. In the embodiment, the pH is 2. In the embodiment, the pH is 3. In the embodiment, the pH is 4. In the embodiment, the pH is 5. In the embodiment, the pH is 6. In the embodiment, the pH is 7. In the embodiment, the pH is 8. In the embodiment, the pH is 9. In the embodiment, the pH is 10. In the embodiment, the pH is about 1. In the embodiment, the pH is about 2. In the embodiment, the pH is about 3. In the embodiment, the pH is about 4. In the embodiment, the pH is about 5. In the embodiment, the pH is about 6. In the embodiment, the pH is about 7. In the embodiment, the pH is about 8. In the embodiment, the pH is about 9. In the embodiment, the pH is about 10.

[0336] In the embodiment, the first nucleophilic moiety is substantially protonated at low pH (e.g., pH about 1 to about 5). In the embodiment, the first nucleophilic moiety is substantially protonated in the range of pH 5 to 7. In the embodiment, the first nucleophilic moiety is cationic. In the embodiment, the first nucleophilic moiety contains a cationic nitrogen (e.g., a cationic amine).

[0337] In an embodiment, the first nucleophilic moiety can be attached to a pH-labile protecting group. Terms such as "pH-labile protecting group" refer, in the ordinary and customary sense, to a chemical moiety that can protect another functional group attached thereto, and the protecting group can be cleaved under specific pH conditions (e.g., conditions that lower the pH) or can be inactivated as a protecting group. In one embodiment, the pH-labile protecting group is -CO2-t-Bu, a group that is removed under acidic conditions (e.g., pH less than 7). Additional protecting groups for nucleophiles can also include protecting groups that are cleaved by light, heat, nucleophiles, and bases.

[0338] In an embodiment, the pH-sensitive sacrificial domain has the following formula: [Chemical formula] wherein: z2 is an integer of 2 or more; n1 is an integer from 0 to 50; Z is a nucleophilic moiety; X 1 is a bond, -C(R 5 )(R 6 )-, -C(R 5 )(R 6 )-C(R 7 )(R 8 )-, -O-C(R 5 )(R 6 )-, or -O-C(R 5 )(R 6 )-C(R 7 )(R 8 ); X 2 is -O- or -S-; R 1 , R 2 , R 5 , R 6 , R 7 , and R 8is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0339] In an embodiment, the pH-sensitive sacrificial domain has the following formula

Chemical formula

[0340] In an embodiment, the pH-sensitive sacrificial domain has the structure of the following formula.

Chemical formula

[0341] In formulas (XII), (XIII), (XIV), (XV), (XVI), and (XVII), R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 are independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, R 1 , R 2 , R 5 , R 6 , R 7 , and R 8is, independently, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In embodiments, R 1 、R 2 、R 5 、R 6 、R 7 、and R 8 are, independently, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 1 、R 2 、R 5 、R 6 、R 7 、and R 8 are, independently, hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl). In embodiments, R 1 、R 2 、R 5 、R 6 、R 7 、and R 8 are hydrogen.

[0342] In embodiments, the pH-sensitive sacrificial domain has the following formula:

Chemical formula

[0343] In an embodiment, R 24 , R 25 , and R 26 are independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In an embodiment, R 24 , R 25 , and R 26 are independently substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In an embodiment, R 1.1 , R 24 , R 25 , and R 26is, independently, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 24 , R 25 , and R 26 are, independently, hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl). In embodiments, R 24 , R 25 , and R 26 are, independently, hydrogen.

[0344] In Formulas (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX) provided herein, including embodiments thereof, R 1 , R 1A , R 2A , R 3A , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 24 , R 25 , R 26 , R 40 , R 41 , R 42 , R 201 , R 202 , and R 203 are, independently, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In an embodiment, R 1 , R 1A , R 2A , R 3A , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 24 , R 25 , R 26 , R 40 , R 41 , R 42 , R 201 , R 202 , and R 203 are, independently, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In an embodiment, R 1 , R 1A , R 2A , R 3A , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 24 , R 25 , R26 , R 40 , R 41 , R 42 , R 201 , R 202 , and R 203 are, independently, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 1 , R 1A , R 2A , R 3A , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 24 , R 25 , R 26 , R 40 , R 41 , R 42 , R 201 , R 202 , and R 203 are, independently, hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl). In embodiments, R 1 , R 1A , R 2A , R 3A , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 40 , R 41 , R 42 , R 201 , R 202 , and R 203 is hydrogen.

[0345] In Formulas (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX) provided herein, including that embodiment, R 40 , R 41 , and R 42 can be substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered). In an embodiment, R 40 , R 41 , and R 42 are substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl. In an embodiment, R 40 , R 41 , and R 42 are independently hydrogen or substituted or unsubstituted alkyl. In an embodiment, R 40 , R 41 , and R 42 are independently hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl). In an embodiment, R 40 , R 41 , and R 42 are hydrogen.

[0346] In an embodiment, Z is a nucleophilic moiety. In an embodiment, Z is -S-, -OR 13 -, -S + R 13 -, -NR 13 -, or -N + (R 13 )(H)-, where R 13 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In an embodiment, Z is -S-. In an embodiment, Z is -S + R 13- is. In an embodiment, Z is -NR 13 - is. In an embodiment, Z is -N + (R 13 )(H)- is. In an embodiment, Z is -S + H- is. In an embodiment, Z is -NH-. In an embodiment, Z is -N + H2- is. In an embodiment, Z is -OH-. In an embodiment, Z is -N + (R 13 )(H)- and R 13 is hydrogen.

[0347] In an embodiment, R 13 is independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). In an embodiment, R 13 is independently substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl. In an embodiment, R 13is, independently, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 13 is, independently, hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl). In embodiments, R 13 is hydrogen. In embodiments, R 13 is -NH3 + . In embodiments, R 13 is -NH2.

[0348] In embodiments, R 13A is, independently, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, R 13A is, independently, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In embodiments, R 13Ais independently unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 1A3 is independently hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl). In embodiments, R 13A is hydrogen. In embodiments, R 13A is -NH3 + . In embodiments, R 13A is -NH2.

[0349] In embodiments, Z is

Chemical formula

[0350] In embodiments, R 13 , R 14 , R 15 , R 16 , R 17, R 18 , and R 19 are, independently, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 are, independently, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In embodiments, R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 are, independently, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 13 , R 14 , R 15 , R16 , R 17 , R 18 , and R 19 are, independently, hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl).

[0351] In an embodiment, X 5 is -N + (R 13 )(H), and R 13 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0352] In an embodiment, the pH-sensitive sacrificial domain has the following formula (XX): [Chemical formula] having, wherein z2 is as defined herein.

[0353] In an embodiment, the pH-sensitive sacrificial domain has the following formula (XXb): [Chemical formula] having, wherein z2 is as defined herein.

[0354] In an embodiment, the pH-sensitive sacrificial domain has the following formula (XXI): [Chemical formula] (XXI) having, wherein z2 and R 13A are as defined herein.

[0355] In an embodiment, the pH-sensitive sacrificial domain has the following formula (XXIa): [Chemical formula] having, wherein z2 and R 13Ais as defined herein.

