Multifunctional Glycoconjugate Assisted Nanocrystalline Drug Delivery for Tumor Targeting and Permeabilization of Lysosomal-Mitochondrial Membrane

Abstract

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.

Nanocrystals of Poorly Soluble Drugs: Drug Bioavailability and Physicochemical Stability

“…The enhanced permeability, the retention effect, and the endocytosis receptor that were mediated permit the penetration of the docetaxel system into the cells of tumor mass. Excellent tumor inhibition and less unwanted toxicity were demonstrated in vitro and in vivo [ 150 ].…”

<p>Past, Present, and Future of Anticancer Nanomedicine</p>

“… 15 One strategy to adjust the optimal blood circulation time of nanodrugs is to control their polyethylene glycol (PEG)/polylactic acid (PLA) ratio by changing the molecular weight ratios of PEG and PLA. 111 , 112 …”

“…15 One strategy to adjust the optimal blood circulation time of nanodrugs is to control their polyethylene glycol (PEG)/polylactic acid (PLA) ratio by changing the molecular weight ratios of PEG and PLA. 111,112 In some cases, drugs are required to be not only delivered to the targeted tissue, but also into the exact organelle in the tumor cell 111,113,114 by using the intracellular uptake pathways. 111 A conventional target organelle is the mitochondria, since mitochondria attack can deprive the tumor of its energy.…”

“…111,115,116 As mentioned above, nanodrugs have shown great results for tumor targeting, but have shown clearance issues and immune toxicity that still hamper the use of nanodrugs to destroy cancer cells. 112,117 Therefore, to apply these nanodrugs in the clinic, developments must be made to avoid the potential side effects. However, instead of reforming nanodrugs to minimize side effects, other methods of utilizing nanodrugs have been introduced, which is a topic that will be discussed later on.…”

“…Although the clinical application of conventional anticancer nanodrugs was unsuccessful, nanomedical cancer treatment is still considered a promising approach. 112,117,206 This approach includes the use of NPs to stimulate the immune system rather than to directly release cytotoxic anticancer drugs to the cancer cells. Historically, previous approaches of nanodrug therapy focused on direct attacking cancer cells or transporting cytotoxic drugs into cancer cells.…”