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ACS Appl Mater Interfaces. 2018 Oct 10;10(40):33923-33935. doi: 10.1021/acsami.8b11159. Epub 2018 Sep 27.

Design of Tumor Microenvironment-Responsive Drug-Drug Micelle for Cancer Radiochemotherapy.

Author information

1
Brain Hospital , Affiliated Hospital of Xuzhou Medical University , Xuzhou 221002 , P. R. China.
2
The People's Hospital of Jiawang District of Xuzhou , Affiliated Hospital of Xuzhou Medical University Jiawang Branch of Xuzhou , Xuzhou 221000 , P. R. China.
3
Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, School of Chemistry & Materials Science , Jiangsu Normal University , Xuzhou 221002 , P. R. China.

Abstract

Concomitant radiochemotherapy is a major therapeutic strategy for treating malignant tumors. However, the greatest challenge is how to improve the therapeutic effect of radiochemotherapy to achieve the proper synergetic chemo-/radiotherapy for the tumor. In this study, ferrocenium (antitumor effect) and nitroimidazole (hypoxic cell radiosensitization) conjugates were synthesized to form amphiphilic ferrocenium-hexane-nitroimidazole (Fe-NI), which can self-assemble in aqueous solution. The Fe-NI micelles successfully encapsulate the hydrophobic chemotherapy drug doxorubicin (DOX) and are modified with hyaluronic acid (HA) by electrostatic interactions to form HA-Fe-NIs-DOX micelles. HA-Fe-NIs-DOX micelles rapidly release DOX under tumor hypoxia and a high glutathione (GSH) environment and achieve a synergetic chemo-/radiotherapy for the tumor based on the properties of nitroimidazoles and ferrocenes. The biodistribution results obtained in vivo reveal an effective accumulation in the tumor. The HA-Fe-NIs-DOX micelles show a significant radiosensitizing effect on the tumors, and the combination of chemotherapy and radiotherapy is realized for the treatment of tumor in vitro and in vivo. These findings illustrate that HA-Fe-NIs micelles are a promising candidate, which enhances the antitumor effects as a DOX delivery system, owing to the synergistic mechanisms of antitumor agents and chemo-/radiotherapy.

KEYWORDS:

hypoxia and reduction-responsive; micelle; prodrug; radiosensitization; synergetic chemo-/radiotherapy

PMID:
30205681
DOI:
10.1021/acsami.8b11159
[Indexed for MEDLINE]

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