(W1030-01-03) The Design and Assessment of Sustained Release from PLGA/PEG Blend Nanoparticles for Intravenous Application

Purpose: Polymeric nanoparticles (NPs) made of polylactic-co-glycolic acid (PLGA), a family of FDA-approved biodegradable and biocompatible polymers, have been extensively studied as delivery vehicles for poorly water-soluble drugs. An optimized fabrication approach has been fully developed in our lab to prepare highly reproducible PLGA NPs loaded with a BCS class II compound AC1LPSZG by emulsification-evaporation method using high-pressure homogenization. After intravenous (IV) administration of PLGA NPs in rats, pharmacokinetics suggested a rapid clearance due to an unwanted immune response to NPs. Coating NPs with polyethylene glycol (PEG) or "PEGylation" is commonly used to improve blood circulation by reducing immunogenicity and decreasing degradation. However, the surface conjugation heterogeneity or cost of PLGA-PEG copolymers brought some hardens to the product's scalability and limited clinical translation. Recent studies of discoidal polymeric nanoconstructs by mixing long PLGA chains with short PEG chains showed that the binary mixtures could minimize phagocytic cell sequestration through tailoring softness, enabling sustained release. This study established pharmacokinetic profiles of NPs from different blends of PLGA and PEG after IV administration in rats to testify to the novel "stealth" mechanism in vivo.

Methods: The PLGA/PEG blend NPs were custom synthesized through the Design of Experiments (DoE) approach and characterized in terms of size, size distribution, and zeta potential by DLS and morphologically by SEM. The release of encapsulated drugs in vitro and in vivo was measured with UPLC and LCMS assays.

Results: NPs of PEG (10, 20, 30, and 50 wt %) blended with PLGA were synthesized. DoE-based development can prepare size-tunable PLGA/PEG blend NPs within a size range from 110 nm to 170 nm. Drug-loaded PLGA/PEG blend NPs showed a smaller size, high encapsulation efficiency (EE), and increased stability compared to solo PLGA batches. NPs of different blend ratios of PLGA and PEG displayed a variety of pharmaceutic profiles. IV Administration of 2.5 mg/kg of AC1LPSZG loaded PLGA/PEG nanoparticle-encapsulated AC1LPSZG can induce a mean half-life of 33 hours and 20-fold greater bioavailability over the control group injected with PLGA NPs, while rats did not show any signs of side effects.

Conclusion: Blending short PEG chains while synthesizing PLGA NPs contributed to more pronounced blood circulation and bioavailability, suggesting a new strategy of sustained release by evading clearance by the phagocytic system (MPS).

Acknowledgements: The study was funded by the Cancer Prevention & Research Institute of Texas Core Facilities Support Awards (RP180748) and NIH’s Research Centers in Minority Institutes Program (RCMI, U54MD007605).