title: Sustained inhibition of cMET-VEGFR2 signaling using liposome-mediated delivery increases efficacy and reduces toxicity in kidney cancer.
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.
authors.affiliation: Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: akulkarni@research.bwh.harvard.edu.
authors.forename: Ashish A
authors.initials: AA
authors.lastname: Kulkarni
authors.affiliation: Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Vijay Elakkya
authors.initials: VE
authors.lastname: Vijaykumar
authors.affiliation: Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Siva Kumar
authors.initials: SK
authors.lastname: Natarajan
authors.affiliation: Division of Biomedical Engineering, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: vsabbisetti@partners.org.
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Sabbisetti
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008081:Liposomes; D014018:Tissue Distribution; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Kinase inhibitor delivery; Liposomes; Renal cell carcinoma; c-Met inhibitor