Microenvironment-sensing, nanocarrier-mediated delivery of combination chemotherapy for pancreatic cancer

Journal of Cell Communication and Signaling

article

Ray, Priyanka¹  Nair, Gauthami²  Ghosh, Arnab³  Banerjee, Snigdha³  Golovko, Mikhail Y.⁵  Banerjee, Sushanta K.³  Reindl, Katie M.²  Mallik, Sanku⁶  Quadir, Mohiuddin¹ 

[1] Department of Coatings and Polymeric Materials, North Dakota State University;Cellular and Molecular Biology Program, Department of Biology, North Dakota State University;Cancer Research Unit, VA Medical Center;Department of Pathology and Laboratory Medicine, University of Kansas Medical Center;Department of Biomedical Sciences, University of North Dakota;Department of Pharmaceutical Sciences, North Dakota State University

关键词: Extracellular Receptor Kinase (ERK);    Pancreatic cancer;    Nanocarrier;    Drug delivery;   

DOI  :  10.1007/s12079-019-00514-w

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

Limited effectiveness of Raf and MEK inhibitors has impelled the interest to use the inhibitors of Extra-cellular Receptor Kinase (ERK) pathway in combination with Gemcitabine (GEM) in pancreatic cancer. However, off-target abundance of ERK receptors, challenging physico-chemical properties, and dose-limiting toxicity of the inhibitor has presented critical challenges towards fabricating this combination amenable for clinical translation. Herein we report a pharmaceutical nanoformulation of GEM and an ERK inhibitor (SCH 772984) co-stabilized within a pH-sensing nanocarrier (NC, with a hydrodynamic diameter of 161 ± 5.0 nm). The NCs were modularly derived from a triblock, self-assembling copolymer, and were chemically conjugated with GEM and encapsulated with SCH772984 at a loading content of 20.2% and 18.3%, respectively. Through pH-mediated unfolding of the individual blocks of the copolymer, the NCs were able to control the release of encapsulated drugs, traffic through cellular membranes, engage target receptors, suppress proliferation of pancreatic cancer cells, and accumulate at disease sites. Collectively our studies showed the feasibility of co-delivery of a combination chemotherapy consisting of GEM and an ERK inhibitor from a NC platform, which can sense and respond to tumor microenvironment of pancreatic cancer setting.

【 授权许可】

CC BY