Polymeric drug delivery conjugates and methods of making and using thereof
Described herein are biodegradable drug delivery conjugates for effectively delivering bioactive agents to a subject. The drug delivery conjugates comprise a water-soluble high molecular weight linear biodegradable polymer backbone comprising a plurality of linear water-soluble polymeric segments connected to one another by a first (main-chain) cleavable linker, wherein a bioactive agent is covalently bonded to at least one water-soluble polymeric segment, at least one cleavable linker, or a combination thereof. The conjugates possess numerous advantages over prior art delivery conjugates. Also described herein are methods for making and using the conjugates.
1. A drug delivery conjugate or the pharmaceutically acceptable salt or ester thereof comprising two polymeric segments P 1 and P 2 covalently connected to one another by a single first cleavable peptide linker as depicted in formula I,
P 1 -Gly-Phe-Leu-Gly-Lys-Gly-Leu-Phe-Gly-P 2 (I)
wherein an anti-cancer drug is covalently bonded to each polymeric segment via a second cleavable peptide linker,
wherein each polymeric segment comprises the polymerization product of N-(2-hydroxypropyl)methacrylamide (HPMA) and a monomer of formulae II:
wherein Z is the anti-cancer drug, and
wherein the conjugate has a molecular weight from 50 kDa to 150 kDa.
2. The conjugate of claim 1 , wherein each polymeric segment has a molecular weight less than 40 kDa.
3. The conjugate of claim 1 , wherein the anti-cancer drug is paclitaxel, docetaxel, gemcitabine, a platinate, doxorubicin, geldanamycin, epirubicin, or 9-aminocamptothecin.
4. The conjugate of claim 1 , wherein two or more different anti-cancer drugs are covalently bonded to the conjugate.
5. The conjugate of claim 1 , wherein a targeting group is covalently attached to each polymeric segment.
6. The conjugate of claim 5 , wherein the targeting group is an antibody, an antibody fragment, a saccharide, or an epitope binding peptide, or an aptamer.
7. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 7 , wherein the composition is an injectable composition comprising a sterile aqueous medium as the pharmaceutically acceptable carrier.
9. A method for delivering an anti-cancer agent to a subject comprising administering the conjugate of claim 1 to the subject.
10. The conjugate of claim 3 , wherein the platinate is cisplatin, carboplatin, or diaminocyclohexyl platinum.