Conformation of surface-decorating dextran chains affects the pharmacokinetics and biodistribution of doxorubicin-loaded nanoparticles

Abstract

Recent reports showed that subtle modifications of nanoparticle surface properties induced dramatic changes of interactions with serum proteins. The present work was aimed to investigate the effect of the conformation of dextran chains decorating the surface of poly(alkylcyanoacrylate) (PACA) nanoparticles on the pharmacokinetic and biodistribution of a model drug associated with the nanoparticles. Doxorubicin was associated with PACA nanoparticles prepared by anionic emulsion polymerization (AEP) (Dox-AEP) and redox radical emulsion polymerization (RREP) (Dox-RREP). Nanoparticles and the free drug (f-Dox) were injected intravenously to rats to determine the pharmacokinetic and biodistribution of doxorubicin. Curves of the pharmacokinetics showed a rapid phase of distribution followed by a slower elimination phase. Pharmacokinetic parameters of the distribution phase determined for the Dox-RREP were significantly different from those of f-Dox and Dox-AEP, while no difference was observed in the elimination phase of the three formulations. Rats treated with Dox-RREP showed lower Dox concentrations in liver but higher concentrations in heart, lungs, and kidneys compared to those treated with the other formulations. Dox-RREP exhibited a new type of stealth behavior characterized by a short circulation time and a rapid distribution in highly vascularized organs bypassing the MPS. The difference in pharmacokinetic and biodistribution observed between the drugs formulated with the two types of nanoparticles was attributed to the difference in the conformation of the dextran chains stranded on the nanoparticle surface.