Self-Assembling Nanoparticles Based On Amphiphilic Peptides for Drug Delivery Applications

1 . A composition comprising a first amphiphile and optionally a second amphiphile each having the formula S-[B]-[U]-H,

wherein S, independently for each occurrence, is a solubilizing block;

B, independently for each occurrence, is a spacer;

H, independently for each occurrence, is a hydrophobic block;

U, independently for each occurrence, is a linker;

[ ] denotes that the group is optional; and

- denotes that the two adjacent groups are directly attached to one another by a covalent bond or indirectly to one another via a suitable linker X,

wherein the S of the first amphiphile comprises a dendron amplifier linked to two or more solubilizing groups (SGs) each independently selected from an amino, phosphate, hydroxyl, carboxylic acid, phosphoserinyl, an agonist of CD22a, and a sugar moiety, or any combinations thereof,

each sugar moiety is independently selected from mannose, glucosyl, glucosamino, N-acetyl glucosyl, galactosyl, galactosamino, sialyl lewix x, and N-acetyl galactosaminyl, or any combinations thereof;

and at least one drug molecule (D) is noncovalently associated with or covalently bonded directly or via a suitable linker X1 to the first amphiphile and/or the second amphiphile.

2 .- 3 . (canceled)

4 . The composition according to claim 1 , wherein the dendron amplifier comprises repeating monomer units of 1 to 10 generations having between 2 to 6 branches per generation.

5 . (canceled)

6 . The composition according to claim 4 , wherein the repeating monomer units are selected from

(a) -FG1-(CH 2 ) y2 CH(R 1 ) 2 , -FG1-(CH 2 ) y2 C(R 1 ) 3 , -FG1-(CH 2 CH 2 O) y2 CH(R 1 ) 2 , -FG1-(CH 2 CH 2 O) y2 C(R 1 ) 3 , -FG1-CH(R 1 ) 2 , and -FG1-C(R 1 ) 3 ,

wherein

R 1 , independently for each occurrence, is selected from —(CH 2 ) y3 -FG2, —(OCH 2 CH 2 ) y3 -FG2, and —CH 2 (OCH 2 CH 2 ) y3 -FG2;

y2 and y3, independently for each occurrence, are an integer of repeating units from 1 to 6;

FG1 is a first functional group; and

FG2 is a second functional group, or

(b) hydroxy acids, amino acids, polyols, polyamines, and amino alcohols.

7 .- 9 . (canceled)

10 . The composition according to claim 1 , wherein the first amphiphile has the structure:

11 . The composition according to claim 1 , wherein the dendron amplifier comprises one or more polyethylene oxide (PEG) monomer units.

12 . The composition according to claim 1 , where the composition comprises a second amphiphile having the formula S-[B]-[U]-H.

13 . The composition according to claim 12 , wherein

the S of the second amphiphile is a hydrophilic polymer; and/or

the B of the second amphiphile is selected from peptides or hydrophilic polymers comprising from between about 1 to about 36 monomer units; and/or

the B of the first amphiphile is selected from hydrophilic polymers comprising from between about 1 to about 36 monomer units.

14 . (canceled)

15 . The composition according to claim 13 , wherein the hydrophilic polymer comprises monomeric units selected from HEMA, HPMA, PEG, and zwitterionic betaine monomers.

16 .- 17 . (canceled)

18 . The composition according claim 12 , wherein the second amphiphile has the formula S-X6-B-[U]-H,

wherein the linker X6 is selected from enzyme degradable peptides and pH sensitive linkers.

19 .- 24 . (canceled)

25 . The composition according to claim 1 , wherein the H of the first amphiphile and/or second amphiphile comprises a higher alkane, an aromatic group, a fatty acid, a sterol, a polyunsaturated hydrocarbon, squalene, saponins, or a poly(amino acid), and/or a dendron amplifier.

26 .- 27 . (canceled)

28 . The composition according to claim 1 , wherein each H independently comprises a poly(amino acid) comprising monomers selected from hydrophobic amino acids (M), reactive amino acids (N), spacer amino acids (O), charged amino acids (P), and combinations thereof, provided that at least one of M or N is present.

