pH-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer

• DOI: 10.1021/acs.molpharmaceut.0c00499
• Publication Date: 2020-11-25T04:52:01Z
• Authors: Priyanka Ray; Debasmita Dutta; Inamul Haque; Gauthami Nair; Jiyan Mohammed; Meredith Parmer; Narendra Kale; Megan Orr; Pooja Jain; Snigdha Banerjee; Katie M. Reindl; Sanku Mallik; Suman Kambhampati; Sushanta K. Banerjee; Mohiuddin Quadir
• Keywords: Growth inhibition; IC50; Combination therapy

Pancreatic ductal adenocarcinoma (PDAC), a metabolic disorder, remains one of the leading cancer mortality sources worldwide. An initial response to treatments, such as gemcitabine (GEM), is often followed by emergent resistance reflecting an urgent need for alternate therapies. The PDAC GEM could be due ERK1/2 activity. However, successful ERKi therapy hindered low ligand efficiency, poor drug delivery, and toxicity. In this study, overcome these limitations, we have designed pH-responsive nanoparticles (pHNPs) with size range 100–150 nm simultaneous delivery (SCH 772984) tolerable doses. These pHNPs are polyethylene glycol (PEG)-containing amphiphilic polycarbonate block copolymers tertiary amine side chains. They systemically stable capable improving in vitro vivo at cellular environment's acidic pH. functional analysis indicates that nanomolar doses or significantly decreased 50% growth inhibition (IC50) cells when encapsulated compared free drugs. combination displayed synergistic inhibitory effect. Unexpectedly, uncover minimum effective dose promotes activities on cells. Furthermore, found pHNP-encapsulated was superior unencapsulated therapy. Our findings, thus, reveal simple, yet efficient, approach limitations clinical applications present new model sensitization no minimal