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

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

In Depth Analysis of Pressure-Sensitive Adhesive Patch-Assisted Delivery of Memantine and Donepezil Using Physiologically Based Pharmacokinetic Modeling and in Vitro/in Vivo Correlations

The objective of this work was to evaluate the feasibility of transdermal delivery of two widely prescribed dementia drugs for the Alzheimer’s disease. In this regard, the drug in adhesive patches of memantine (ME) co-loaded with donepezil (DO) was prepared using an ethylene vinyl acetate polymer and characterized for drug content, the crystallinity of drugs in the polymer matrix, and in vitro permeation. To understand the different physical and chemical processes underlying the percutaneous absorption, it is required to employ a comprehensive model that accounts for the anatomy and physiology of the skin. A transdermal physiologically based pharmacokinetic (TPBPK) model was developed and was integrated in a compartmental pharmacokinetic model to predict the plasma drug concentrations in rats. The model predictions showed a good fit with the experimental data, as evaluated by the prediction error calculated for both drugs. It was evident from the simulations that the drug diffusivity and partition coefficient in the polymer matrix are the critical parameters that affect the drug release from the vehicle and subsequently influence the in vivo pharmacokinetic profile. Moreover, a correlation function was built between the in vitro permeation data and in vivo absorption for both ME and DO. A good point-to-point in vitro/in vivo correlation (IVIVC, Level A correlation) was achieved by predicting the plasma concentrations with convolution for the entire study duration. The results of our study suggested that the implementation of mechanistic modeling along with IVIVC can be a valuable tool to evaluate the relative effects of formulation variables on the bioavailability from transdermal delivery systems

Vitamin B6 Tethered Endosomal pH Responsive Lipid Nanoparticles for Triggered Intracellular Release of Doxorubicin

This study reports the development of Vitamin B6 (VitB6) modified pH sensitive charge reversal nanoparticles for efficient intracellular delivery of Doxorubicin (DOX). Herein, VitB6 was conjugated to stearic acid, and the nanoparticles of the lipid were formulated by solvent injection method (DOX-B6-SA-NP). Because of the p<i>K</i>_a (5.6) of VitB6, DOX-B6-SA-NP showed positive charge and enhanced release of DOX at pH 5. Confocal microscopy illustrated that DOX-B6-SA-NP treatment kept higher DOX accumulation inside the cells than conventional pH insensitive lipid nanoparticles (DOX-SA-NP). The cationic charge of nanoparticles subsequently facilitated the endosomal escape and promoted the nuclear accumulation of DOX. Furthermore, in vitro cytotoxicity, apoptosis, cell cycle arrest, and mitochondrial membrane depolarization studies supported the enhanced efficacy of DOX-B6-SA-NP in comparison to free DOX and DOX-SA-NP. Intravenous pharmacokinetics and biodistribution investigations indicated that pH sensitive nanoparticles can significantly prolong the blood circulation time of DOX in biological system and increase the drug accumulation to tumor site. Consequent to this, DOX-B6-SA-NP also exhibited much enhanced therapeutic efficacy and lower toxicity in tumor-bearing rats compared to free DOX. The reduction in toxicity was confirmed by histological and survival analysis. In conclusion, these results suggest that the VitB6 modified charge reversal nanoparticles can be a novel platform for the successful delivery of anticancer drugs