The major hurdle in successful anti-cancer drug delivery remains the inability of potent cytotoxic drugs to be efficiently delivered to tumor tissue while causing minimal side effects to healthy cells and tissues. Here we report on paclitaxel-functionalized RAFT (Reversible Addition-Fragmentation chain Transfer) chain transfer agent (CTA) via an acid-cleavable acetal linkage. Paclitaxel, a widely-used hydrophobic anti-cancer drug and conjugation to a RAFT-CTA comprises a novel strategy for designing responsive polymer-drug conjugates. This paclitaxel-CTA allows excellent control over polymerization of hydrophilic acrylates and acrylamides. Even at low degrees of polymerization the formation of stable soluble or micellar conjugates is obtained. In response to an acidic pH, the acetal bond between the drug and the polymer chain is cleaved, leading to liberation of the original unmodified paclitaxel. We show detailed physico-chemical characterization of the polymer-drug conjugates and assessed the in vitro performance of the system on human ovarian cancer cell lines. In contrast to paclitaxel that is formulated via mere hydrophobic entrapment into amphiphilic such as lipids and block copolymers, our approach could avoid immediate drug release upon administration. Thereby peak drug levels in the bloodstream are avoided and systemic side effects reduced. Furthermore, our approach allows introduction of additional functionality such as tracer molecules (e.g. fluorophores) of targeting ligands, either by co-polymerization or by post-polymerization transformation of the thiocarbonate end-group of the RAFT CTA.

Acid-cleavable acetal-linked paclitaxel-polymer conjugates via a drug-functionalized RAFT CTA approach

251st National Meeting (2016)

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