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

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Abstract
6A,6D-Bis-(2-amino-2-carboxylethylthio)-6A,6D-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 (Mw 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 (high molecular weight polymer (Mw 97 kDa), glyglygly linker and 6 wt % CPT loading) and HG6 (high MW polymer (Mw 97 kDa), gly 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 IC50'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.