Enhanced Cellular Internalization and On-Demand Intracellular Release of Doxorubicin by Stepwise pH-/Reduction-Responsive Nanoparticles
| Autor: | Chen-xi Qu, Yang Liu, Ye-juan Zhou, Wei-liang Chen, Shu-di Yang, Fang Li, Xue-nong Zhang, Zhi-qiang Yuan, Ji-zhao Li, Wen-jing Zhu, Chun Liu, Xiao-feng Zhou, Ben-gang You |
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| Rok vydání: | 2016 |
| Předmět: |
Materials science
media_common.quotation_subject Intracellular pH education PH reduction 02 engineering and technology Pharmacology 010402 general chemistry 01 natural sciences Mice Drug Delivery Systems medicine Extracellular Animals Humans General Materials Science Doxorubicin Internalization health care economics and organizations media_common Drug Carriers Mice Inbred BALB C technology industry and agriculture Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology Endolysosome 0104 chemical sciences Drug Liberation Drug delivery Biophysics Nanoparticles 0210 nano-technology Intracellular medicine.drug |
| Zdroj: | ACS applied materialsinterfaces. 8(47) |
| ISSN: | 1944-8252 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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