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

Abstract

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

Palladium-Catalyzed intramolecular Cyclization of ‘2-bromo-1,5- di-ene-7-yne’System: A Versatile Route to the Poly-ene Substituted Cyclohexenols

“…Several applications and usefulness have been cited in recent publications ranging from natural product derivation to biomedical applications 15,17,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] .…”

CCN5 activation by free or encapsulated EGCG is required to render triple‐negative breast cancer cell viability and tumor progression

“…Western blot analysis was performed to determine the expression levels of the apoptotic proteins, EMT‐related proteins, and CCN5 in untreated and EGCG‐treated BC cell lines using our previous method 26 . Chemiluminescence signal was detected by Super Signal ULTRA Chemiluminescent Substrate (Pierce, Rockford, IL, USA), using ID Image Analysis Software Version 3.6 (Eastman Kodak Company, Rochester, NY, USA).…”

Synthesis and Biological Properties of Coumarin Derivatives. A Review

“…Most of them reported the synthesis and their biological applications in pharmaceutical industry as likely therapeutic molecules. In fact, nanomaterials play a key role in numerous applications whether in the synthesis of interesting heterocyclic building blocks, [147][148][149][150][151][152][153] nanomedicines, [154][155][156][157][158][159][160][161][162][163] or theoretical and physical aspects. [164][165][166][167][168][169][170][171] Currently and as perspective, our research group is interested to investigate a new methodology for the synthesis of polyfunctionalized coumarins adopting multicomponent approaches under sustainable conditions in the presence of iron-based NPs@Layered Double Hydroxides nanocomposites as catalysts.…”