[0356] In an embodiment, the lipophilic polymer domain (LP 1 or LP 2 ) has the following formula: [Chemical formula] wherein n2 is an integer from 1 to 100, and R 20 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0357] In an embodiment, R 20 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In an embodiment, R 20is substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In embodiments, R 20 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 20 is hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl).

[0358] In embodiments, R 20 is unsubstituted C1-C 30 alkyl. In embodiments, R 20 is unsubstituted C1-C 20 alkyl. In embodiments, R 20 is unsubstituted C8-C 30 alkyl. In embodiments, R 20 is unsubstituted C8-C 20 alkyl. In embodiments, R 20 is unsubstituted C9-C 20 alkyl. In embodiments, R 20 is unsubstituted C9-C 18 alkyl. In embodiments, R 20 is unsubstituted C 18 alkyl. In embodiments, R 20 is unsubstituted C 17 alkyl. In embodiments, R 20 is unsubstituted C 16 alkyl. In embodiments, R 20 is unsubstituted C 15 alkyl. In embodiments, R20 is unsubstituted C 14 alkyl. In an embodiment, R 20 is unsubstituted C 13 alkyl. In an embodiment, R 20 is unsubstituted C 12 alkyl. In an embodiment, R 20 is unsubstituted C 11 alkyl. In an embodiment, R 20 is unsubstituted C 10 alkyl. In an embodiment, R 20 is unsubstituted C9 alkyl. In an embodiment, R 20 is unsubstituted C8 alkyl. In an embodiment, R 20 is unsubstituted C7 alkyl. In an embodiment, R 20 is unsubstituted C6 alkyl. In an embodiment, R 20 is unsubstituted C5 alkyl. In an embodiment, R 20 is unsubstituted C4 alkyl. In an embodiment, R 20 is unsubstituted C3 alkyl. In an embodiment, R 20 is unsubstituted C2 alkyl.

[0359] In an embodiment, R 20 is unsubstituted C1-C 30 alkenyl. In an embodiment, R 20 is unsubstituted C1-C 20 alkenyl. In an embodiment, R 20 is unsubstituted C8-C 30 alkenyl. In an embodiment, R 20 is unsubstituted C8-C 20 alkenyl. In an embodiment, R 20 is unsubstituted C9-C 20 alkenyl. In an embodiment, R 20 is unsubstituted C9-C 18 alkenyl. In an embodiment, R 20 is unsubstituted C 18 alkenyl. In an embodiment, R 20 is unsubstituted C 17 alkenyl. In an embodiment, R 20 is unsubstituted C16 is alkenyl. In an embodiment, R 20 is unsubstituted C 15 is alkenyl. In an embodiment, R 20 is unsubstituted C 14 is alkenyl. In an embodiment, R 20 is unsubstituted C 13 is alkenyl. In an embodiment, R 20 is unsubstituted C 12 is alkenyl. In an embodiment, R 20 is unsubstituted C 11 is alkenyl. In an embodiment, R 20 is unsubstituted C 10 is alkenyl. In an embodiment, R 20 is unsubstituted C9 alkenyl. In an embodiment, R 20 is unsubstituted C8 alkenyl. In an embodiment, R 20 is unsubstituted C7 alkenyl. In an embodiment, R 20 is unsubstituted C6 alkenyl. In an embodiment, R 20 is unsubstituted C5 alkenyl. In an embodiment, R 20 is unsubstituted C4 alkenyl. In an embodiment, R 20 is unsubstituted C3 alkenyl. In an embodiment, R 20 is unsubstituted C2 alkenyl.

[0360] In an embodiment, R 20 is a stearyl moiety (e.g., unsubstituted C 18 alkyl). In an embodiment, R 20 is an oleyl moiety (e.g., unsubstituted C 18 alkenyl). In an embodiment, R 20 is a linoleyl moiety (e.g., unsubstituted C 18 alkenyl). In an embodiment, R 20 is a dodecyl moiety (e.g., unsubstituted C 12 alkyl). In an embodiment, R 20 is a nonenyl moiety (e.g., unsubstituted C9 alkenyl). In an embodiment, R 20 is

Chemical formula

[0361] In an embodiment, R 1 and R 2 are, independently, hydrogen or substituted or unsubstituted alkyl.

[0362] In an embodiment, n1 is 2.

[0363] In an embodiment, X2 is -O-.

[0364] In an embodiment, z1 or z3 is, independently, an integer from 10 to 40.

[0365] In an embodiment, z2 is, independently, an integer from 3 to 20.

[0366] In an embodiment, LP 1 has the following formula,

Chemical formula

[0367] wherein n21 is an integer from 1 to 100,

[0368] R 201 is, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In an embodiment, n21 is from 10 to 40. In an embodiment, R 201 is unsubstituted C 12 alkyl.

[0369] In an embodiment, R 201is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), a substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, R 201 is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In embodiments, R 201 is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 201 is hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl).

[0370] In embodiments, R 201 is unsubstituted C1-C 30 alkyl. In embodiments, R 201 is unsubstituted C1-C 20 alkyl. In embodiments, R 201 is unsubstituted C8-C 30 alkyl. In embodiments, R 201 is unsubstituted C8-C 20is alkyl. In an embodiment, R 201 is unsubstituted C9-C 20 is alkyl. In an embodiment, R 201 is unsubstituted C9-C 18 is alkyl. In an embodiment, R 201 is unsubstituted C 18 is alkyl. In an embodiment, R 201 is unsubstituted C 17 is alkyl. In an embodiment, R 201 is unsubstituted C 16 is alkyl. In an embodiment, R 201 is unsubstituted C 15 is alkyl. In an embodiment, R 201 is unsubstituted C 14 is alkyl. In an embodiment, R 201 is unsubstituted C 13 is alkyl. In an embodiment, R 201 is unsubstituted C 12 is alkyl. In an embodiment, R 201 is unsubstituted C 11 is alkyl. In an embodiment, R 201 is unsubstituted C 10 is alkyl. In an embodiment, R 201 is unsubstituted C9 alkyl. In an embodiment, R 201 is unsubstituted C8 alkyl. In an embodiment, R 201 is unsubstituted C7 alkyl. In an embodiment, R 201 is unsubstituted C6 alkyl. In an embodiment, R 201 is unsubstituted C5 alkyl. In an embodiment, R 201 is unsubstituted C4 alkyl. In an embodiment, R 201 is unsubstituted C3 alkyl. In an embodiment, R 201 is unsubstituted C2 alkyl.

[0371] In an embodiment, R 201 is unsubstituted C1-C 30 is alkenyl. In an embodiment, R 201 is unsubstituted C1-C 20 is alkenyl. In an embodiment, R 201is unsubstituted C8 - C 30 alkenyl. In an embodiment, R 201 is unsubstituted C8 - C 20 alkenyl. In an embodiment, R 201 is unsubstituted C9 - C 20 alkenyl. In an embodiment, R 201 is unsubstituted C9 - C 18 alkenyl. In an embodiment, R 201 is unsubstituted C 18 alkenyl. In an embodiment, R 201 is unsubstituted C 17 alkenyl. In an embodiment, R 201 is unsubstituted C 16 alkenyl. In an embodiment, R 201 is unsubstituted C 15 alkenyl. In an embodiment, R 201 is unsubstituted C 14 alkenyl. In an embodiment, R 201 is unsubstituted C 13 alkenyl. In an embodiment, R 201 is unsubstituted C 12 alkenyl. In an embodiment, R 201 is unsubstituted C 11 alkenyl. In an embodiment, R 201 is unsubstituted C 10 alkenyl. In an embodiment, R 201 is unsubstituted C9 alkenyl. In an embodiment, R 201 is unsubstituted C8 alkenyl. In an embodiment, R 201 is unsubstituted C7 alkenyl. In an embodiment, R 201 is unsubstituted C6 alkenyl. In an embodiment, R 201 is unsubstituted C5 alkenyl. In an embodiment, R 201 is unsubstituted C4 alkenyl. In an embodiment, R 201 is unsubstituted C3 alkenyl. In an embodiment, R 201 is unsubstituted C2 alkenyl.

