Indomethacin-grafted and pH-sensitive dextran micelles for overcoming inflammation-mediated multidrug resistance in breast cancer

[Display omitted] •IND-grafted dextran micelles by acetal linkage with loading DOX overcomed tumor MDR.•These micelles showed an accelerated drug release at acid tumor environments.•IND efficiently increased intracellular DOX concentration by reducing MPR1 levels.•IND could remove apoptosis-resistan...

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Bibliographic Details
Published in:Carbohydrate polymers 2020-06, Vol.237, p.116139-116139, Article 116139
Main Authors: Zeng, Xiaoli, Cheng, Xu, Zheng, Yan, Yan, Guoqing, Wang, Xin, Wang, Jun, Tang, Rupei
Format: Article
Language:English
Subjects:
Dextran
Indomethacin
Multidrug resistance
pH-sensitivity
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Summary:[Display omitted] •IND-grafted dextran micelles by acetal linkage with loading DOX overcomed tumor MDR.•These micelles showed an accelerated drug release at acid tumor environments.•IND efficiently increased intracellular DOX concentration by reducing MPR1 levels.•IND could remove apoptosis-resistance by down-regulating bcl-2/bax rate.•These particles possessed higher antitumor effect and excellent biosafety. We first synthesized indomethacin (IND)-grafted dextran copolymer by acetal or ester linkage, which self-assembled with doxorubicin (DOX) into prodrug micelles (IDAC/DOX or IDES/DOX) with the size of ∼200 nm. In vitro drug release test verified IDAC/DOX could trigger more DOX and IND release by the hydrolysis of acetal than that of ester linkage. A series cells experiments demonstrated pH-sensitive IDAC/DOX could greatly improve cellular uptake and intracellular drug accumulation, thus enhancing DOX toxicity in drug-resistant tumor cells. IDAC/DOX was capable of reversing tumor multidrug resistance (MDR) through reducing multidrug resistance-associated protein 1 (MRP1) level (0.23-fold vs control group) and regulating bcl-2/bax pathway, eventually induced more apoptosis in MCF-7/ADR cells. These nanoparticles possessed long-term blood-circulation and high tumor accumulation, thereby reducing side effect and increasing bioavailability. Anti-tumor evaluation showed that IDAC/DOX possessed the highest tumor growth inhibition (TGI, 92.5 %), which might provide a promising way to overcome malignant tumor resistance.
ISSN:0144-8617
1879-1344
DOI:10.1016/j.carbpol.2020.116139