Telodendrimers and nanocarriers and methods of using same
Provided are functional segregated telodendrimers having, for example, two or three functional segments. The telodendrimers can have one or more crosslinking groups (e.g., reversible photocrosslinking groups). The telodendrimers can aggregate to form nanocarriers. Cargo such as drugs, imaging probes, and other materials may be sequestered in the core of the aggregates via non-covalent or covalent interactions with the telodendrimers. Such nanocarriers may be used in drug delivery applications and imaging applications.
1. A compound of formula (I):
wherein
PEG is a polyethylene glycol moiety, wherein PEG has a molecular weight of 44 Da to 100 kDa;
A is optional and is a monomer or oligomer;
X is a branched monomer unit;
each L 1 is independently optional and is a linker group;
each L 2 is independently optional and a linker group,
wherein at least one of L 1 and/or at least one of L 2 are present;
D 1 is a dendritic polymer moiety having one or more branched monomer units (X), a plurality of end groups, and optionally, one or more linker groups L 1 ;
D 2 is a dendritic polymer having one or more branched monomer units (X), a plurality of end groups, and optionally, one or more linker groups (L 3 );
each L 3 is independently optional or a linker group linked to the focal point group of the dendritic polymer and monomer unit (X);
R 1 is an end group of the dendritic polymer and is independently at each occurrence in the compound selected from the group consisting of a cholic acid moiety or derivative or analog thereof, a coumarin moiety or derivative or analog thereof, a riboflavin moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof and R 2 is an end group of the dendritic polymer and is independently at each occurrence in the compound selected from the group consisting of a rhein moiety or derivative or analog thereof, a bile acid moiety or derivative or analog thereof, a cholesterol moiety or derivative or analog thereof, a coumarin moiety or derivative or analog thereof, a curcumine moiety or derivative or analog thereof, a flavin moiety or derivative or analog thereof, a isoflavin moiety or derivative or analog thereof, a riboflavin moiety or derivative or analog thereof, a retinol moiety or derivative or analog thereof, a retinoic acid moiety or derivative or analog thereof, a chlorogenic acid moiety or derivative or analog thereof, an anthraquinone moiety or derivative or analog thereof, a xanthenone moiety or derivative or analog thereof, a Vitamin E moiety or derivative or analog thereof, a D-α-tocopherol succinate moiety or derivative or analog thereof, a quercetin moiety or derivative or analog thereof, a chenodeoxylcholic acid moiety or derivative or analog thereof, terpenoids, steroids, vitamins, lipids, and fatty acids,
wherein R 1 and R 2 are not the same, and
when R 1 and/or R 2 are not end groups each R 1 and/or R 2 is linked to one of the end groups;
subscript x is an integer from 2 to 64, wherein subscript x is equal to the number of end groups on the dendritic polymer;
subscript y is an integer from 2 to 64, wherein subscript y is equal to the number of end groups on the dendritic polymer;
subscript p is an integer from 1 to 32; and
subscript m is an integer from 1 to 32.
2. The compound of claim 1 , wherein at each occurrence in the compound the branched monomer unit (X) is independently selected from the group consisting of a diamino carboxylic acid moiety, a dihydroxy carboxylic acid moiety, and a hydroxyl amino carboxylic acid moiety.
3. The compound of claim 2 , wherein at each occurrence in the compound the diamino carboxylic acid is independently selected from the group consisting of 2,3-diamino propanoic acid, 2,4-diaminobutanoic acid, 2,5-diaminopentanoic acid (ornithine), 2,6-diaminohexanoic acid (lysine), (2-Aminoethyl)-cysteine, 3-amino-2-aminomethyl propanoic acid, 3-amino-2-aminomethyl-2-methyl propanoic acid, 4-amino-2-(2-aminoethyl) butyric acid, and 5-amino-2-(3-aminopropyl) pentanoic acid.
4. The compound of claim 2 , wherein the diamino carboxylic acid moiety is an amino acid moiety.
5. The compound of claim 2 , wherein each branched monomer unit X is lysine moiety.
6. The compound of claim 1 , wherein the compound is selected from the group consisting of:
wherein each branched monomer unit is lysine moiety.
7. The compound of claim 1 , wherein at each occurrence in the compound the linker L 1 , L 2 , and L 3 each are independently selected from the group consisting of a polyethylene glycol moiety, polyserine moiety, enzyme cleavable peptide moiety, disulfide bond moiety and acid labile moiety, polyglycine moiety, poly(serine-glycine) moiety, aliphatic amino acid moieties, 6-amino hexanoic acid moiety, 5-amino pentanoic acid moiety, 4-amino butanoic acid moiety, and beta-alanine moiety.