[0372] In an embodiment, R 201is a stearyl moiety (e.g., unsubstituted C 18 alkyl). In an embodiment, R 201 is an oleyl moiety (e.g., unsubstituted C 18 alkenyl). In an embodiment, R 201 is a linoleyl moiety (e.g., unsubstituted C 18 alkenyl). In an embodiment, R 201 is a dodecyl moiety (e.g., unsubstituted C 12 alkyl). In an embodiment, R 201 is a nonenyl moiety (e.g., unsubstituted C9 alkenyl). In an embodiment, R 201 is

Chemical formula

[0373] In an embodiment, n21 is 5 and R 201 is unsubstituted C 18 alkenyl. In an embodiment, the unsubstituted C 18 alkenyl is oleyl.

[0374] In an embodiment, LP 2 has the following formula:

Chemical formula

[0375] In an embodiment, R 202is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, R 202 is a substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl. In embodiments, R 202 is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 202 is hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl).

[0376] In embodiments, R 202 is unsubstituted C1-C 30 alkyl. In embodiments, R 202 is unsubstituted C1-C 20 alkyl. In embodiments, R 202 is unsubstituted C8-C 30 alkyl. In embodiments, R 202 is unsubstituted C8-C 20is alkyl. In an embodiment, R 202 is unsubstituted C9-C 20 is alkyl. In an embodiment, R 202 is unsubstituted C9-C 18 is alkyl. In an embodiment, R 202 is unsubstituted C 18 is alkyl. In an embodiment, R 202 is unsubstituted C 17 is alkyl. In an embodiment, R 202 is unsubstituted C 16 is alkyl. In an embodiment, R 202 is unsubstituted C 15 is alkyl. In an embodiment, R 202 is unsubstituted C 14 is alkyl. In an embodiment, R 202 is unsubstituted C 13 is alkyl. In an embodiment, R 202 is unsubstituted C 12 is alkyl. In an embodiment, R 202 is unsubstituted C 11 is alkyl. In an embodiment, R 202 is unsubstituted C 10 is alkyl. In an embodiment, R 202 is unsubstituted C9 alkyl. In an embodiment, R 202 is unsubstituted C8 alkyl. In an embodiment, R 202 is unsubstituted C7 alkyl. In an embodiment, R 202 is unsubstituted C6 alkyl. In an embodiment, R 202 is unsubstituted C5 alkyl. In an embodiment, R 202 is unsubstituted C4 alkyl. In an embodiment, R 202 is unsubstituted C3 alkyl. In an embodiment, R 202 is unsubstituted C2 alkyl.

[0377] In an embodiment, R 202 is unsubstituted C1-C 30 is alkenyl. In an embodiment, R 202 is unsubstituted C1-C 20 is alkenyl. In an embodiment, R 202is unsubstituted C8 - C 30 alkenyl. In an embodiment, R 202 is unsubstituted C8 - C 20 alkenyl. In an embodiment, R 202 is unsubstituted C9 - C 20 alkenyl. In an embodiment, R 202 is unsubstituted C9 - C 18 alkenyl. In an embodiment, R 202 is unsubstituted C 18 alkenyl. In an embodiment, R 202 is unsubstituted C 17 alkenyl. In an embodiment, R 202 is unsubstituted C 16 alkenyl. In an embodiment, R 202 is unsubstituted C 15 alkenyl. In an embodiment, R 202 is unsubstituted C 14 alkenyl. In an embodiment, R 202 is unsubstituted C 13 alkenyl. In an embodiment, R 202 is unsubstituted C 12 alkenyl. In an embodiment, R 202 is unsubstituted C 11 alkenyl. In an embodiment, R 202 is unsubstituted C 10 alkenyl. In an embodiment, R 202 is unsubstituted C9 alkenyl. In an embodiment, R 202 is unsubstituted C8 alkenyl. In an embodiment, R 202 is unsubstituted C7 alkenyl. In an embodiment, R 202 is unsubstituted C6 alkenyl. In an embodiment, R 202 is unsubstituted C5 alkenyl. In an embodiment, R 202 is unsubstituted C4 alkenyl. In an embodiment, R 202 is unsubstituted C3 alkenyl. In an embodiment, R 202 is unsubstituted C2 alkenyl.

[0378] In an embodiment, R 202is a stearyl moiety (e.g., unsubstituted C 18 alkyl). In an embodiment, R 202 is an oleyl moiety (e.g., unsubstituted C 18 alkenyl). In an embodiment, R 202 is a linoleyl moiety (e.g., unsubstituted C 18 alkenyl). In an embodiment, R 202 is a dodecyl moiety (e.g., unsubstituted C 12 alkyl). In an embodiment, R 202 is a nonenyl moiety (e.g., unsubstituted C9 alkenyl). In an embodiment, R 202 is

Chemical formula

[0379] In an embodiment, n22 is from 10 to 35. In an embodiment, R 202 is unsubstituted C 12 alkenyl.

[0380] In an embodiment, n22 is 5 and R 202 is unsubstituted C9 alkenyl. In an embodiment, the unsubstituted C9 alkenyl is nonenyl.

[0381] In an embodiment, the lipophilic polymer domain is a compound of the following formula (Ia):

Chemical formula

[0382] In an embodiment, R 20 is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), a substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In an embodiment, R 20 is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In an embodiment, R 20 is an unsubstituted alkyl, an unsubstituted heteroalkyl, an unsubstituted cycloalkyl, an unsubstituted heterocycloalkyl, an unsubstituted aryl, or an unsubstituted heteroaryl. In an embodiment, R 20 is hydrogen or an unsubstituted alkyl (e.g., C1-C6 alkyl).

[0383] In an embodiment, R 21is a substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, R 21 is a substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl. In embodiments, R 21 is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 21 is hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl).

[0384] In embodiments, the lipophilic polymer has the following structure: [Chemical formula] wherein X 7 is independently -O-, -NH-, -CO2-, -CONH-, -O2C-, or -NHCO-, and R 22is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 23 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In an embodiment, R 22 is an oligoglycol moiety.

[0385] In an embodiment, R 22 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In an embodiment, R 22 is substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl. In an embodiment, R 22is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In an embodiment, R 22 is hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl).

[0386] In an embodiment, the lipophilic polymer domain (e.g., LP 1 LP 2 ) has the following formula:

Chemical formula

[0387] In an embodiment, R 1 , R 2 , R 3 , R 4 are independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In an embodiment, R 1 , R 2 , R 3 , R 4 are, independently, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In an embodiment, R 1 , R 2 , R 3 , R 4 are, independently, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In an embodiment, R 1 , R 2 , R 3 , R 4 are, independently, hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl). In an embodiment, R 1 , R 2 , R 3 , R 4 is hydrogen.

