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

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• 作者：Ashish A. Kulkarni ; PhD^a ; ^c ; ^{akulkarni@research.bwh.harvard.edu" class="auth_mail" title="E-mail the corresponding author} ; ^{ashishk@mit.edu" class="auth_mail" title="E-mail the corresponding author} ; Vijay Elakkya Vijaykumar ; BS^b ; ^c ; Siva Kumar Natarajan^a ; ^c ; Shiladitya Sengupta ; PhD^a ; ^c ; ^d ; ^e ; Venkata S. Sabbisetti ; PhD^b ; ^c ; ^{vsabbisetti@partners.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Renal cell carcinoma ; Liposomes ; c-Met inhibitor ; Kinase inhibitor delivery
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：12
• 期：7
• 页码：1853-1861
• 全文大小：1608 K

文摘

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.