Synthesis of Linear, β-Cyclodextrin-Based Polymers and Their Camptothecin Conjugates

Abstract

6 A,6 D -Bis-(2-amino-2-carboxylethylthio)-6 A,6 D -dideoxy-β-cyclodextrin 1, a diamino acid derivative of β-cyclodextrin, is synthesized and condensed with difunctionalized PEG comonomers to give linear, high molecular weight ( M w over 50 kDa) β-cyclodextrin-based polymers ( 2 − 4 ) with pendant functionality (carboxylate). 2 − 4 are all highly soluble in aqueous solutions (over 200 mg/mL). 20- O -trifluoroglycinylcamptothecin, 5a, and 20- O -trifluoroglycinylglycinylglycinylcamptothecin, 5b, are synthesized and conjugated to 2 to give polymer−camptothecin (CPT) prodrugs. The solubility of CPT is increased by more than three orders of magnitude when it is conjugated to 2 . The rates of CPT release from the conjugates HGGG6 ( h igh molecular weight polymer ( M w 97 kDa), g ly g ly g ly linker and 6 wt % CPT loading) and HG6 ( h igh MW polymer ( M w 97 kDa), g ly linker and 6 wt % CPT loading) in either mouse or human plasma are dramatically accelerated over the rates of pure hydrolysis at pH = 7.4, indicating the presence of enzymatic cleavage as a rate-determining step at this pH in the release of the CPT. The pH of aqueous solution has a large effect on hydrolysis rate of CPT from HGGG6 and HG6; the lower the pH, the slower the rate in the range at 4.1 ≤ pH ≤ 13.1. The IC 50 's of polymer 2e, CPT, and the CPT conjugates HG6 and HGGG6 are found to be cell-line dependent with LS174T, HT29, A2780, and PC3 cells using in vitro MTT assays. The parent polymer 2e has very low toxicity to all cultured cells tested.