Enhanced Cellular Internalization and On-Demand Intracellular Release of Doxorubicin by Stepwise pH-/Reduction-Responsive Nanoparticles

Abstract

The efficient delivery of antitumor agents to tumor sites faces numerous obstacles, such as poor cellular uptake and slow intracellular drug release. In this regard, smart nanoparticles (NPs) that respond to the unique microenvironment of tumor tissues have been widely used for drug delivery. In this study, novel charge-reversal and reduction-responsive histidine-grafted chitosan-lipoic acid NPs (HCSL-NPs) were selected for efficient therapy of breast cancer by enhancing cell internalization and intracellular pH- and reduction-triggered doxorubicin (DOX) release. The surface charge of HCSL-NPs presented as negative at physiological pH and reversed to positive at the extracellular and intracellular pH of the tumor. In vitro release investigation revealed that DOX/HCSL-NPs demonstrated a sustained drug release under the physiological condition, whereas rapid DOX release was triggered by both endolysosome pH and high-concentration reducing glutathione (GSH). These NPs exhibited enhanced internalization at extracellular pH, rapid intracellular drug release, and improved cytotoxicity against 4T1 cells in vitro. Excellent tumor penetrating efficacy was also found in 4T1 tumor spheroids and solid tumor slices. In vivo experiments demonstrated that HCSL-NPs exhibited excellent tumor-targeting ability in tumor tissues as well as excellent antitumor efficacy and low systemic toxicity in breast tumor-bearing BALB/c mice. These results indicated that the novel charge-reversal and reduction-responsive HCSL-NPs have great potential for targeted and efficient delivery of chemotherapeutic drugs in cancer treatments.

Redox-Sensitive and Hyaluronic Acid-Functionalized Nanoparticles for Improving Breast Cancer Treatment by Cytoplasmic 17α-Methyltestosterone Delivery

“…Thereafter, an equal amount of EDC and NHS (0.05 g) were added to the solution of LA (0.05 g) in ethanol under stirring at 45 • C for 15 min. The amide bonds were formed after addition of CS solution into the LA solution under stirring at 45 • C for 12 h. Afterwards, dialysis tube (12 kDa MWCO) was utilized for 24 h against dH 2 O and finally the freeze-dried NPs were obtained [20].…”

“…[18,19]. Thereafter, MT was encapsulated into the hydrophobic core of the nanoparticle containing a disulfide bond of Lipoic acid (LA) utilized as a reduction part [20].…”

“…HA was absorbed to the surface of the CSLA-NPs via electrostatic interactions between CS and HA, rather than by chemical conjugation [24]. CSLA-NPs were prepared via the acylation reaction between the CS and LA [20]. HA and CSLA-NPs were formed via electrostatic interactions and purified by dialysis method and filtration.…”

<p>Dual Receptor-Targeted and Redox-Sensitive Polymeric Micelles Self-Assembled from a Folic Acid-Hyaluronic Acid-SS-Vitamin E Succinate Polymer for Precise Cancer Therapy</p>

“…Recently, stimuli-responsive micelles have been developed to trigger rapid and complete drug release in tumor cells according to the unique physiological conditions of the tumor microenvironment. 36,37 It is generally known that the concentration of glutathione (GSH) in the tumor intracellular milieu is much higher than that of the extracellular milieu. 38 This redox-heterogeneous environment provides the basis of on-demand drug release at tumor sites.…”

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

“…Previous studies showed that charged-conversional NPs gained satisfactory balance between targeting efficiency and cellular uptake. [11][12][13] Slow and incomplete drug release within tumor cells is another challenge for efficient delivery of antitumor agents since most antitumor drugs achieve their therapeutic effects by reacting with nuclei or organelles.…”