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

Abstract
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.
AuthorsXiaoli Zeng, Xu Cheng, Yan Zheng, Guoqing Yan, Xin Wang, Jun Wang, Rupei Tang
JournalCarbohydrate polymers (Carbohydr Polym) Vol. 237 Pg. 116139 (Jun 01 2020) ISSN: 1879-1344 [Electronic] England
PMID32241443 (Publication Type: Journal Article)
CopyrightCopyright © 2020 Elsevier Ltd. All rights reserved.
Chemical References
  • Dextrans
  • Drug Carriers
  • Micelles
  • Doxorubicin
  • Indomethacin
Topics
  • Adenocarcinoma (drug therapy)
  • Animals
  • Breast Neoplasms (drug therapy)
  • Dextrans (chemistry)
  • Doxorubicin (administration & dosage)
  • Drug Carriers (therapeutic use)
  • Drug Resistance, Multiple (drug effects)
  • Drug Resistance, Neoplasm (drug effects)
  • Female
  • Humans
  • Indomethacin (chemistry)
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Micelles
  • Nanoparticles (therapeutic use)

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