<i>In situ</i> synthesis of degradable polymer prodrug nanoparticles

The <i>in situ</i> synthesis of degradable polymer prodrug nanoparticles is still a challenge to be met, which would make it possible to remedy both the shortcomings of traditional formulation of preformed polymers (<i>e.g.</i>, low nanoparticle concentrations) and those of the physical encapsulation of drugs (<i>e.g.</i>, burst release and poor drug loadings). Herein, through the combination of radical ring-opening polymerization (rROP) and polymerization-induced self-assembly (PISA) under appropriate experimental conditions, we report the successful preparation of high-solid content, degradable polymer prodrug nanoparticles, exhibiting multiple drug moieties covalently linked to a degradable vinyl copolymer backbone. Such a rROPISA process relied on the chain extension of a biocompatible poly(ethylene glycol)-based solvophilic block with a mixture of lauryl methacrylate (LMA), cyclic ketene acetal (CKA) and drug-bearing methacrylic esters by reversible addition fragmentation chain transfer (RAFT) copolymerization at 20 wt% solid content. This novel approach was exemplified with two different CKA monomers and two different anticancer drugs, namely paclitaxel and gemcitabine, to demonstrate its versatility. After transferring to water, remarkably stable aqueous suspensions of core-degradable polymer prodrug nanoparticles, 56-225 nm in diameter, with tunable amounts of CKA units (7-26 mol%) and drug loadings of up to 33 wt% were obtained. The incorporation of ester groups in the copolymers was demonstrated by hydrolytic degradation of both the copolymers and the nanoparticles under accelerated conditions. The nanoparticles showed significant cytotoxicity against A549 cells, used as a lung cancer model. Fluorescence labeling of the solvophilic block also enabled effective monitoring of cell internalization by confocal microscopy, with potential for theranostic applications.