Prediction of silica nanoparticle biodistribution using a calibrated physiologically based model: Unbound fraction and elimination rate constants for the kidneys and phagocytosis identified as major determinants.
Madison Parrot, Joseph Cave, Maria J Pelaez, Hamidreza Ghandehari, Prashant Dogra, Venkata Yellepeddi
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Abstract
Objectives: This study aimed to develop a minimal physiologically based pharmacokinetic (mPBPK) model to predict the biodistribution of silica nanoparticles (SiNPs) and evaluate how variations in surface charge, size, porosity, and geometry influence their systemic disposition.
Materials: The mPBPK model was calibrated using in vivo pharmacokinetic data from mice administered aminated, mesoporous, and rod-shaped SiNPs. Human data were collected from clinical trial data from Cornell dots.
Materials: The mPBPK model incorporated physiological parameters and nanoparticle-specific characteristics to simulate SiNP biodistribution and was built in Matlab 2024a. Global sensitivity analysis identified influential parameters, including the unbound fraction and elimination rate constants for the kidneys and mononuclear phagocyte system (MPS). The model was extrapolated to predict human pharmacokinetics, with accuracy evaluated using Pearson correlation coefficients. Non-compartmental analysis (NCA) assessed organ-specific accumulation and biodistribution patterns.
Results: Global sensitivity analysis revealed that the unbound fraction and elimination rate constants for the kidneys and MPS were major determinants of SiNP biodistribution. NCA indicated that aminated SiNPs initially accumulated in the liver, spleen, and kidneys but redistributed due to their high unbound fraction, while mesoporous SiNPs localized in the lungs. Rod-shaped SiNPs exhibited high lung exposure. The extrapolated model showed high predictive accuracy, with Pearson correlation coefficients of 0.98 for mice and 0.99 for humans.
Conclusion: The mPBPK model effectively predicts the pharmacokinetics of diverse SiNPs, offering insights to optimize nanoparticle-based drug delivery systems and facilitating their translation from preclinical models to clinical applications.
期刊介绍：
The International Journal of Clinical Pharmacology and Therapeutics appears monthly and publishes manuscripts containing original material with emphasis on the following topics: Clinical trials, Pharmacoepidemiology - Pharmacovigilance, Pharmacodynamics, Drug disposition and Pharmacokinetics, Quality assurance, Pharmacogenetics, Biotechnological drugs such as cytokines and recombinant antibiotics. Case reports on adverse reactions are also of interest.
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