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Redox-triggered mitoxantrone prodrug micelles for overcoming multidrug-resistant breast cancer

Hongzhi Qiao1, Zhenzhu Zhu2, Dong Fang1

  • 1a Jiangsu Engineering Research Centre for Efficient Delivery System of TCM, School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.

Journal of Drug Targeting
|June 7, 2017
PubMed

Insights

This study developed a novel TPGS-based micelle (TSMm) prodrug that effectively reverses multidrug resistance (MDR) in cancer cells. TSMm demonstrates potent antitumor activity with minimal side effects, offering a promising strategy for cancer chemotherapy.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Cancer Research

Background:

  • Multidrug resistance (MDR) significantly limits the effectiveness of cancer chemotherapy.
  • d-α-Tocopherol polyethylene 1000 succinate (TPGS) shows potential in overcoming MDR by re-sensitizing resistant cancer cells.

Purpose of the Study:

  • To synthesize and characterize a TPGS-based prodrug micelle (TSMm) loaded with mitoxantrone (MTO) for enhanced cancer treatment.
  • To evaluate the efficacy of TSMm in reversing MDR in cancer cells and its antitumor activity in vivo.

Main Methods:

  • Synthesis of a TPGS-MTO prodrug via a disulfide bond, assembled into micelles (TSMm) with a diameter of ~46.5 nm.
  • In vitro cytotoxicity assays using MDA-MB-231/MDR cells, intracellular retention studies, and ATP activity assessment.
  • In vivo antitumor efficacy studies in xenograft nude mice and tumor targeting verification using imaging.

Main Results:

  • TSMm micelles effectively delivered MTO in a glutathione- (GSH-) responsive manner, leading to rapid drug release within tumor cells.
  • TSMm demonstrated superior inhibition of resistant breast tumor cell growth compared to free MTO or non-cleavable micelles.
  • TSMm promoted MTO nuclear accumulation, reversed MDR, showed specific tumor targeting, and exhibited significant antitumor effects with negligible side effects in vivo.

Conclusions:

  • TSMm represents a promising prodrug candidate for overcoming MDR in cancer.
  • The disulfide bond-mediated drug release mechanism enhances therapeutic outcomes and reduces systemic toxicity.
Keywords:
MitoxantroneTPGSmultidrug resistanceprodrug micellesredox-sensitive

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