EPR effect and development of new strategy for nanoparticle delivery via remodeling tumor microenvironment based on tumor vasculature targeting

Abstract

A discovery of the EPR effect allowed for remarkable progress in a delivery of anti-cancer therapeutics using cancer-targeting nanoparticle. However, recent report on meta-analysis among several clinical trial with patients treated with liposomal doxorubicin revealed that liposomal doxorubicin was not superior to free doxorubicin in terms of therapeutic effect. This difference would be caused by the difference between non-clinical model and clinical model with regard to growth speed, tumor growth speed, tumor microenvironment, endpoint (tumor size vs. over survival). We would like to introduce this report in detail. In addition, to evaluate the effect of tumor microenvironment on the delivery of nanoparticle and to enhance that through remodeling tumor microenvironment, we have recently developed a new strategy that remodeling tumor microenvironment by siRNA delivery to tumor vasculature enhanced the intratumoral distribution of nanoparticles. Specifically in hyperangiogenic cancer, anti-angiogenic therapy by vascular endothelial growth factor receptor 2 (VEGFR2) enhanced the delivery of nanoparticles to tumor tissue, which was inconsistent with previous report. We herein would like to explain this contradiction in terms of tumor microenvironment and introduce our new strategy.