Orthogonal characterization and pharmacokinetic studies of polylactide-polyethyleneglycol polymeric nanoparticles with different physicochemical properties

To optimize prolonged and sustained delivery of polylactide-block-polyethyleneglycol polymeric nanoparticles (PLA-PEG NPs), in terms of the PLA isomer and molecular weight, we performed orthogonal physicochemical characterization and evaluated the pharmacokinetics of tamoxifen (TAM)-loaded PLA-PEG NPs. DL-lactide- (DL-PEG NP), L-lactide- (L-PEG NPs), and stereocomplex-based (SC-PEG NPs) PLA-PEGs, with two different PLA to PEG ratios (12k–5k and 5k–5k Da) were synthesized, and NPs were prepared by anti-solvent precipitation. Size exclusion chromatography, multi-angle light scattering, dynamic light scattering, and 1H nuclear magnetic resonance studies revealed that SC-PEG NPs (12k–5k) had a compact structure and the highest PEG density, followed by L-PEG NPs (12k–5k), DL-PEG NPs (12k–5k), and all PLA-PEG NPs (5k–5k). Additionally, solid-phase extraction indicated that SC-PEG NPs (12k–5k) had the highest drug loading content and the lowest surface TAM adsorption, of the PLA-PEGs evaluated. These results were explained by the crystallinity of the PLA core, which was analyzed by X-ray diffraction. In the pharmacokinetic studies, 14C-TAM-loaded 111In-SC-PEG NPs (12k–5k) exhibited the highest area under the plasma concentration-time curve, followed by L-PEG NPs (12k–5k) and DL-PEG NPs (12k–5k), after intravenous injection in mice. These results indicate that SC-PEG NPs (12k–5k) are promising drug carriers for the sustained and prolonged delivery of TAM.