[0388] In an embodiment, the lipophilic polymer domain has the following formula (Ic): [Chemical formula] and in the formula, R 200is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and n200 is an integer of 2 or more. In an embodiment, R 200 is an oligo glycol moiety. In an embodiment, R 200 is an amine - terminal oligo glycol moiety. The term "oligo glycol moiety" refers to

Chemical formula

Chemical formula

[0389] In an embodiment, R 200 is a substituted or unsubstituted alkyl (e.g., C1 - C8, C1 - C6, C1 - C4, or C1 - C2), substituted or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered, 2 - to 6 - membered, 4 - to 6 - membered, 2 - to 3 - membered, or 4 - to 5 - membered), substituted or unsubstituted cycloalkyl (e.g., C3 - C8, C3 - C6, C4 - C6, or C5 - C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered, 3 - to 6 - membered, 4 - to 6 - membered, 4 - to 5 - membered, or 5 - to 6 - membered), substituted or unsubstituted aryl (e.g., C6 - C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 - to 10 - membered, 5 - to 9 - membered, or 5 - to 6 - membered). In an embodiment, R 200is substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl. In embodiments, R 200 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 200 is hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl). In embodiments, R 200 is hydrogen.

[0390] In embodiments, the lipophilic polymer domain has the following formula: [Chemical formula] wherein R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 300 and R 301 are independently hydrogen or substituted or unsubstituted alkyl, and n300 is as defined herein. In embodiments, R 302 is an oligo glycol moiety. In embodiments, R is an amine-terminated oligo glycol moiety. In embodiments, R 300 , R 301 , and R 302 are hydrogen.

[0391] In embodiments, R 300 , R301 and R 302 is, independently, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). In embodiments, R 300 , R 301 , and R 302 is, independently, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl. In embodiments, R 300 , R 301 , and R 302 is, independently, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 300 , R 301 , and R 302 is, independently, hydrogen or unsubstituted alkyl (e.g., C1-C6 alkyl).

[0392] In an embodiment, the lipophilic polymer domain has the following formula, where R is defined therein as stearyl, oleyl, linoleyl, dodecyl, nonyl, and cholesterol. [Chemical formula]

[0393] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein LP 1 , LP 2 , IM, L 2 , R 2A , z1, z2, z3, and z4 are defined as herein.

[0394] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein LP 1 , LP 2 , IM, L 1 , L 2 , R 2A , z1, z2, z3, and z4 are defined as herein. In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein LP 1 , LP 2 , IM, L 1 , L 2 , R 2A , z1, z2, z3, and z4 are defined as herein. In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein LP 1 , LP 2 , IM, L 1, L 2 , R 2A , z1, z2, z3, and z4 are defined as herein. In embodiments, the cationic amphiphilic polymer has the following formula:

Chemical formula

Chemical formula

[0395] In embodiments, z1, z3, and z4 may independently be integers in the range of 2 to 100, 2 to 90, 2 to 80, 2 to 70, 2 to 60, 2 to 50, 2 to 40, 2 to 30, 2 to 2, or 2 to 10, and at least one of z1 or z3 is not 0. In embodiments, z1, z3, and z4 may independently be integers in the range of 2 to 100 or 2 to 50, and at least one of z1 or z3 is not 0.

[0396] In the embodiment, z1 is 0. In the embodiment, z1 is 1. In the embodiment, z1 is 2. In the embodiment, z1 is 3. In the embodiment, z1 is 4. In the embodiment, z1 is 5. In the embodiment, z1 is 6. In the embodiment, z1 is 7. In the embodiment, z1 is 8. In the embodiment, z1 is 9. In the embodiment, z1 is 10. In the embodiment, z1 is 11. In the embodiment, z1 is 12. In the embodiment, z1 is 13. In the embodiment, z1 is 14. In the embodiment, z1 is 15. In the embodiment, z1 is 16. In the embodiment, z1 is 17. In the embodiment, z1 is 18. In the embodiment, z1 is 19. In the embodiment, z1 is 20. In the embodiment, z1 is 21. In the embodiment, z1 is 22. In the embodiment, z1 is 23. In the embodiment, z1 is 24. In the embodiment, z1 is 25. In the embodiment, z1 is 26. In the embodiment, z1 is 27. In the embodiment, z1 is 28. In the embodiment, z1 is 29. In the embodiment, z1 is 30. In the embodiment, z1 is 31. In the embodiment, z1 is 32. In the embodiment, z1 is 33. In the embodiment, z1 is 34. In the embodiment, z1 is 35. In the embodiment, z1 is 36. In the embodiment, z1 is 37. In the embodiment, z1 is 38. In the embodiment, z1 is 39. In the embodiment, z1 is 40. In the embodiment, z1 is 41. In the embodiment, z1 is 42. In the embodiment, z1 is 43. In the embodiment, z1 is 44. In the embodiment, z1 is 45. In the embodiment, z1 is 46. In the embodiment, z1 is 47. In the embodiment, z1 is 48. In the embodiment, z1 is 49. In the embodiment, z1 is 50. In the embodiment, z1 is 51. In the embodiment, z1 is 52. In the embodiment, z1 is 53. In the embodiment, z1 is 54. In the embodiment, z1 is 55. In the embodiment, z1 is 56. In the embodiment, z1 is 57. In the embodiment, z1 is 58.In the embodiment, z1 is 59. In the embodiment, z1 is 60. In the embodiment, z1 is 61. In the embodiment, z1 is 62. In the embodiment, z1 is 63. In the embodiment, z1 is 64. In the embodiment, z1 is 65. In the embodiment, z1 is 66. In the embodiment, z1 is 67. In the embodiment, z1 is 68. In the embodiment, z1 is 69. In the embodiment, z1 is 70. In the embodiment, z1 is 71. In the embodiment, z1 is 72. In the embodiment, z1 is 73. In the embodiment, z1 is 74. In the embodiment, z1 is 75. In the embodiment, z1 is 76. In the embodiment, z1 is 77. In the embodiment, z1 is 78. In the embodiment, z1 is 79. In the embodiment, z1 is 80. In the embodiment, z1 is 81. In the embodiment, z1 is 82. In the embodiment, z1 is 83. In the embodiment, z1 is 84. In the embodiment, z1 is 85. In the embodiment, z1 is 86. In the embodiment, z1 is 87. In the embodiment, z1 is 88. In the embodiment, z1 is 89. In the embodiment, z1 is 90. In the embodiment, z1 is 91. In the embodiment, z1 is 92. In the embodiment, z1 is 93. In the embodiment, z1 is 94. In the embodiment, z1 is 95. In the embodiment, z1 is 96. In the embodiment, z1 is 97. In the embodiment, z1 is 98. In the embodiment, z1 is 99. In the embodiment, z1 is 100.

