Design and Evaluation of PEGylated Liposomal Formulation of a Novel Multikinase Inhibitor for Enhanced Chemosensitivity and Inhibition of Metastatic Pancreatic Ductal Adenocarcinoma

Vijay Sagar Madamsetty, Krishnendu Pal, Shamit Kumar Dutta, Enfeng Wang, James R Thompson, Raj Kumar Banerjee, Thomas R Caulfield, Kabir Mody, Yun Yen, Debabrata Mukhopadhyay, Hsu-Shan Huang

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9 引文 斯高帕斯(Scopus)

摘要

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among cancers. Chemotherapy is the standard first-line treatment, but only modest survival benefits are observed. With the advent of targeted therapies, epidermal growth factor receptor (EGFR) has been acknowledged as a prospective target in PDAC since it is overexpressed in up to 60% of cases. Similarly, the tyrosine-protein kinase Met (cMET) is also overexpressed in PDAC (27-60%) and is a prognostic marker for poor survival. Interestingly, EGFR and cMET share some common signaling pathways including PI3K/Akt and MAPK pathways. Small molecule inhibitors or bispecific antibodies that can target both EGFR and cMET are therefore emerging as novel options for cancer therapy. We previously developed a dual EGFR and cMET inhibitor (N19) that was able to inhibit tumor growth in nonsmall cell lung cancer models resistant to EGFR tyrosine kinase inhibitors (TKI). Here, we report the development of a novel liposomal formulation of N19 (LN19) and showed significant growth inhibition and increased sensitivity toward gemcitabine in the pancreatic adenocarcinoma orthotopic xenograft model. Taken together, our results suggest that LN19 can be valued as an effective combination therapy with conventional chemotherapy such as gemcitabine for PDAC patients.

原文英語
頁(從 - 到)2703-2713
頁數11
期刊Bioconjugate Chemistry
30
發行號10
早期上線日期10月 4 2019
DOIs
出版狀態已發佈 - 10月 16 2019

ASJC Scopus subject areas

  • 生物工程
  • 生物技術
  • 生物醫學工程
  • 藥理
  • 藥學科學
  • 有機化學

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