(596am) Physiologically Based Pharmacokinetic and Pharmacodynamic Approach to Nanoparticle Biodistribution and Tumor Uptake: A Comparison Between Gold Nanoparticles and Spions Nanoparticles

Authors: 
Galvis, A. A., Universidad de los Andes
Vargas, R. D., Universidad de los Andes
Vargas, W. L., Universidad de los Andes


Nanomedicine and nanostructured materials research have been in exponential growth during the last decade, several efforts have been focused on the nanoparticle design. Nevertheless, the knowledge about nanoparticles absorption, distribution, metabolism and excretion (ADME) has been growing more slowly, in fact these ADME parameters are required in order to obtain the pharmacokinetic and pharmacodynamic of these nano-sized materials.

Physiologically based pharmacokinetic models (PBPK) are mathematical strategies developed in order to analyze ADME properties for pharmaceutical compounds, treating the organs such as compartmental structures with several interconnections modeled by differential equations. Therefore, the appeal of PBPKs arises from accurate prediction models for concentration profiles by varying: doses, exposure duration and routes of administration. In addition these models have been useful for interspecies scalability.

The aim of the current study is to provide in silico physiological based pharmacokinetic models for the dynamic biodistribution of gold nanoparticles and superparamagnetic iron oxide nanoparticles (SPION´s) both coated with different surface modifiers typical for each kind of particles (dextran, polyetileneglicol, and citrate), analyzing surface charge and size effects into the model. To date, there are few studies on how the surface charges of nanocarriers impact their biodistribution, pharmacokinetics and tumor uptake.

 The proposed models are focused on dynamic cancer treatment strategies, a comparison between gold nanoparticles and SPION´s is developed, and issues such as liver or lymphatic system bioaccumulation and metabolism are specially treated, using experimental data for the most relevant organs (compartments). In addition, exploratory models for tumor evolution are included into the model to provide a PBPK model for chemotherapy agents and tumor-targeted substances coupled to gold nanoparticles.

 The PBPK models includes separation between venous and arterial blood pools, and the main organs for nanoparticles biodistribution have been modeled in detail (i.e. Liver, lungs, kidneys, spleen, hearth, brain), Additionally, the parameters for this model have been adjusted and validated using different kinds of preclinical  data in mice.