[0397] In the embodiment, z3 is 0. In the embodiment, z3 is 1. In the embodiment, z3 is 2. In the embodiment, z3 is 3. In the embodiment, z3 is 4. In the embodiment, z3 is 5. In the embodiment, z3 is 6. In the embodiment, z3 is 7. In the embodiment, z3 is 8. In the embodiment, z3 is 9. In the embodiment, z3 is 10. In the embodiment, z3 is 11. In the embodiment, z3 is 12. In the embodiment, z3 is 13. In the embodiment, z3 is 14. In the embodiment, z3 is 15. In the embodiment, z3 is 16. In the embodiment, z3 is 17. In the embodiment, z3 is 18. In the embodiment, z3 is 19. In the embodiment, z3 is 20. In the embodiment, z3 is 21. In the embodiment, z3 is 22. In the embodiment, z3 is 23. In the embodiment, z3 is 24. In the embodiment, z3 is 25. In the embodiment, z3 is 26. In the embodiment, z3 is 27. In the embodiment, z3 is 28. In the embodiment, z3 is 29. In the embodiment, z3 is 30. In the embodiment, z3 is 31. In the embodiment, z3 is 32. In the embodiment, z3 is 33. In the embodiment, z3 is 34. In the embodiment, z3 is 35. In the embodiment, z3 is 36. In the embodiment, z3 is 37. In the embodiment, z3 is 38. In the embodiment, z3 is 39. In the embodiment, z3 is 40. In the embodiment, z3 is 41. In the embodiment, z3 is 42. In the embodiment, z3 is 43. In the embodiment, z3 is 44. In the embodiment, z3 is 45. In the embodiment, z3 is 46. In the embodiment, z3 is 47. In the embodiment, z3 is 48. In the embodiment, z3 is 49. In the embodiment, z3 is 50. In the embodiment, z3 is 51. In the embodiment, z3 is 52. In the embodiment, z3 is 53. In the embodiment, z3 is 54. In the embodiment, z3 is 55. In the embodiment, z3 is 56. In the embodiment, z3 is 57. In the embodiment, z3 is 58.In the embodiment, z3 is 59. In the embodiment, z3 is 60. In the embodiment, z3 is 61. In the embodiment, z3 is 62. In the embodiment, z3 is 63. In the embodiment, z3 is 64. In the embodiment, z3 is 65. In the embodiment, z3 is 66. In the embodiment, z3 is 67. In the embodiment, z3 is 68. In the embodiment, z3 is 69. In the embodiment, z3 is 70. In the embodiment, z3 is 71. In the embodiment, z3 is 72. In the embodiment, z3 is 73. In the embodiment, z3 is 74. In the embodiment, z3 is 75. In the embodiment, z3 is 76. In the embodiment, z3 is 77. In the embodiment, z3 is 78. In the embodiment, z3 is 79. In the embodiment, z3 is 80. In the embodiment, z3 is 81. In the embodiment, z3 is 82. In the embodiment, z3 is 83. In the embodiment, z3 is 84. In the embodiment, z3 is 85. In the embodiment, z3 is 86. In the embodiment, z3 is 87. In the embodiment, z3 is 88. In the embodiment, z3 is 89. In the embodiment, z3 is 90. In the embodiment, z3 is 91. In the embodiment, z3 is 92. In the embodiment, z3 is 93. In the embodiment, z3 is 94. In the embodiment, z3 is 95. In the embodiment, z3 is 96. In the embodiment, z3 is 97. In the embodiment, z3 is 98. In the embodiment, z3 is 99. In the embodiment, z3 is 100.

[0398] In the embodiment, z4 is 1. In the embodiment, z4 is 2. In the embodiment, z4 is 3. In the embodiment, z4 is 4. In the embodiment, z4 is 5. In the embodiment, z4 is 6. In the embodiment, z4 is 7. In the embodiment, z4 is 8. In the embodiment, z4 is 9. In the embodiment, z4 is 10. In the embodiment, z4 is 11. In the embodiment, z4 is 12. In the embodiment, z4 is 13. In the embodiment, z4 is 14. In the embodiment, z4 is 15. In the embodiment, z4 is 16. In the embodiment, z4 is 17. In the embodiment, z4 is 18. In the embodiment, z4 is 19. In the embodiment, z4 is 20. In the embodiment, z4 is 21. In the embodiment, z4 is 22. In the embodiment, z4 is 23. In the embodiment, z4 is 24. In the embodiment, z4 is 25. In the embodiment, z4 is 26. In the embodiment, z4 is 27. In the embodiment, z4 is 28. In the embodiment, z4 is 29. In the embodiment, z4 is 30. In the embodiment, z4 is 31. In the embodiment, z4 is 32. In the embodiment, z4 is 33. In the embodiment, z4 is 34. In the embodiment, z4 is 35. In the embodiment, z4 is 36. In the embodiment, z4 is 37. In the embodiment, z4 is 38. In the embodiment, z4 is 39. In the embodiment, z4 is 40. In the embodiment, z4 is 41. In the embodiment, z4 is 42. In the embodiment, z4 is 43. In the embodiment, z4 is 44. In the embodiment, z4 is 45. In the embodiment, z4 is 46. In the embodiment, z4 is 47. In the embodiment, z4 is 48. In the embodiment, z4 is 49. In the embodiment, z4 is 50. In the embodiment, z4 is 51. In the embodiment, z4 is 52. In the embodiment, z4 is 53. In the embodiment, z4 is 54. In the embodiment, z4 is 55. In the embodiment, z4 is 56. In the embodiment, z4 is 57. In the embodiment, z4 is 58. In the embodiment, z4 is 59.In the embodiment, z4 is 60. In the embodiment, z4 is 61. In the embodiment, z4 is 62. In the embodiment, z4 is 63. In the embodiment, z4 is 64. In the embodiment, z4 is 65. In the embodiment, z4 is 66. In the embodiment, z4 is 67. In the embodiment, z4 is 68. In the embodiment, z4 is 69. In the embodiment, z4 is 70. In the embodiment, z4 is 71. In the embodiment, z4 is 72. In the embodiment, z4 is 73. In the embodiment, z4 is 74. In the embodiment, z4 is 75. In the embodiment, z4 is 76. In the embodiment, z4 is 77. In the embodiment, z4 is 78. In the embodiment, z4 is 79. In the embodiment, z4 is 80. In the embodiment, z4 is 81. In the embodiment, z4 is 82. In the embodiment, z4 is 83. In the embodiment, z4 is 84. In the embodiment, z4 is 85. In the embodiment, z4 is 86. In the embodiment, z4 is 87. In the embodiment, z4 is 88. In the embodiment, z4 is 89. In the embodiment, z4 is 90. In the embodiment, z4 is 91. In the embodiment, z4 is 92. In the embodiment, z4 is 93. In the embodiment, z4 is 94. In the embodiment, z4 is 95. In the embodiment, z4 is 96. In the embodiment, z4 is 97. In the embodiment, z4 is 98. In the embodiment, z4 is 99. In the embodiment, z4 is 100.

