pH-triggered charge-reversal and redox-sensitive drug release polymer micelles co-deliver doxorubicin and triptolide for prostate tumor therapy

Abstract

AimTo significantly promote cancer cell uptake and to achieve combination therapy and on-demand drug release, a pH-triggered charge-switchable and redox-responsive drug-release nanovehicle was developed in this study.Materials and methodsThe nanocarrier was constructed by conjugating 3,3′-dithiodipropionic acid-modified doxorubicin (DTPA-DOX) and 2,3-dimethylmaleic anhydride (DMA) to the side amino groups of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) and by encapsulating triptolide (TRI) into the hydrophobic core. The surface charge of the obtained nanocarriers (DA-ss-DT) can change from negative to positive in response to tumor extracellular acidity pH, and the nanocarriers capably release two drugs in response to intracellular high glutathione (GSH) environment.ResultsCompared to the control group, the in vitro cellular uptake of DA-ss-DT by human prostate cancer PC-3 cells was significantly promoted in slightly acidic conditions, and the drug could be rapidly released in the high concentration of GSH conditions. The in vitro and in vivo antitumor experiments exhibited that the DA-ss-DT nanoparticles have a great antitumor effect in comparison to the control group.ConclusionThese findings demonstrated that the DA-ss-DT nanoparticles supply a useful strategy for promoting cellular uptake and synergetic anticancer therapy.

High murine blood persistence of phage T3 and suggested strategy for phage therapy

“…The following data suggest that single-plaque AGE can also screen for high persistence via screening for negative σ high in magnitude. Experience with non-phage drug delivery vehicles has been that overall persistence is increased by negative σ and decreased by positive σ [32, 33], although some innate immune systems do remove particles with negative σ [34].…”

The Application of Nanotechnology in the Codelivery of Active Constituents of Plants and Chemotherapeutics for Overcoming Physiological Barriers during Antitumor Treatment

“…is increased the blood concentration of AMD and half-life of AMD in the plasma. PEG-modi ed nanoparticles, PEG-modi ed grafted polymers, PEG-modi ed polymeric micelles, and PEG-modi ed dendrimers all have been shown to increase the half-life of drugs in blood circulation [43][44][45][46][47]101]. However, several studies also observed that continuous injection of PEG-modi ed nanoparticles could induce immune responses and thus lead to accelerated blood clearance (ABC) [102,103].…”

“…pHresponsive nanocarriers, such as liposomes, nanoparticles, nanogels, polymer-drug conjugates, and micelle, have been designed and reported to have good efficacy and function [127]. Inorganic substances like calcium phosphate, chitosan, closed mesoporous silica nanoparticle pores (MSNPs), and poly(styrene-co-N,N′-dimethylaminoethyl methacrylate nanoparticles (P(St-co-DMAEMA))complexes and mPEG-b-PMaIPG (methoxy-polyethylene glycols (PEG)-bpoly (d-galactopyranose)) nanoparticles have been demonstrated to be sensitive to relatively small pH changes and have good drug release and relatively high antitumor activity [44,49,60,62,63]. Yang et al [61] synthesized the pHsensitive polymer (poly(ethylene glycol)-benzoic iminepoly(gamma-benzyl-l-aspartate)-b-poly(1-vinylimidazole) block copolymer (PPBV) and developed a multistage pHresponsive micelle system for the codelivery of PTX and CUR for the treatment of breast cancer CSCs.…”

<p>Cascade-Targeting of Charge-Reversal and Disulfide Bonds Shielding for Efficient DOX Delivery of Multistage Sensitive MSNs-COS-SS-CMC</p>

“…16,17 The current challenge is to prompt efficient endosomal escape and improve the degradation of nanoparticles in the cytoplasm of cancer cells. 18,19 On the other hand, in view of the pH variation in tumor tissues (pH 6.5-6.9), endo/lysosomes (pH 5.0-5.5) and normal physiological environment (pH 7.4), [20][21][22] pHinduced charge-reversible nanoparticles have been extensively reported to spontaneously improve cellular uptake and controllable drug release through the enhanced permeability and retention effects. 23,24 The negative charge renders nanoparticles with stealth characteristics to avoid non-specific protein binding and prolong retention time.…”