Stepwise pH-responsive nanoparticles for enhanced cellular uptake and on-demand intracellular release of doxorubicin

Abstract

Physicochemical properties, including particle size, zeta potential, and drug release behavior, affect targeting efficiency, cellular uptake, and antitumor effect of nanocarriers in a formulated drug-delivery system. In this study, a novel stepwise pH-responsive nanodrug delivery system was developed to efficiently deliver and significantly promote the therapeutic effect of doxorubicin (DOX). The system comprised dimethylmaleic acid-chitosan-urocanic acid and elicited stepwise responses to extracellular and intracellular pH. The nanoparticles (NPs), which possessed negative surface charge under physiological conditions and an appropriate nanosize, exhibited advantageous stability during blood circulation and enhanced accumulation in tumor sites via enhanced permeability and retention effect. The tumor cellular uptake of DOX-loaded NPs was significantly promoted by the first-step pH response, wherein surface charge reversion of NPs from negative to positive was triggered by the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response in endo/lysosome acidic environment elicited the on-demand intracellular release of DOX from NPs, thereby increasing cytotoxicity against tumor cells. Furthermore, stepwise pH-responsive NPs showed enhanced antiproliferation effect and reduced systemic side effect in vivo. Hence, the stepwise pH-responsive NPs provide a promising strategy for efficient delivery of antitumor agents.

Chitosan-Based Nanomaterials for Drug Delivery

“…Zhang et al developed stepwise pH-responsive nanoparticles to release doxorubicin on demand [ 140 ]. The nanoparticles contained pH responsive dimethylmaleic acid and urocanic acid, and the DOX-loaded NPs could stepwise response to extracellular and intracellular pH after being injected to the tumor bearing mice.…”

Chitosan as a Natural Copolymer with Unique Properties for the Development of Hydrogels

“…Several drugs and polyphenolsencapsulated inside chitosan moieties were synthesized such as catechin and epigallocatechin [16], tamoxifen [17], alendronate sodium [18], insulin [19] and peptide [20]. These nanoparticles are delivered in severalapproachesincluding injection drug delivery [21], topical drug delivery [22], colon-targeted drug delivery [23], carcinoma therapy [24] and gene delivery [25]. They are further administrated as oral delivery, injectable delivery, or in cream like form (See Table 1).…”

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

“…33 Furthermore, the nanoparticles exhibited significant accumulation in the liver and spleen, which might be due to the capture of reticular endothelial system. 50…”

“…21,29 Therefore, many surface charge-switchable nanoparticles have been developed for drug delivery. [30][31][32] These nanoparticles could maintain negative surface charge under blood circulation, while quickly changing to positive charge at the slightly acidic tumor tissues. For example, Yuan et al 33 reported a chargereversal nanoparticle based on zwitterionic polymers, and this nanoparticle could effectively enhance cellular uptake.…”