(338c) Understanding the Role of Block-Length on Nanoparticle Assembly of Poly(2-hydroxyethyl methacrylate)-Block-Poly(lactic acid) Via Flash Nanoprecipitation

Nanoparticle drug delivery systems (NDDS) predominantly utilize poly(ethylene glycol) (PEG) based stabilizing coronas due to its biocompatibility, stealth effect, and low opsonization. PEG has been increasingly reported to generate anti-PEG antibodies that contribute to an increased clearance of NDDS. This increased immunogenicity warrants evaluation of alternative stealth materials for NDDS. Poly(2-hydroxyethyl methacrylate) (pHEMA) is a hydrophilic, water-swellable, and FDA approved biocompatible polymer widely used in medicine, which can be utilized as an alternative material to generate the NDDS corona.

This work evaluates the use of pHEMA as a stabilizer for nanoparticles generated via the well-established Flash NanoPrecipitation (FNP) process. We synthesized a library of poly(lactic acid)-block-poly(2-hydroxyethyl methacrylate) (PLA-PHEMA) amphiphilic block copolymers (BCPs) with varying pHEMA molecular weight to elucidate the influence of molecular weight on nanoparticle assembly via FNP and to expand the polymeric stabilizer material repertoire for FNP. Assembly of polymeric nanoparticles with a pHEMA-corona has not yet been reported using FNP. Using a bifunctional initiator, ring opening polymerization (ROP) was used to initially synthesize a 10 kDa PLA block and subsequently atom transfer radical polymerization (ATRP) was used to synthesize pHEMA blocks with a range of molecular weights from 0.5 kDa to 5 kDa.

We observed a strong dependence of pHEMA molecular weight on nanoparticle assembly. BCPs with pHEMA blocks larger than 3 kDa were not able to form nanoparticles, while BCPs with smaller blocks robustly formed nanoparticles. This behavior can be explained by the dependence of pHEMA water solubility on the pHEMA molecular weight. The pHEMA-water chi parameter at molecular weights above 3 kDa approaches and then exceeds that of PLA-water. Thus pHEMA chains above 3 kDa decrease in water solubility and cannot sterically stabilize nanoparticles. With smaller pHEMA blocks, the nanoparticle size was tunable between 50 and 200 nm. Encapsulation of both vitamin E and rubrene aided in the assembly of nanoparticles with pHEMA molecular weights below 3 kDa. The cytotoxicity of 100 nm pHEMA stabilized nanoparticles was evaluated in F11 neuronal cells and found to have no significant cytotoxicity. Rubrene encapsulated pHEMA nanoparticles were found to be taken-up by these F11 cells.

We have demonstrated the use of pHEMA as a PEG-alternative stabilizer for FNP nanoparticles. The choice of pHEMA molecular weight is critical for both nanoparticle stability and assembly. This work ultimately expands the types of nanoparticle surfaces available for FNP and provides a framework for alternative biocompatible surfaces used in drug delivery nanoparticles.