Sustained inhibition of cMET-VEGFR2 signaling using liposome-mediated delivery increases efficacy and reduces toxicity in kidney cancer

• Published in: Nanomedicine 2016-10, Vol.12 (7), p.1853-1861
• Main Authors: Kulkarni, Ashish A., PhD, Vijaykumar, Vijay Elakkya, Natarajan, Siva Kumar, Sengupta, Shiladitya, PhD, Sabbisetti, Venkata S., PhD
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - administration & dosage; c-Met inhibitor; Cell Line, Tumor; Humans; Internal Medicine; Kidney Neoplasms - drug therapy; Kinase inhibitor delivery; Liposomes; Renal cell carcinoma; Tissue Distribution; Vascular Endothelial Growth Factor Receptor-2 - drug effects; Vascular Endothelial Growth Factor Receptor-2 - physiology
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2016.04.002

Abstract c-Met pathway is implicated in the resistance to anti-VEGF therapy in renal cell carcinoma (RCC). However, clinical translation of therapies targeting these pathways has been limited due to dose-limiting toxicities, feedback signaling, and low intratumoral drug accumulation. Here, we developed liposomes encapsulating a multi-receptor tyrosine kinase inhibitor (XL184) to explore the possibility of improving intratumoral concentration, enhancing antitumor efficacy and reducing toxicities. The liposomes showed increased cytotoxicity than XL184, and resulted in a sustained inhibition of phosphorylation of Met, AKT and MAPK pathways in RCC cells. In a RCC tumor xenograft model, the liposomes induced sustained inhibition of tumor growth as compared to XL184, consistent with higher inhibition of kinase signaling pathways. Biodistribution studies revealed higher accumulation of the liposomes in tumor, which translated into lower toxicities. This study shows the use of liposomes for effective inhibition of multi-kinase pathways, which can potentially emerge as a new treatment for RCC.