Self-Assembled Polymeric Nanoparticles of Organocatalytic Copolymerizated d,l-Lactide and 2-Methyl 2-Carboxytrimethylene Carbonate

Polymeric nanoparticles are important for the selective delivery of hydrophobic cancer drugs to tumors, yet most of the polymers studied are limited by compositional diversity. To overcome this limitation, a series of poly(d,l-lactide-co-2-methyl-2-carboxytrimethylene carbonate) (P(LA-co-TMCC)) was synthesized with low polydispersity index (PDI: 1.25 to 1.36) using organocatalytic ring-opening copolymerization with pyrenebutanol initiation and 1-[3,5-bis(trifluoromethyl) phenyl]-3-[(1R,2R)-(−)-2(dimethylamino) cyclohexyl] thiourea (thiourea-amine) catalysis. The reactivity ratio was estimated at 1.1 for LA and 0.072 for benzyl-protected TMCC. We controlled the copolymer molar mass and composition by varying monomer-to-initiator ratios and monomer feed ratios. Methoxy-terminated poly(ethylene glycol) amine (MeO-PEG-NH₂) was coupled to the carboxylic acid groups of the TMCC copolymer backbone using carbodiimide chemistry. The resulting amphiphilic copolymer self-assembled in aqueous solution to form nanoparticles with a narrow size distribution. Smaller nanoparticles formed when borate buffer (vs water) were present during the self-assembly process. The physical properties of the nanoparticles, such as size, critical micelle concentration (CMC), and ζ potential were affected by the hydrophilic PEG chain length and the hydrophobic backbone composition. Those nanoparticles with the lowest CMC are thought to be sufficiently stable for targeted delivery in cancer.