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

Comb copolymer analogues of poly(lactic acid)-polyethylene glycol block copolymers (PLA--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--PEG 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--POEGMA475 and P(L)LA--POEGMA2000 block copolymers were synthesized activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and fabricated into self-assembled nanoparticles using flash nanoprecipitation confined impinging jet mixing. Linear-comb copolymer analogues based on PLA--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--PEG 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. studies showed all NP types could passively accumulate within implanted CT26 tumors but with different accumulation profiles, with P(L)LA--POEGMA2000 NPs showing continuous accumulation throughout the full 24 h monitoring period whereas tumor accumulation of P(L)LA--POEGMA475 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.