Protein Binding Affinity of Polymeric Nanoparticles as a Direct Indicator of Their Pharmacokinetics

Abstract

Polymeric nanoparticles (NPs) are an important category of drug delivery systems, and their <i>in vivo</i> fate is closely associated with delivery efficacy. Analysis of the protein corona on the surface of NPs to understand the <i>in vivo</i> fate of different NPs has been shown to be reliable but complicated and time-consuming. In this work, we establish a simple approach for predicting the <i>in vivo</i> fate of polymeric NPs. We prepared a series of poly(ethylene glycol)-<i>block</i>-poly(d,l-lactide) (PEG-<i>b</i>-PLA) NPs with different protein binding behaviors by adjusting their PEG densities, which were determined by analyzing the serum protein adsorption. We further determined the protein binding affinity, denoted as the equilibrium association constant (<i>K</i>_A), to correlate with <i>in vivo</i> fate of NPs. The <i>in vivo</i> fate, including blood clearance and Kupffer cell uptake, was studied, and the maximum concentration (<i>C</i>_max), the area under the plasma concentration-time curve (AUC), and the mean residence time (MRT) were negatively linearly dependent, while Kupffer cell uptake was positively linearly dependent on <i>K</i>_A. Subsequently, we verified the reliability of the approach for <i>in vivo</i> fate prediction using poly(methoxyethyl ethylene phosphate)-<i>block</i>-poly(d,l-lactide) (PEEP-<i>b</i>-PLA) and poly(vinylpyrrolidone)-<i>block</i>-poly(d,l-lactide) (PVP-<i>b</i>-PLA) NPs, and the linear relationship between the <i>K</i>_A value and their PK parameters further suggests that the protein binding affinity of polymeric NPs can be a direct indicator of their pharmacokinetics.