Morphological insights in oxidative sensitive nanocarrier pharmacokinetics, targeting, and photodynamic therapy

Nanoparticle (NP) morphology holds significant importance in nanomedicine, particularly concerning its implications for biological responses. This study investigates the impact of synthesizing polymers with varying degrees of methionine (MET) polymerization on three distinct drug delivery systems: spherical micelles, worm-like micelles, and vesicles, all loaded with the photosensitizer chlorin e6 (Ce6). We analyzed their distribution at both cellular and animal levels, revealing how NP morphology influences cellular uptake, subcellular localization, penetration of multicellular spheroids, blood half-life, and biodistributions across major organs. Employing a physiologically based pharmacokinetic (PBPK) model enabled us to simulate diverse distribution patterns and quantify the targeting efficiency of NPs toward tumors. Our investigation elucidates that spherical micelles exhibit lower accumulation levels within the reticuloendothelial system, potentially mitigating adverse side effects despite their higher glomerular filtration rate. This nuanced understanding underscores the complex interplay between NP morphology and biological responses, providing valuable insights into optimizing therapeutic efficacy while minimizing undesirable effects. We thus report the integration of experimental analyses with PBPK modeling to elucidate the topological characteristics of NP, thereby shedding light on their distribution patterns, therapeutic efficacy, and potential side effects.