[0399] In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4. In an embodiment, n is 5. In an embodiment, n is 6. In an embodiment, n is 7. In an embodiment, n is 8. In an embodiment, n is 9. In an embodiment, n is 10. In an embodiment, n is 11. In an embodiment, n is 12. In an embodiment, n is 13. In an embodiment, n is 14. In an embodiment, n is 15. In an embodiment, n is 16. In an embodiment, n is 17. In an embodiment, n is 18. In an embodiment, n is 19. In an embodiment, n is 20. In an embodiment, n is 21. In an embodiment, n is 22. In an embodiment, n is 23. In an embodiment, n is 24. In an embodiment, n is 25. In an embodiment, n is 26. In an embodiment, n is 27. In an embodiment, n is 28. In an embodiment, n is 29. In an embodiment, n is 30. In an embodiment, n is 31. In an embodiment, n is 32. In an embodiment, n is 33. In an embodiment, n is 34. In an embodiment, n is 35. In an embodiment, n is 36. In an embodiment, n is 37. In an embodiment, n is 38. In an embodiment, n is 39. In an embodiment, n is 40. In an embodiment, n is 41. In an embodiment, n is 42. In an embodiment, n is 43. In an embodiment, n is 44. In an embodiment, n is 45. In an embodiment, n is 46. In an embodiment, n is 47. In an embodiment, n is 48. In an embodiment, n is 49. In an embodiment, n is 50. In an embodiment, n is 51. In an embodiment, n is 52. In an embodiment, n is 53. In an embodiment, n is 54. In an embodiment, n is 55. In an embodiment, n is 56. In an embodiment, n is 57. In an embodiment, n is 58. In an embodiment, n is 59. In an embodiment, n is 60. In an embodiment, n is 61. In an embodiment, n is 62. In an embodiment, n is 63. In an embodiment, n is 64.In the embodiment, n is 65. In the embodiment, n is 66. In the embodiment, n is 67. In the embodiment, n is 68. In the embodiment, n is 69. In the embodiment, n is 70. In the embodiment, n is 71. In the embodiment, n is 72. In the embodiment, n is 73. In the embodiment, n is 74. In the embodiment, n is 75. In the embodiment, n is 76. In the embodiment, n is 77. In the embodiment, n is 78. In the embodiment, n is 79. In the embodiment, n is 80. In the embodiment, n is 81. In the embodiment, n is 82. In the embodiment, n is 83. In the embodiment, n is 84. In the embodiment, n is 85. In the embodiment, n is 86. In the embodiment, n is 87. In the embodiment, n is 88. In the embodiment, n is 89. In the embodiment, n is 90. In the embodiment, n is 91. In the embodiment, n is 92. In the embodiment, n is 93. In the embodiment, n is 94. In the embodiment, n is 95. In the embodiment, n is 96. In the embodiment, n is 97. In the embodiment, n is 98. In the embodiment, n is 99. In the embodiment, n is 100.

[0400] In the embodiment, n1 is 0. In the embodiment, n1 is 1. In the embodiment, n1 is 2. In the embodiment, n1 is 3. In the embodiment, n1 is 4. In the embodiment, n1 is 5. In the embodiment, n1 is 6. In the embodiment, n1 is 7. In the embodiment, n1 is 8. In the embodiment, n1 is 9. In the embodiment, n1 is 10. In the embodiment, n1 is 11. In the embodiment, n1 is 12. In the embodiment, n1 is 13. In the embodiment, n1 is 14. In the embodiment, n1 is 15. In the embodiment, n1 is 16. In the embodiment, n1 is 17. In the embodiment, n1 is 18. In the embodiment, n1 is 19. In the embodiment, n1 is 20. In the embodiment, n1 is 21. In the embodiment, n1 is 22. In the embodiment, n1 is 23. In the embodiment, n1 is 24. In the embodiment, n1 is 25. In the embodiment, n1 is 26. In the embodiment, n1 is 27. In the embodiment, n1 is 28. In the embodiment, n1 is 29. In the embodiment, n1 is 30. In the embodiment, n1 is 31. In the embodiment, n1 is 32. In the embodiment, n1 is 33. In the embodiment, n1 is 34. In the embodiment, n1 is 35. In the embodiment, n1 is 36. In the embodiment, n1 is 37. In the embodiment, n1 is 38. In the embodiment, n1 is 39. In the embodiment, n1 is 40. In the embodiment, n1 is 41. In the embodiment, n1 is 42. In the embodiment, n1 is 43. In the embodiment, n1 is 44. In the embodiment, n1 is 45. In the embodiment, n1 is 46. In the embodiment, n1 is 47. In the embodiment, n1 is 48. In the embodiment, n1 is 49. In the embodiment, n1 is 50.

[0401] In the embodiment, n2 is 1. In the embodiment, n2 is 2. In the embodiment, n2 is 3. In the embodiment, n2 is 4. In the embodiment, n2 is 5. In the embodiment, n2 is 6. In the embodiment, n2 is 7. In the embodiment, n2 is 8. In the embodiment, n2 is 9. In the embodiment, n2 is 10. In the embodiment, n2 is 11. In the embodiment, n2 is 12. In the embodiment, n2 is 13. In the embodiment, n2 is 14. In the embodiment, n2 is 15. In the embodiment, n2 is 16. In the embodiment, n2 is 17. In the embodiment, n2 is 18. In the embodiment, n2 is 19. In the embodiment, n2 is 20. In the embodiment, n2 is 21. In the embodiment, n2 is 22. In the embodiment, n2 is 23. In the embodiment, n2 is 24. In the embodiment, n2 is 25. In the embodiment, n2 is 26. In the embodiment, n2 is 27. In the embodiment, n2 is 28. In the embodiment, n2 is 29. In the embodiment, n2 is 30. In the embodiment, n2 is 31. In the embodiment, n2 is 32. In the embodiment, n2 is 33. In the embodiment, n2 is 34. In the embodiment, n2 is 35. In the embodiment, n2 is 36. In the embodiment, n2 is 37. In the embodiment, n2 is 38. In the embodiment, n2 is 39. In the embodiment, n2 is 40. In the embodiment, n2 is 41. In the embodiment, n2 is 42. In the embodiment, n2 is 43. In the embodiment, n2 is 44. In the embodiment, n2 is 45. In the embodiment, n2 is 46. In the embodiment, n2 is 47. In the embodiment, n2 is 48. In the embodiment, n2 is 49. In the embodiment, n2 is 50. In the embodiment, n2 is 51. In the embodiment, n2 is 52. In the embodiment, n2 is 53. In the embodiment, n2 is 54. In the embodiment, n2 is 55. In the embodiment, n2 is 56. In the embodiment, n2 is 57. In the embodiment, n2 is 58. In the embodiment, n2 is 59.In an embodiment, n2 is 60. In an embodiment, n2 is 61. In an embodiment, n2 is 62. In an embodiment, n2 is 63. In an embodiment, n2 is 64. In an embodiment, n2 is 65. In an embodiment, n2 is 66. In an embodiment, n2 is 67. In an embodiment, n2 is 68. In an embodiment, n2 is 69. In an embodiment, n2 is 70. In an embodiment, n2 is 71. In an embodiment, n2 is 72. In an embodiment, n2 is 73. In an embodiment, n2 is 74. In an embodiment, n2 is 75. In an embodiment, n2 is 76. In an embodiment, n2 is 77. In an embodiment, n2 is 78. In an embodiment, n2 is 79. In an embodiment, n2 is 80. In an embodiment, n2 is 81. In an embodiment, n2 is 82. In an embodiment, n2 is 83. In an embodiment, n2 is 84. In an embodiment, n2 is 85. In an embodiment, n2 is 86. In an embodiment, n2 is 87. In an embodiment, n2 is 88. In an embodiment, n2 is 89. In an embodiment, n2 is 90. In an embodiment, n2 is 91. In an embodiment, n2 is 92. In an embodiment, n2 is 93. In an embodiment, n2 is 94. In an embodiment, n2 is 95. In an embodiment, n2 is 96. In an embodiment, n2 is 97. In an embodiment, n2 is 98. In an embodiment, n2 is 99. In an embodiment, n2 is 100.

