A Smart pH-Sensitive Delivery System for Enhanced Anticancer Efficacy via Paclitaxel Endosomal Escape

Abstract

Micelles are highly attractive nano-drug delivery systems for targeted cancer therapy. While they have been demonstrated to significantly alleviate the side-effects of their cargo drugs, the therapy outcomes are usually suboptimal partially due to ineffective drug release and endosome entrapment. Stimulus-responsive nanoparticles have allowed controlled drug release in a smart fashion, and we want to use this concept to design novel micelles. Herein, we reported pH-sensitive paclitaxel (PTX)-loaded poly (ethylene glycol)-phenylhydrazone-dilaurate (PEG-BHyd-dC12) micelles (PEG-BHyd-dC12/PTX). The micelles were spherical, with an average particle size of ∼135 nm and a uniform size distribution. The pH-responsive properties of the micelles were certified by both colloidal stability and drug release profile, where the particle size was strikingly increased accompanied by faster drug release as pH decreased from 7.4 to 5.5. As a result, the micelles exhibited much stronger cytotoxicity than the pH-insensitive counterpart micelles against various types of cancer cells due to the hydrolysis of the building block polymers and subsequent rapid PTX release. Overall, these results demonstrate that the PEG-BHyd-dC12 micelle is a promising drug delivery system for cancer therapy.

Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease

“…It inhibits proliferation, viability, and repair capabilities impairing nitric oxide (NO) signaling or increasing its permeability [167]. TMAO, a gut metabolite derived from the fermentation of dietary choline/phosphatidylcholine, L-carnitine or betaine, also induces endothelial damage, with activation of NALP3 inflammasome [168], cellular inflammation, ROS production, and has been associated with atherothrombosis [169].…”

Nanoscopy for endosomal escape quantification

“…Whilst significant progress has been made on developing a rich formulation databank of NP for cytosolic delivery (16,17), our understanding of the physiochemical and biological requisites for achieving endosomal escape has loitered (20,(26)(27)(28)(29)(30)(31). Our grasp of these mechanisms is hampered by the limitations of the standard techniques used to localise and quantify them.…”

“…1). Endosomal entrapment thus represents one of the main bottlenecks in using NP systems for gene therapy (20,(26)(27)(28) and proteins or small molecular drugs for the treatment of a variety of diseases (20,(29)(30)(31).…”

Interaction of small molecules with the SARS-CoV-2 main protease in silico and in vitro validation of potential lead compounds using an enzyme-linked immunosorbent assay

“…300 compounds were selected for screening against M pro . This comprised of 211 phenolic compounds and 13 fatty acids sourced from the OliveNet™ Library ( Bonvino et al, 2018 ), and an additional 76 ligands based on known protease inhibitors and antibiotics, as well as compounds with antiviral, anti-inflammatory, anti-parasitic, anti-malarial, antioxidant and anti-ageing properties ( Yan et al, 2020 ; Zakaryan et al, 2017 ; Agbowuro et al, 2018 ; Agostini et al, 2018 ; Amici et al, 2006 ; Chan et al, 2017 ; Chen et al, 2019a ; Davies, 2010 ; Gbinigie and Frie, 2020 ; Huemer, 2015 ; Ichikawa et al, 2013 ; Khaerunnisa et al, 2020 ; Kim et al, 2019a , 2018 ; Krueger et al, 2015 ; Liang et al, 2020a ; Lin et al, 2018 , 2017 ; Lu et al, 2017 ; Moghadamtousi et al, 2014 ; Moghaddam et al, 2014 ; Mohammadi Pour et al, 2019b ; Richardson et al, 2020 ; Rogosnitzky et al, 2020 ; Vankadari, 2020 ; Zhou et al, 2020a , b ). A full list of the ligands that were screened can be found in the supplementary information (Table S1).…”