Precision Stealth Nanofibers via PET‐RAFT Polymerisation: Synthesis, Crystallization‐driven Self‐assembly and Cellular Uptake Studies

Stealth precision polymer nanofibers show great promise as therapeutic delivery systems. However, existing systems are largely limited to poly(ethylene glycol) (PEG) and suffer from challenging functionalization, hampering their translation. This work develops a modular, easily functionalizable platform for biocompatible stealth nanofibers based on a combination of ring-opening polymerisation (ROP), photoinduced electron/energy transfer reversible addition-fragmentation chain transfer (PET-RAFT) polymerisation, and crystallization-driven self-assembly (CDSA). Low length-dispersity poly(fluorenetrimethylenecarbonate)-b-poly(N-(2-hydroxypropyl) methacrylamide) (PFTMC-b-PHPMA) nanofibers may be produced in a single-step via CDSA, with a length that is dependent on the PHPMA DP_n. Separately, living CDSA leads to nanofibers with length control between 30 nm and ca. 700 nm. Incorporation of fluorescein into the PET-RAFT polymerization results in fluorescent PFTMC-b-PHPMA block copolymers that can undergo CDSA, forming fluorescent nanoparticles for preliminary cell studies. PFTMC-b-PHPMA nanofibers exhibited minimal toxicity to cells as well as limited cellular association, in line with previous studies on neutral polymer nanofibers. In comparison, PFTMC-b-PHPMA nanospheres exhibited no cellular association. These results indicate that the unique shape and core-crystallinity of PFTMC-b-PHPMA nanofibers ideally positions them for use as therapeutic delivery systems. Overall, the results described herein provide the basis for a modular, easily functionalizable platform for precision stealth polymer nanofibers for a variety of prospective biomedical applications.