The effect of comb length on the in vitro and in vivo properties of self-assembled poly(oligoethylene glycol methacrylate)-based block copolymer nanoparticles

Comb copolymer analogues of poly(lactic acid)-polyethylene glycol block copolymers (PLA-b-PEG) offer potential to overcome the inherent chemistry and stability limitations of their linear block copolymer counterparts. Herein, we examine the differences between P(L)LA(10K)-b-PEG(10K) and linear-comb copolymer analogues thereof in which the linear PEG block is replaced by poly(oligo(ethylene glycol) methacrylate) (POEGMA) blocks with different side chain (comb) lengths but the same overall molecular weight. P(L)LA(10K)-b-POEGMA475(10K) and P(L)LA(10K)-b-POEGMA2000(10K) block copolymers were synthesized via activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and fabricated into self-assembled nanoparticles using flash nanoprecipitation via confined impinging jet mixing. Linear-comb copolymer analogues based on PLA-b-POEGMA yielded smaller but still well-controlled nanoparticle sizes (88 +/- 2 nm and 114 +/- 1 nm respectively compared to 159 +/- 2 nm for P(L)LA(10K)-b-PEG(10K) nanoparticles) that exhibited improved colloidal stability relative to linear copolymer-based nanoparticles over a 15 day incubation period while maintaining comparably high cytocompatibility, although the comb copolymer analogues had somewhat lower loading capacity for doxorubicin hydrochloride. Cell spheroid studies showed that the linear-comb copolymers promoted enhanced tumor transport and thus cell killing compared to conventional linear block copolymers. In vivo studies showed all NP types could passively accumulate within implanted CT26 tumors but with different accumulation profiles, with P(L)LA(10K)-b-POEGMA2000(10K) NPs showing continuous accumulation throughout the full 24 h monitoring period whereas tumor accumulation of P(L)LA(10K)-b-POEGMA475(10K) NPs was significant only between 8 h and 24 h. Overall, the linear-comb copolymer analogues exhibited superior stability, biodistribution, spheroid penetration, and inherent tunability over linear NP counterparts.