Abstract
Enhancing tumor targeting of nanocarriers has been a major strategy for advancing clinical translation of cancer nanomedicines. Herein, we report a head-to-head comparison between 5 nm renal clearable and 30 nm non-renal clearable gold nanoparticle (AuNP)-based drug delivery systems (DDSs) in the delivery of doxorubicin (DOX). While the two DDSs themselves had comparable tumor targeting, we found their different vascular permeability played an even more important role than blood retention in the delivery and intratumoral transport of DOX, of which tumor accumulation, efficacy, and therapeutic index were enhanced 2, 7, and 10-fold, respectively, for the 5 nm DDS over 30 nm one. These findings indicate that ultrahigh vascular permeability of renal clearable nanocarriers can be utilized to further improve anticancer drug delivery without the need for prolonged blood retention.