29 . The composition according to claim 28 , wherein each H independently comprises a poly(amino acid) having the formula:

-(M) m -(N) n -(O) o -(P) p -R 3 ,

wherein

m, n, o and p each independently denote an integer of 0 to 100, wherein the sum of m, n, o, and p is less than or equal to 100, and at least one of m and n is not 0;

R 3 is selected from hydrogen, NH 2 , NH—CH 3 , NH—(CH 2 ) y5 CH 3 , OH, or a D either connected directly or through a suitable linker X1; and

y5 is an integer selected from 1 to 6.

30 .- 31 . (canceled)

32 . The composition according to claim 29 , wherein

P, when present, is

 wherein each R 5 , independently, is a group that comprises 1 to 2 charged functional groups; and/or

O, when present, is

 wherein each Q, independently, is selected from (CH 2 ) y6 and (CH 2 CH 2 O) y7 CH 2 CH 2 ; each y6 is independently selected from an integer from 1 to 6; and each y7 is independently selected from an integer from 1 to 4; and/or

N, when present, is

 wherein each X1, independently, is a suitable linker; and each D, independently, is a drug molecule; and/or

M, when present, is

 wherein each R 4 , independently, is

 wherein α is aryl or heteroaryl; X2 is present or absent and when present is a suitable linker; y8 is selected from an integer from 0 and 6; and Z 1 , Z 2 , and Z 3 are each independently selected from hydrogen, fluorine, hydroxy, amino, alkyl, and fluoroalkyl.

33 .- 46 . (canceled)

47 . The composition according to claim 32 , wherein each R 4 is independently selected from:

48 .- 61 . (canceled)

62 . The composition according to claim 1 , wherein the at least one drug molecule D is an inhibitor of mTORC1 and/or mTORC2.

63 .- 76 . (canceled)

77 . The composition according to claim 1 , wherein the first amphiphile and/or the second amphiphile have the structure:

wherein b is an integer from 1 to 48,

wherein b is an integer from 1 to 36,

wherein b is an integer from 1 to 36,

wherein L 1A is an alkylene linker; and L 2A is an amino, amido, ester, peptide, or nitrogen containing heterocyclyl linker,

wherein L 1B is an alkylene-C(O)-NH— linker; and L 2A is an amino, amido, peptide, or nitrogen containing heterocyclyl linker, or

wherein L 1B is a

linker L 2B is an amino, amido, or peptide linker; and R 1B is NH 2 or

78 .- 79 . (canceled)

80 . The composition according to claim 1 , wherein the first amphiphile and/or the optional second amphiphile have the structure:

81 . A method of selectively delivering the at least one drug molecule (D) to a target cell or tissue in a subject, comprising administering to the subject a composition according to claim 1 .

82 .- 85 . (canceled)

86 . A method of treating a cancer, an infectious disease, a chronic viral infection, or an inflammatory disease in a subject in need thereof, comprising administering to the subject a composition according to claim 1 .

87 . (canceled)

88 . A method of preventing or inhibiting an immune response in a subject against a second drug molecule (D2) or an expression system (D2e), wherein the method comprises administering to the subject a composition comprising:

at least one amphiphile; and

a first drug molecule (D1) selected from inhibitors of mTORC1 and/or mTORC2,

wherein the composition is administered to the subject at a time 1 (T1) and the second drug molecule (D2) or the expression system (D2e) is administered to the subject at a time (T2).

89 .- 120 . (canceled)

121 . The method according to claim 88 , wherein the at least one amphiphile of the composition has the formula S-[B]-[U]-H,

wherein S, independently for each occurrence, is a solubilizing block;

B, independently for each occurrence, is a spacer;

H, independently for each occurrence, is a hydrophobic block;

U, independently for each occurrence, is a linker;

[ ] denotes that the group is optional; and

- denotes that the two adjacent groups are directly attached to one another by a covalent bond or indirectly to one another via a suitable linker X,

wherein the S of the first amphiphile comprises a dendron amplifier linked to two or more solubilizing groups (SGs) each independently selected from an amino, phosphate, hydroxyl, carboxylic acid, phosphoserinyl, an agonist of CD22a, and a sugar moiety, or any combinations thereof,

each sugar moiety is independently selected from mannose, glucosyl, glucosamino, N-acetyl glucosyl, galactosyl, galactosamino, sialyl lewix x, and N-acetyl galactosaminyl, or any combinations thereof; and

the first drug molecule (D1) is noncovalently associated with or covalently bonded directly or via a suitable linker X1 to the at least one amphiphile.

122 .- 134 . (canceled)