Targeting Precision Nanomedicines to the Tumor Microenvironment
Many precision medicines, such as kinase inhibitors, must reach tumors at relatively high concentrations to achieve a therapeutic response. Disseminated tumors, however, are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated a new target to localize personalized drugs to the tumor microenvironment. P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, was studied for its potential to use the same mechanism to arrest nanomedicines at the tumor vessels. We developed a nanoparticle drug carrier platform using a fucosylated polysaccharide with nanomolar affinity to P-selectin to localize targeted therapies at the tumor site and away from healthy tissues to obviate dose-limiting toxicities and concomitantly improve therapeutic index. We found that the nanoparticles targeted MEK and PI3K inhibitors to tumor sites in both primary and metastatic models, resulting in superior anti-tumor efficacy and the striking reduction of toxicities. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression, suggesting a potential strategy to target disparate drug classes to almost any solid tumor.
Adriana Haimovitz-Friedman is an Attending Radiation Biologist in the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center (MSKCC). Her work focuses on mechanism of radiation-induced damage to the endothelial cells both in normal and in tumor tissues. Her work showed that radiation induces apoptotic cell death in endothelial cells both in vitro and in vivo and that this apoptotic pathway is not p53 dependent, but rather dependent on activation of the enzyme Acid Sphingomyelinase (ASMase). In the last three years she has been collaborating with the Heller Lab working on targeting precision nanomeds to the tumor microenvironment. Dr. Haimovitz-Friedman obtained her PhD in Experimental Medicine from the Hebrew University, Jerusalem, Israel. She did one year of Postdoctoral Fellowship in the laboratory of David Rosenstreich at Albert Einstein in New York before being recruited by the Chairman of Radiation Oncology department at MSKCC to open new Laboratories in his department. She is a recipient of the Bankir Cancer Research Award.