[0402] In the embodiment, z2 is 2. In the embodiment, z2 is 3. In the embodiment, z2 is 4. In the embodiment, z2 is 5. In the embodiment, z2 is 6. In the embodiment, z2 is 7. In the embodiment, z2 is 8. In the embodiment, z2 is 9. In the embodiment, z2 is 10. In the embodiment, z2 is 11. In the embodiment, z2 is 12. In the embodiment, z2 is 13. In the embodiment, z2 is 14. In the embodiment, z2 is 15. In the embodiment, z2 is 16. In the embodiment, z2 is 17. In the embodiment, z2 is 18. In the embodiment, z2 is 19. In the embodiment, z2 is 20. In the embodiment, z2 is 21. In the embodiment, z2 is 22. In the embodiment, z2 is 23. In the embodiment, z2 is 24. In the embodiment, z2 is 25. In the embodiment, z2 is 26. In the embodiment, z2 is 27. In the embodiment, z2 is 28. In the embodiment, z2 is 29. In the embodiment, z2 is 30. In the embodiment, z2 is 31. In the embodiment, z2 is 32. In the embodiment, z2 is 33. In the embodiment, z2 is 34. In the embodiment, z2 is 35. In the embodiment, z2 is 36. In the embodiment, z2 is 37. In the embodiment, z2 is 38. In the embodiment, z2 is 39. In the embodiment, z2 is 40. In the embodiment, z2 is 41. In the embodiment, z2 is 42. In the embodiment, z2 is 43. In the embodiment, z2 is 44. In the embodiment, z2 is 45. In the embodiment, z2 is 46. In the embodiment, z2 is 47. In the embodiment, z2 is 48. In the embodiment, z2 is 49. In the embodiment, z2 is 50. In the embodiment, z2 is 51. In the embodiment, z2 is 52. In the embodiment, z2 is 53. In the embodiment, z2 is 54. In the embodiment, z2 is 55. In the embodiment, z2 is 56. In the embodiment, z2 is 57. In the embodiment, z2 is 58. In the embodiment, z2 is 59. In the embodiment, z2 is 60.In the embodiment, z2 is 61. In the embodiment, z2 is 62. In the embodiment, z2 is 63. In the embodiment, z2 is 64. In the embodiment, z2 is 65. In the embodiment, z2 is 66. In the embodiment, z2 is 67. In the embodiment, z2 is 68. In the embodiment, z2 is 69. In the embodiment, z2 is 70. In the embodiment, z2 is 71. In the embodiment, z2 is 72. In the embodiment, z2 is 73. In the embodiment, z2 is 74. In the embodiment, z2 is 75. In the embodiment, z2 is 76. In the embodiment, z2 is 77. In the embodiment, z2 is 78. In the embodiment, z2 is 79. In the embodiment, z2 is 80. In the embodiment, z2 is 81. In the embodiment, z2 is 82. In the embodiment, z2 is 83. In the embodiment, z2 is 84. In the embodiment, z2 is 85. In the embodiment, z2 is 86. In the embodiment, z2 is 87. In the embodiment, z2 is 88. In the embodiment, z2 is 89. In the embodiment, z2 is 90. In the embodiment, z2 is 91. In the embodiment, z2 is 92. In the embodiment, z2 is 93. In the embodiment, z2 is 94. In the embodiment, z2 is 95. In the embodiment, z2 is 96. In the embodiment, z2 is 97. In the embodiment, z2 is 98. In the embodiment, z2 is 99. In the embodiment, z2 is 100.

[0403] In the embodiment, z5 is 1. In the embodiment, z5 is 2. In the embodiment, z5 is 3. In the embodiment, z5 is 4. In the embodiment, z5 is 5. In the embodiment, z5 is 6. In the embodiment, z5 is 7. In the embodiment, z5 is 8. In the embodiment, z5 is 9. In the embodiment, z5 is 10.

[0404] In an embodiment, the cationic amphiphilic polymer has any of the above-described formulas in which z2 is an integer from 2 to 100. In an embodiment, z2 can be an integer within the range of 2 to 100, 2 to 90, 2 to 80, 2 to 70, 2 to 60, 2 to 50, 2 to 40, 2 to 30, 2 to 2, or 2 to 10. In an embodiment, z2 is an integer from 2 to 100 or 2 to 50.

[0405] In an embodiment, the cationic amphiphilic polymer has any of the above-described formulas in which z5 is an integer from 1 to 3. In some other embodiments, z5 is 1 or 3. In still some other embodiments, z5 is 1. In some other embodiments, z5 is 3.

[0406] In an embodiment, the cationic amphiphilic polymer has any of the above-described formulas in which R 2 is hydrogen.

[0407] In an embodiment, the cationic amphiphilic polymer has any of the above-described formulas in which L 2 is a bond.

[0408] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0409] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0410] In the embodiment, the cationic amphiphilic polymer has the following formula:

Chemical formula

[0411] In the embodiment, the cationic amphiphilic polymer has the following formula:

Chemical formula

[0412] In the embodiment, the cationic amphiphilic polymer has the following formula:

Chemical formula

[0413] In the embodiment, the cationic amphiphilic polymer has the following formula:

Chemical formula

[0414] In the embodiment, the cationic amphiphilic polymer has the following formula:

Chemical formula

[0415] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0416] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0417] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0418] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0419] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 4, n22 is 4, and z2 is 8.

[0420] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 4, n22 is 4, and z2 is 8.

[0421] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 4, n22 is 4, and z2 is 8.

[0422] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 4, L 1 is -O-, n22 is 4, and z2 is 8.

[0423] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 4, n22 is 4, and z2 is 8.

[0424] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 4, L 1 is -O-, n22 is 4, and z2 is 8.

[0425] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 5, n22 is 6, and z2 is 10.

[0426] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 5, L 1 is -O-, n22 is 6, and z2 is 10.

[0427] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 5, n22 is 6, and z2 is 10.

[0428] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 5, L 1 is -O-, n22 is 6, and z2 is 10.

[0429] In an embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] wherein n21 is 5, n22 is 6, and z2 is 10.

[0430] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0431] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0432] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0433] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0434] In an embodiment, the cationic amphiphilic polymer has the following formula,

Chemical formula

[0435] In the embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] In the formula, n21 is 14, R 201 is dodecyl, and z2 is 8.

[0436] In the embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] In the formula, n21 is 14, L 1 is -O-, R 201 is dodecyl, and z2 is 8.

[0437] In the embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] In the formula, n21 is 14, R 201 is dodecyl, and z2 is 8.

[0438] In the embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] In the formula, n21 is 14, L 1 is -O-, R 201 is dodecyl, and z2 is 8.

[0439] In the embodiment, the cationic amphiphilic polymer has the following formula: [Chemical formula] In the formula, n21 is 14, R 201 is dodecyl, and z2 is 8.

