A Robust Approach to Enhance Tumor-selective Accumulation of Nanoparticles

Yuan Qiao 1* , Xin Huang 1* , Sridhar Nimmagadda 2* , Renyuan Bai 3* , Verena Staedtke 3 , Catherine A. Foss 2 , Ian Cheong 1 , Matthias Holdhoff 1 , Yoshinori Kato 2 , Martin G. Pomper 2 , Gregory J. Riggins 3 , Kenneth W. Kinzler 1 , Luis A. Diaz, Jr 1 , Bert Vogelstein 1 , Shibin Zhou 1 1 The Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and Sidney Kimmel Cancer Center at the Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA 2 Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA 3 Department of Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA * These authors contributed equally to this work Keywords: Tumor, Vasculature, Nanoparticle, Inflammation, TNF-α Received: February 28, 2011; Accepted: March 1, 2011; Published: March 1, 2011; Correspondence: Shibin Zhou, e-mail: // // Abstract While nanoparticles have shown great promise as drug carriers in cancer therapy, their effectiveness is critically dependent on the structural characteristics of the tumor vasculature. Here we demonstrate that several agents capable of inducing vascular responses akin to those observed in inflammatory processes enhance the accumulation of nanoparticles in tumors. The vascular-active agents tested in this study included a bacterium, a pro-inflammatory cytokine, and microtubule-destabilizing drugs. Using radiolabeled nanoparticles, we show that such agents can increase the tumor to blood ratio of radioactivity by more than 20-fold compared to nanoparticles alone. Moreover, vascular-active agents dramatically improved the therapeutic effect of nanoparticles containing radioactive isotopes or chemotherapeutic agents. This resulted in cures of animals with subcutaneous tumors and significantly prolonged the survival of animals with orthotopic brain tumors. In principle, a variety of vascular-active agents and macromolecular anticancer formulations can be combined, which makes this approach broadly applicable and particularly suited for the treatment of patients who have failed standard therapies.