Poly(HPMA)-based copolymers with biodegradable side chains able to self-assemble into nanoparticles

Poly(N-(2-Hydroxypropyl) methacrylamide) (poly(HPMA)) is gaining pharmaceutical attention in replacement to PEG as a hydrophilic stabilizer for polymer nanoparticles (NPs) devoted to systemic administration.[1] This is due to its biocompatibility, prolonged circulation time and, compared to PEG, to the avoidance of allergic reactions and of the accelerated blood clearance effect.[2, 3] In this work, a lipophilic HPMA-based macromonomer with a predetermined and controllable structure is synthesized for the first time attaching a short oligo(caprolactone) chain obtained via Ring Opening Polymerization (ROP) to the HPMA using a succinic acid unit as a spacer. This biodegradable monomer (hereinafter HPMA-CL) was then used to synthesize well-defined amphiphilic block copolymers comprising a hydrophilic poly(HPMA) block and a hydrophobic poly(HPMA-CL) segment via Reversible Addition-Fragmentation Transfer (RAFT) polymerization. The combination of ROP and RAFT allows the production of a library of polymers with a predetermined and controlled structure that are able to self-assemble in water into biodegradable NPs with different size. In particular, such NPs are designed to degrade in aqueous environment into completely water soluble poly(HPMA), with a molecular weight that is below the critical threshold for the renal excretion. This is a very important feature since it allows to avoid polymer accumulation into the body once the NPs are injected.[4] The degradation time is a function of the number of caprolactone units in the HPMA-CL macromonomer and of its degree of polymerization in the NP forming copolymer. Then, the polymer structure can be adjusted to obtain the desired degradation time. Finally, the possibility for such nanoparticles to physically incorporate and mediate the release of a lipophilic antineoplastic drug was evaluated in the case of Trabectedin. The formulation proved to be biocompatible and to sustainedly release the drug for up to 24 hours. Please click Additional Files below to see the full abstract