Redox-triggered activation of nanocarriers for mitochondria-targeting cancer chemotherapy

Abstract

The importance of mitochondrial delivery of an anticancer drug to cancer cells has been recognized to improve therapeutic efficacy. The introduction of lipophilic cations, such as triphenylphosphonium (TPP), onto the surface of nanocarriers was utilized to target mitochondria via strong electrostatic interactions between positively charged TPP and the negatively charged mitochondrial membrane. However, the highly positive charge nature of TPP leads to rapid clearance from the blood, decrease of circulation lifetime, and nonspecific targeting of mitochondria of cells. Here, we report a strategy for improving the anticancer efficacy of paclitaxel via redox triggered intracellular activation of mitochondria-targeting. The lipid-polymer hybrid nanoparticles (LPNPs) are composed of poly(d,l-lactide-co-glycolide) (PLGA), a TPP-containing amphiphilic polymer (C-PEG-TPP) and a reduction-responsive amphiphilic polymer (DLPE-S-S-mPEG). The charges of TPP in LPNPs were almost completely shielded by surface coating of a PEG layer, ensuring high tumor accumulation. After uptake by cancer cells, the surface charges of LPNPs were recovered due to the detachment of PEG under intracellular reductive conditions, resulting in rapid and precise localization in mitochondria. This kind of simple, easy and practicable mitochondria-targeting nanoplatform showed high anticancer activity, and the activatable strategy is valuable for developing a variety of nanocarriers for application in the delivery of other drugs.

A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F

“…Nanoparticle is used as drug delivery system to improve therapeutic efficacy by increasing solubility and organ targeting through electrostatic interactions or receptor and/or membrane binding ( Zhou et al, 2017 ).…”

Redox-Responsive Disulfide Bond-Bridged mPEG-PBLA Prodrug Micelles for Enhanced Paclitaxel Biosafety and Antitumor Efficacy

“…On the one hand, the good stability of PPSP and PPCP is attributed to the small CMC of the polymer prodrugs, which produces a satisfying self-assembly behavior. On the other hand, a π-π conjugation effect may occur between PTX molecules in the hydrophilic segment of the polymer prodrugs, which can increase auto-agglutination of the hydrophilic segment and thereby strengthen core agglomeration in micelles (32, 46, 47).…”

“…The change in particle size distribution of PPSP from one peak to two peaks can be interpreted as follows. Disulfide bonds in PPSP molecules break quickly in an environment with a high GSH concentration, which induces the release of a large amount of PTX and disappearance of π-π conjugation between PTX molecules in the micelle cores (32, 46, 47). As a result, the agglomeration force in the hydrophilic segment is weakened, and the micelle immediately collapses.…”

“…In contrast, the particle size and PDI of PPCP changed only slightly after incubation with different concentrations (0 mM, 2 μM, 10 mM, and 40 mM) of GSH solution within 24 h (Figure 5B), demonstrating that PPCP was not redox sensitive. This is likely because the PPCP molecules do not contain disulfide bonds, and the C-C bond that connects mPEG-PBLA and PTX has no redox sensitivity (46, 47).…”

Recent Advances of pH‐Induced Charge‐Convertible Polymer‐Mediated Inorganic Nanoparticles for Biomedical Applications

“…At the tumor sites, the surface charge of the NPs would switch to positive to enhance their adhesion to tumor cells. [ 19 ] Charge conversion would be activated as a response to specific biological signals, such as pH change, [ 20 ] redox status, [ 21 ] reactive oxygen species (ROS) levels, [ 22 ] light, [ 23 ] and enzyme. [ 24 ] Among them, pH shows unique advantages for triggering charge switch, due to the pH differences between the tumor extracellular environment (pH 6.5–6.8) and normal tissues (pH ≈ 7.4).…”