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Multifunctional Glycoconjugate Assisted Nanocrystalline Drug Delivery for Tumor Targeting and Permeabilization of Lysosomal-Mitochondrial Membrane.
ACS Applied Materials & Interfaces 2018 May 24
Nanotechnology has emerged as the most successful strategy for targeting drug payloads to tumors with the potential to overcome the problems of low concentration at the target site, nonspecific distribution, and untoward toxicities. Here, we synthesized a novel polymeric conjugate comprising chondroitin sulfate A and polyethylene glycol using carbodiimide chemistry. We further employed this glycoconjugate possessing the propensity to provide stability, stealth effects, and tumor targeting via CD44 receptors, all in one, to develop a nanocrystalline system of docetaxel (DTX@CSA-NCs) with size < 200 nm, negative zeta potential, and 98% drug content. Taking advantage of the enhanced permeability and retention effect coupled with receptor mediated endocytosis, the DTX@CSA-NCs cross the peripheral tumor barrier and penetrate deeper into the cells of tumor mass. In MDA-MB-231 cells, this enhanced cellular uptake was observed to exhibit a higher degree of cytotoxicity and arrest in the G2 phase in a time dependent fashion. Acting via a mitochondrial-lysosomotropic pathway, DTX@CSA-NCs disrupted the membrane potential and integrity and outperformed the clinically used formulation. Upon intravenous administration, the DTX@CSA-NCs showed better pharmacokinetic profile and excellent 4T1 induced tumor inhibition with significantly less off target toxicity. Thus, this glycoconjugate stabilized nanocrystalline formulation has the potential to take nano-oncology a step forward.
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