Nanomedicines to effect and interrogate transendothelial transport

Daniel Heller ^1,2 Daniel Tylawsky ^1,2 Praveen Raju ^4,5,9 Hiroto Kiguchi ¹ Matthew Greenblatt ³ Jake Vaynshteyn ⁵ Jeffrey Gerwin ⁵ Janki Shah ¹ Matija Snuderl ⁸ Yosi Shamay ⁷ Emma Grabarnik ¹ Zvi Yaari ¹

¹Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, USA
²Department of Pharmacology, Weill Cornell Medicine, USA
³Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, USA
⁴Department of Pediatrics, Weill Cornell Medicine, USA
⁵Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, USA
⁶Departments of Pathology & Laboratory Medicine, Nationwide Children's Hospital and the Ohio State University, USA
⁷Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Israel
⁸Department of Pathology, NYU Langone Medical Center, USA
⁹Department of Pediatrics, Memorial Sloan Kettering Cancer Center, USA

Kinase inhibitors, which target key effectors of cancer signaling pathways, constitute a major component of precision oncology. However, such drugs can affect the same signaling pathways in healthy tissues, which often leads to dose-limiting toxicities. We are developing nanomedicine platforms to obviate dose-limiting toxicities of kinase inhibitors and thereby improve therapeutic index in solid tumors. We developed nanoparticle strategies to target kinase inhibitors to tumor vasculature targets, including upregulated P-selectin and caveolin-1. P-selectin is expressed endogenously on activated endothelium in tumors, and it can be greatly induced by ionizing radiation to result in improved delivery. We developed kinase inhibitor-loaded, P-selectin-targeted nanoparticles which improve biodistribution to tumors with activated endothelium. Our data shows improved efficacy of kinase inhibitors, and the abrogation of dose-limiting toxicities, such as skin rash and hyperglycemia, to improve therapeutic index. The nanoparticles also resulted in prolonged inhibition of the drug targets in tumor tissues, constituting a significant modulation of the kinase inhibitor pharmacologic properties, including in intracranial tumors.