Functional segregated telodendrimers and nanocarriers and methods of making and using same
View Patent ↗Provided are multiply functional telodendrimers. The telodendrimers can be used for combination drug delivery. The telodendrimers may have one or more crosslinking groups (e.g., reversible photocrosslinking groups). The telodendrimers can aggregate to form nanocarriers. Cargo such as combinations of 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,
wherein PEG is optionally present, is a polyethylene glycol moiety, and has a molecular weight of 44 Da to 100 kDa;
X is a branched monomer unit;
each L 1 is independently optional and is a linker group;
each L 2 is a linker group;
each L 3 is independently optional and is a linker group;
each L 4 is independently optional and is a linker group,
wherein the linker groups is selected from the group consisting of a polyethylene glycol moiety, a polyserine moiety, an enzyme cleavable moiety, a disulfide bond moiety, an acid labile moiety, a polyglycine moiety, a poly(serine-glycine) moiety, an aliphatic amino acid moiety, a 6-amino hexanoic acid moiety, a 5-amino pentanoic acid moiety, a 4-amino butanoic acid moiety, and a beta-alanine moiety;
F is a functional reactive moiety that is a moiety of R 1 ;
R 1 is independently at each occurrence in the compound selected from the group consisting of a catechol, a boronic acid, a carboxylic acid, an acylhydrazine, a hydroxyl, an amine, a thiol, and a ketone for labile bond formation, wherein one or more drug(s) are optionally conjugated to one or more R 1 groups; or a positively charged moiety;
each R 2 independently at each occurrence in the compound is selected from the group consisting of a hydrophobic group, a hydrophilic group, an amphiphilic group, a reversible photocrosslinking group, and a drug;
and subscript m is an integer from 0 to 32.
2. The compound of claim 1 , 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.
3. The compound of claim 1 , wherein the diamino carboxylic acid moiety is an amino acid moiety.
4. The compound of claim 1 , wherein each branched monomer unit X is lysine moiety.
5. The compound of claim 1 , wherein each R 2 is independently selected from a rhein moiety, cholic acid moiety, cholesterol moiety, coumarin moiety, curcumin moiety, flavin moiety, isoflavin moiety, riboflavin moiety, retinol moiety, retinoic acid moiety, chlorogenic acid moiety, anthraquinone moiety, xanthenone moiety, Vitamin E moiety, D-α-tocopherol succinate moiety, vitamins, lipids, fatty acids, bile acids, naturally-isolated compound moieties, and drugs.
6. The compound of claim 1 , wherein at each occurrence in the compound the linker groups L 1 , L 2 , L 3 , and L 4 are independently selected from the group consisting of:
7. The compound of claim 1 , wherein the linker L 1 , L 2 , L 3 , L 4 or a combination thereof comprises a cleavable group.
8. The compound of claim 7 , wherein the cleavable group is a disulfide cleavable moiety.
9. The compound of claim 1 , wherein the (PEG) m -X— portion of the compound is selected from the group consisting of:
wherein each K is lysine.
10. The compound of claim 1 , wherein each R 2 is a reversible photocrosslinking group.
11. The compound of claim 10 , wherein the reversible photocrosslinking group is coumarin moiety, 4-methylcoumarin moiety, cinnamic acid moiety, chlorogenic acid moiety, or a combination thereof.
12. A nanocarrier comprising a plurality of compounds of claim 1 .
13. The nanocarrier of claim 12 , wherein the nanocarrier further comprises a hydrophobic drug and/or a non-hydrophobic drug, and, optionally, an imaging agent.
14. The nanocarrier of claim 12 , wherein the compounds have an intermediate layer and the intermediate layer has at least one drug conjugated thereto.
15. The compound of claim 5 , wherein R 2 is selected from the group consisting of the cholic acid moiety, the coumarin moiety, the riboflavin moiety, the rhein moiety, the cholesterol moiety, the vitamin E moiety, and C 9 -C 20 fatty acids.
16. The compound of claim 1 , wherein PEG is present.
17. The compound of claim 16 , wherein the (PEG) m -X— portion of the compound is selected from the group consisting of:
wherein each K is lysine.
18. The compound of claim 1 , wherein L 1 , L 2 , L 3 , and L 4 are present and each selected from the group consisting of: