pH and Reduction Dual-Sensitive Copolymeric Micelles for Intracellular Doxorubicin Delivery

Abstract

This study develops novel pH and reduction dual-sensitive micelles for the anticancer drug doxorubicin (DOX) delivery owing to the fact that the tumor tissues show low pH and high reduction environment. These sub-100 nm micelles present a core-shell structure under physiological conditions, but quickly release the loaded drugs responding to acidic and reductive stimuli. With disulfide bonds in each repeat unit of poly(β-amino ester)s, the novel copolymer was synthesized via Michael addition polymerization from 2,2'-dithiodiethanol diacrylate, 4,4'-trimethylene dipiperidine, and methoxy-PEG-NH(2). DOX released faster from micelles in a weakly acidic environment (pH 6.5) than at pH 7.4 or in the presence of a higher concentration (5 mM) of reducing agent (DTT). The release is even more effective in a scenario of both stimuli (pH 6.5 and 5 mM DTT). MTT assay showed that the DOX-loaded micelles had a higher cytotoxicity for HepG2 tumor cells than DOX at higher concentrations, and that blank micelles had a very low cytotoxicity to the tumor cells. Confocal microscopy observation showed that the micelles can be quickly internalized, effectively deliver the drugs into nuclei, and inhibit cell growth. These results present the copolymer as a novel and effective pH and reduction dual-responsive nanocarrier to enhance drug efficacy for cancer cells.

Self-assembly of pH-sensitive fluorinated peptide dendron functionalized dextran nanoparticles for on-demand intracellular drug delivery

“…Within the last decade, persistent efforts have been made in the development of stimuli-responsive drug delivery systems that can, when exposed to external stimuli, produce physicochemical changes that favor drug release at the target site. Depending on the target, typical biological stimuli have been exploited for triggered drug release including temperature [1], pH [2][3][4], magnetic field [5,6], redox potential [7][8][9], enzymes [10][11][12] or two parameters at the same time [13][14][15]. pH controlled release systems are particularly more interesting because we can find physiologically the pH gradients relevant for drug targeting.…”

Reduction-Responsive Polymeric Micelles and Vesicles for Triggered Intracellular Drug Release

“…injection. Reduction and pH dual-sensitive SCL micelles were developed via self-assembly of aldehydecontaining P(OEGMA-co-p-(methacryloxyethoxy)benzaldehyde)-b-PCL diblock copolymer in NH 4 OAc buffer followed by cross-linking using difunctional dithiolbis (propanoic dihydrazide) (25). These dual-sensitive SCL micelles, although greatly retarded CPT release at pH 7.4, exhibited the fastest CPT release in response to 10 mM DTT at pH 5.0, which was comparable to that of NCL control.…”

Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment

“…Many previous studies have reported that drug delivery vehicles with pH-sensitive chemical bonds accelerate drug delivery and cause release at a lower pH. 16,17 Iron oxide nanoparticles (IONPs), a promising magnetic resonance imaging (MRI) agent, are extensively used in the field of cancer theranostics; they facilitate the description of targeted therapeutic drugs and the diagnosis of the lesion areas. 18,19 Researchers have verified that external magnetic induction allows DOX-containing nanoparticles to preferentially concentrate at the tumor site, and thereby increase the drug levels for an enhanced therapeutic effect.…”