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

Abstract

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.

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] .…”

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.…”

Domino Suzuki-Miyaura Cross-Coupling and Oxidative Condensation Reaction: An Approach Towards Synthesis of Phenanthridine and Its Analogues

“…1, 4), 24 antibacterial, anti-infectives, antprotozoal, antituberculosis, antitrypanosomiasis compounds 5,18,19,[25][26][27][28][29][30][31][32] . The phenanthridine ring systems are also used in lockable colorimetric fluorescence molecular switch, PET tracers, and in material science applications 4,15,22,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] .…”