Evaluation of anticancer effect of micelle-encapsulated doxorubicin using gamma-distributed delay model

Abstract

In clinical trials of nanoparticle-based anticancer drug delivery systems, an inexplicable lack of correlation between the function imparted to the nanoparticles and their therapeutic effects is noted. To elucidate the cause of this lack of correlation, we developed a pharmacokinetic-pharmacodynamic (PK-PD) model of tumor growth kinetics in a tumor-bearing rat model injected with polymeric micelle-encapsulated doxorubicin (DOX) using parameters related to tumor accumulation and anticancer activity. DOX was loaded onto a polyethylene glycol-peptide block polymer (PEG-poly(D/F)n: PPDF) via an amide bond to prepare sustained-release polymeric micelles (PPDF-DOX) and folic acid receptor-targeting polymeric micelles (FA-PPDF-DOX). Plasma concentration–time profiles and pharmacokinetic parameters of DOX released from PPDF-DOX into the tumors were examined using microdialysis analysis on the tumors in Walker 256 tumor-bearing rats after PPDF-DOX administration. PPDF-DOX and FA-PPDF-DOX showed delayed tumor accumulation for up to 4 h after injection. Therefore, the analysis was performed using a three-compartment model, incorporating a gamma-distributed delay model between the central and tumor compartments. The PK model was used to simulate eight repeated doses administered every other day. The cumulative area under the curve of FA-PPDF-DOX was 4.2-fold higher than that of PPDF-DOX. The PK-PD model analysis was performed based on intratumoral DOX concentration profiles and changes in tumor diameter. The time efficacy index—a measure of drug efficacy—indicated a 45k-fold higher antitumor effect of FA-PPDF-DOX over that of PPDF-DOX. These results suggest that the active-targeting function versus the effect of sustained-release polymeric micelles may depend on the delayed tumor retention of anticancer drugs.