Long-lasting Cross-linked PLGA-Inspired Nanoparticles from One-pot Nanopolymerization of Precisely Sequenced Short Oligolactoglycolic Acid Dimethacrylates

Poly(lactic-co-glycolic acid) (PLGA) is a widely utilized polymer for biomedical applications due to its biocompatibility and degradability in vivo. Traditional methods of fabrication of drug-loaded nanoparticles (NPs) employ the random sequence form of linear PLGA to yield non-crosslinked polymeric NPs that form when the polymer nanoprecipitates out of solution. Given the large-scale use of PLGA-based polymeric drug delivery systems to date, it is crucial to be able to control the ratio and sequence of lactic and glycolic components in the overall drug delivery system, which in turn can impact factors such as stability, drug loading, drug release and degradability. In this work, we present a novel PLGA-inspired NP polymerization technique, which allows the formation of NPs via the cross-linking of precisely sequenced short oligolactoglycolic acid dimethacrylates (OLGADMAs). Following the synthesis of a range of OLGADMAs we successfully generated a library of NPs via this rapid and surfactant-free nanopolymerization method, which permits the simultaneous NP formation and encapsulation of drugs such as dexamethasone. Our results indicate that NPs produced through this nanopolymerization technique with precisely controlled sequences exhibit heightened stability compared to conventionally sequenced and non-sequence controlled PLGA, as evidenced by minimal pH changes over a five-week span. This improved stability is attributed to simultaneous crosslinking and co-polymerization of the OLGADMAs. Moreover, the long-acting NPs demonstrated minimal cytotoxicity and uniform cellular uptake in vitro. We conclude that the ability to precisely regulate the sequence of short PLGA-inspired monomers and employ a unique in situ nanopolymerizing reaction results in exceptionally stable NPs for sustained drug delivery and opens exciting possibilities for the development of a range of long-lasting drug delivery systems with programmable structure and function.