[0440] In the embodiment, the cationic amphiphilic polymer has the following formula: [Chem.] wherein n21 is 14, L 1 is -O-, R 201 is dodecyl, and z2 is 8. ...

Claims

1. having the following formula, 【Chemical Formula 1】 where n21 is from 10 to 20, and z2 is from 3 to 10; or, having the following formula, 【Chemical Formula 2】 where n22 is from 10 to 35, and z2 is from 5 to 20; Here, R １Ａ is hydrogen, CN, OH, NH ２ , COOH, CONH ２ , NO ２ , SH, SO ３ H, SO ４ H, SO ２ NH ２ , NHNH ２ , ONH ２ , NHCO-NHNH ２ , NHCO-NH ２ , NHSO ２ H, NHCO-H, NHCO-OH, NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R ２０１ and R ２０２ each independently is unsubstituted C ８ - C ３０ alkyl or unsubstituted C ８ - C ３０ alkenyl, a cationic amphiphilic polymer.

2. The cationic amphiphilic polymer according to claim 1, wherein n21 is 14, R ２０１ is dodecyl, and z2 is 8.

3. The cationic amphiphilic polymer according to claim 1, wherein n22 is 14, R ２０２ is dodecyl, and z2 is 7.

4. R ２０１ and R ２０２ each of which is independently stearyl, oleyl, linoleyl, dodecyl, nonyl, or cholesterol, the cationic amphiphilic polymer according to claim 1.

5. A mixture comprising a first cationic amphiphilic polymer and a second cationic amphiphilic polymer, wherein the first cationic amphiphilic polymer is the cationic amphiphilic polymer according to any one of claims 1 to 4, and the second cationic amphiphilic polymer has the following formula: 【Formula 3】 wherein n23 is from 1 to 100, z6 is from 5 to 15, R ３Ａ is hydrogen, CN, OH, NH ２ , COOH, CONH ２ , NO ２ , SH, SO ３ H, SO ４ H, SO ２ NH ２ , NHNH ２ , ONH ２ , NH C(O)NHNH ２ , NH C(O)NH ２ , NHSO ２ H, NH C(O)H, NH C(O)OH, NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R ２０３ is unsubstituted C ８ ~C ３０ alkyl or unsubstituted C ８ ~C ３０ alkenyl, the mixture.

6. n23 is 13, z6 is 11, and R ２０３ is dodecyl, the mixture according to claim 5.

7. The mixture according to claim 5 or 6, comprising a 1:1 mixture of a first cationic amphiphilic polymer and a second cationic amphiphilic polymer.

8. A cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer according to any one of claims 1 to 4 or a mixture according to any one of claims 5 to 7.

9. A pharmaceutical composition comprising a cationic amphiphilic polymer according to any one of claims 1 to 4, a mixture according to any one of claims 5 to 7, or a cell-permeable complex according to claim 8, and a pharmaceutical excipient.

10. The following formula: 【Chemical Formula 4】 In the formula, R １Ａ , n21 and z2 are as defined in claim 1, and R ２０１ is as defined in claim 1 or claim 4, A pharmaceutical composition comprising a cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer of.

11. Use of a cationic amphiphilic polymer according to any one of claims 1 to 4, a mixture according to any one of claims 5 to 7, a cell-permeable complex according to claim 8 or a pharmaceutical composition according to claim 9 or 10 in the manufacture of a medicament for delivering a nucleic acid to cells in vitro or in vivo.

12. Use according to claim 11, wherein the cell is a lung cell, a reticulocyte or a hematopoietic stem cell.

13. Use according to claim 11 or 12, wherein the medicament is for use in the treatment of lung diseases.

14. The use according to claim 13, wherein the lung disease is lung cancer, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, bronchiectasis, pulmonary edema, pulmonary fibrosis, pulmonary hypertension, pneumonia, tuberculosis, interstitial lung disease (ILD), restrictive lung disease, or pleurisy of the lung.

15. The use according to claim 13, wherein the lung disease is pneumonia.

16. The use according to claim 15, wherein the pneumonia is acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), idiopathic interstitial pneumonia (IIP), or bronchiolitis obliterans organizing pneumonia (BOOP) associated with organizing pneumonia.

17. The use according to claim 13, wherein the lung disease is interstitial lung disease (ILD).

18. The use according to claim 17, wherein the ILD is pulmonary sarcoidosis, respiratory bronchiolitis-associated interstitial lung disease (RBILD), or interstitial pulmonary fibrosis (IPF).

19. The use according to claim 11 or 12, wherein the medicament is for use in inducing an immune response for the treatment, prevention, or reduction of the likelihood of onset of a disease or condition selected from autoimmune diseases, inflammatory diseases, cancer diseases, infectious diseases, metabolic diseases, developmental diseases, cardiovascular diseases, liver diseases, intestinal diseases, endocrine diseases, or neurological diseases.

20. An in vitro method of transfecting a cell with a nucleic acid, the method comprising contacting the cell with a cationic amphiphilic polymer according to any one of claims 1 to 4, a mixture according to any one of claims 5 to 7, or a cell-permeable complex according to claim 8.

21. The in vitro method according to claim 20, wherein the cell is a reticulocyte, a hematopoietic stem cell, or a lung cell.

22. In the manufacture of a medicament for transfecting a nucleic acid into a lung cell, the following formula: 【Chemical Formula 5】 wherein, R １Ａ , n21 and z2 are as defined in claim 1, and R ２０１ is as defined in claim 1 or claim 4, Use of a cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer.

23. n21 is 14, R ２０１ is dodecyl, and z2 is 8, the use according to claim 22.

24. A composition comprising a cell-permeable complex comprising a nucleic acid non-covalently bound to a mixture comprising a first cationic amphiphilic polymer and a second cationic amphiphilic polymer for use in a method of transfecting a nucleic acid into reticulocyte cells, hematopoietic stem cells or lung cells, The first cationic amphiphilic polymer has the following formula, 【Chemical formula 6】 wherein, R １Ａ , n21 and z2 are as defined in claim 1, and R ２０１ is as defined in claim 1 or claim 4, The second cationic amphiphilic polymer has the following formula, 【Chemical formula 7】 n23 is from 1 to 100, z6 is from 5 to 15, R ３Ａ is hydrogen, CN, OH, NH ２ , COOH, CONH ２ , NO ２ , SH, SO ３ H, SO ４ H, SO ２ NH ２ , NHNH ２ , ONH ２ , NH C(O)NHNH ２ , NH C(O)NH ２ , NHSO ２H, NHCHO, NHCOOH, NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R ２０３ is unsubstituted C ８ - C ３０ alkyl or unsubstituted C ８ - C ３０ alkenyl, a composition.

25. n21 is 14, R ２０１ is dodecyl, and z2 is 8, the composition according to claim 24.

26. n23 is 13, R ２０３ is dodecyl, and z6 is 11, the composition according to claim 24 or 25.

27. In the manufacture of a medicament for transfecting nucleic acids into lung cells, the following formula: The following formula: 【Chemical Formula 8】 wherein R １Ａ , n22 and z2 are as defined in claim 1, and R ２０２ is as defined in claim 1 or claim 4, use of a cell-permeable complex comprising a nucleic acid non-covalently bound to a cationic amphiphilic polymer of.

28. n22 is 14, R ２０２ is dodecyl, and z2 is 7, the use according to claim 27.

Images