8. The compound of claim 1 , wherein at each occurrence in the compound the linker L 1 , L 2 , and L 3 are independently selected from the group consisting of:
9. The compound of claim 1 , wherein the linker L 1 , L 2 , L 3 , or a combination thereof comprises a cleavable group.
10. The compound of claim 9 , wherein the cleavable group is a disulfide cleavable moiety.
11. The compound of claim 1 , wherein the (PEG) m -A- portion of the compound is selected from the group consisting of:
wherein each K is lysine.
12. The compound of claim 1 , wherein a portion of or each R 1 is a reversible photocrosslinking group.
13. The compound of claim 12 , wherein the reversible photocrosslinking group is coumarin moiety, 4-methylcoumarin moiety, chlorogenic acid moiety or derivative or analog thereof, or a combination thereof.
14. The compound of claim 6 , wherein x=4; y=4, m=1, PEG is 5 kDa; R 1 is a coumarin moiety; each R 2 is independently selected from the group consisting of cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcumine moiety or derivative or analog thereof, and riboflavin moiety or derivative or analog thereof; L 1 is optional or a disulfide bond moiety; L 2 is an ethylene glycol linker; and L 3 is optional or an ethylene glycol linker.
15. The compound of claim 1 , wherein x=2 to 16; y=2 to 64, m=1 to 8, PEG is 1 to 40 kDa; each R 1 is independently selected from a coumarin moiety or derivative or analog thereof, a cinnamic acid moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof; each R 2 is independently selected from the group consisting of cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcumine moiety or derivative or analog thereof, and riboflavin moiety or derivative or analog thereof; L 1 is optional or a disulfide bond moiety; L 2 is an ethylene glycol linker; and L 3 is optional or an ethylene glycol linker.
16. The compound of claim 6 , wherein x=4; y=4, m=1, PEG is 5 kDa; R 1 is a cholic acid moiety or derivative or analog thereof; each R 2 is independently selected from the group consisting of cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcumine moiety or derivative or analog thereof, riboflavin moiety or derivative or analog thereof, retinoic acid moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof; L 1 is optional or a disulfide bond moiety; L 2 is an ethylene glycol linker; and L 3 is optional or an ethylene glycol linker.
17. The compound of claim 1 , wherein x=2 to 16; y=2 to 64, m=1 to 8, PEG is 1 to 40 kDa; each R 1 is independently selected from the group consisting of a cholic acid moiety or derivative or analog thereof moiety, riboflavin moiety or derivative or analog thereof, and a chlorogenic acid moiety or derivative or analog thereof; each R 2 is independently selected from the group consisting of cholic acid moiety or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, rhein moiety or derivative or analog thereof, Vitamin E moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcumine moiety or derivative or analog thereof, riboflavin moiety or derivative or analog thereof, and retinoic acid moiety or derivative or analog thereof; L 1 is optional or a disulfide bond moiety; L 2 is an ethylene glycol linker; and L 3 is optional or an ethylene glycol linker.
18. A nanocarrier comprising a plurality of compounds of claim 1 .
19. The nanocarrier of claim 18 , wherein the nanocarrier further comprises a hydrophobic drug or an imaging agent.
20. The compound of claim 1 , wherein x=4 and y=2 or 4.
21. The compound of claim 1 , wherein p=1 and x=4.
22. The compound of claim 1 , wherein p=2 and x=4.
23. The compound of claim 1 , wherein R 2 is a rhein moiety or group or derivative or analog thereof, bile acid moiety or group or derivative or analog thereof, flavin moiety or group or derivative or analog thereof, isoflavin moiety or group or derivative or analog thereof, riboflavin moiety or group or derivative or analog thereof, retinol moiety or group or derivative or analog thereof, retinoic acid moiety or group or derivative or analog thereof, Vitamin E moiety or group or derivative or analog thereof, cholesterol moiety or derivative or analog thereof, coumarin moiety or derivative or analog thereof, curcumine moiety or derivative or analog thereof, heptadecanoic acid and other fatty acid derivative or analog thereof.
24. The compound of claim 1 , wherein R 1 is a cholic acid moiety or derivative or analog thereof.
25. The compound of claim 1 , wherein R 1 is 4-methylcoumarin moiety or derivative or analog thereof.
26. The compound of claim 1 , wherein the compound forms an intermediate layer comprising R 1 end groups.