Well‐Defined Polymer–Paclitaxel Prodrugs by a Grafting‐from‐Drug Approach

Abstract

We report on the design of a polymeric prodrug of the anticancer agent paclitaxel (PTX) by a grafting-from-drug approach. A chain transfer agent for reversible addition fragmentation chain transfer (RAFT) polymerization was efficiently and regioselectively linked to the C2' position of paclitaxel, which is crucial for its bioactivity. Subsequent RAFT polymerization of a hydrophilic monomer yielded well-defined paclitaxel-polymer conjugates with high drug loading, water solubility, and stability. The versatility of this approach was further demonstrated by ω-end post-functionalization with a fluorescent tracer. In vitro experiments showed that these conjugates are readily taken up into endosomes where native PTX is efficiently cleaved off and then reaches its subcellular target. This was confirmed by the cytotoxicity profile of the conjugate, which matches those of commercial PTX formulations based on mere physical encapsulation.

Telechelic polymers from reversible-deactivation radical polymerization for biomedical applications

“…Following a similar concept to that for the construction of a-biotin, o-Dox PAAm, a drug and a fluorescent dye were positioned at each polymer chain-end to combine therapeutic and imaging abilities. 29 This was achieved by combining the ''drug-initiated'' synthesis of an a-drug polymer conjugate and its post-functionalization to link the fluorescent dye at the o-extremity. In brief, paclitaxel (Ptx) was first conjugated to a RAFT agent and a short, well-defined poly(N,N-dimethylacrylamide) (PDMA) chain was subsequently grown from it.…”

Degradable polymer prodrugs with adjustable activity from drug-initiated radical ring-opening copolymerization

“…The robustness of the drug-initiated method has been illustrated by its application to the synthesis of a variety of different polymer prodrugs constructed by either ring-opening polymerization (ROP) 5 – 9 or reversible-deactivation radical polymerization (RDRP), 10 – 18 including nitroxide-mediated radical polymerization (NMP) 19 or reversible addition-fragmentation chain transfer (RAFT) polymerization. 20 Whereas ROP generated degradable polyester prodrug nanocarriers, they exhibited poor colloidal stability and required post-stabilization by means of macromolecular surfactants, which is a major drawback.…”

Self-stabilized, hydrophobic or PEGylated paclitaxel polymer prodrug nanoparticles for cancer therapy

“…The robustness of the drug-initiated method has been illustrated by its application to a variety of different polymer prodrugs constructed by either ring-opening polymerization (ROP) [29][30][31][32] or reversible-deactivation radical polymerization (RDRP), including nitroxide-mediated radical polymerization (NMP) or reversible addition-fragmentation chain transfer (RAFT) polymerization. [33][34][35][36][37][38][39][40] Promising in vitro and in vivo results in the field of cancer therapy have been reported over the past few years. However, two major concerns currently restricting the wide applicability of this approach still remain:…”