pH-Triggered Release of Platinum Drugs Conjugated to Micelles via an Acid-Cleavable Linker

A new acid-degradable polymer platinum conjugate was prepared by postmodification of a POEGMEMA-b-PHEMA block copolymer obtained by RAFT polymerization. A hydrazone linkage, susceptible to hydrolytic cleavage, was formed by reaction of the carbonyl group of a diamino ligand with the hydrazide-modified copolymer. According to NMR kinetic studies, degradation of the hydrazone bond was observed to be more than 10 times faster at pH 5.5 than at pH 7.4. The platinum drug was introduced on the copolymer by permanent conjugation onto the diamino conjugation sites. The platinated amphiphilic copolymer was subsequently self-assembled into nanosized micelles of 27 nm with the platinum drug safely encapsulated in the core. Extended conjugation time however led to cross-linking and to particles of more than 1000 nm. In vitro experiments revealed a high cytotoxicity for the platinum drug-bearing small micelles compared to the polymer before conjugation. In contrast, the large particle did not show any toxicity since the size prevents endocytosis. However, endocytosis and the subsequent location of the micelles in the acidic endosomes or lysosomes are necessary to trigger the release of the toxic platinum drug. In contrast, the small drug loaded micelle exhibited a toxicity superior to the underlying low-molecular-weight drug (IC50 = 10.5 mu M vs 17 mu M) These hydrolytically degradable nanovectors constitute a promising system for a triggered release of platinum drugs.