Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content

Abstract

Biodistribution of nanoparticles is dependent on their physicochemical properties (such as size, surface charge, and surface hydrophilicity). Clear and systematic understanding of nanoparticle properties' effects on their in vivo performance is of fundamental significance in nanoparticle design, development and optimization for medical applications, and toxicity evaluation. In the present study, a physiologically based pharmacokinetic model was utilized to interpret the effects of nanoparticle properties on previously published biodistribution data. Biodistribution data for five poly(lactic-co-glycolic) acid (PLGA) nanoparticle formulations prepared with varied content of monomethoxypoly (ethyleneglycol) (mPEG) (PLGA, PLGA-mPEG256, PLGA-mPEG153, PLGA-mPEG51, PLGA-mPEG34) were collected in mice after intravenous injection. A physiologically based pharmacokinetic model was developed and evaluated to simulate the mass-time profiles of nanoparticle distribution in tissues. In anticipation that the biodistribution of new nanoparticle formulations could be predicted from the physiologically based pharmacokinetic model, multivariate regression analysis was performed to build the relationship between nanoparticle properties (size, zeta potential, and number of PEG molecules per unit surface area) and biodistribution parameters. Based on these relationships, characterized physicochemical properties of PLGA-mPEG495 nanoparticles (a sixth formulation) were used to calculate (predict) biodistribution profiles. For all five initial formulations, the developed model adequately simulates the experimental data indicating that the model is suitable for description of PLGA-mPEG nanoparticle biodistribution. Further, the predicted biodistribution profiles of PLGA-mPEG495 were close to experimental data, reflecting properly developed property-biodistribution relationships.

Keywords: PBPK model; PEG; PLGA; biodistribution; nanoparticles; relationship.

Figure 1

Schematic diagrams of the blood flow-limited model (A) and the membrane-limited model (B). Arrows indicate the transportation of nanoparticles with the dashed arrows in (B), indicating differing transportation equations from solid arrows in (A). Note: Triangles represent the intravenous administration. Abbreviation: GI, gastrointestinal tract.

Figure 2

Simulation of experimental data using the membrane-limited model. (A) poly(lactic-co-glycolic) acid, (B), poly(lactic-co-glycolic) acid-monomethoxypoly (ethyleneglycol)256, (C) poly(lactic-co-glycolic) acid-monomethoxypoly (ethyleneglycol)153, (D) poly(lactic-co-glycolic) acid-monomethoxypoly (ethyleneglycol)61, and (E) poly(lactic-co-glycolic) acid-monomethoxypoly (ethyleneglycol)34 nanoparticles. Note: Dots represent experimental data and lines represent simulated mass-time curves. Abbreviations: GI, gastrointestinal tract; ID, initial dose.

Figure 3

Simulation of renal (A) and bile (B) excretion for poly(lactic-co-glycolic) acid and poly (ethyleneglycol)-containing nanoparticle formulations. Notes: For renal excretion, dots represent experimental data. Data for bile excretion from the original experimental do not exist. Abbreviations: ID, initial dose; mPEG, monomethoxypoly (ethyleneglycol); PLGA, poly(lactic-co-glycolic) acid.

Figure 4

Predicted biodistribution kinetic profiles of poly(lactic-co-glycolic) acid-monomethoxypoly (ethyleneglycol) 495 nanoparticles (A) and comparison of experimental and predicted values of tissue distribution of poly(lactic-co-glycolic) acid-monomethoxypoly (ethyleneglycol) 495 nanoparticles at 3 hours (B). Abbreviations: GI, gastrointestinal tract; ID, initial dose.