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Van der Waals force-driven indomethacin-ss-paclitaxel nanodrugs for reversing multidrug resistance and enhancing

Wenbo Kang1, Yuanhui Ji1, Yu Cheng1

  • 1Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.

International Journal of Pharmaceutics
|May 9, 2021
PubMed

Insights

This study developed a novel nanodrug by linking indomethacin and paclitaxel. This conjugate effectively reverses multidrug resistance in non-small cell lung cancer by inhibiting MRP1.

Area of Science:

  • Nanomedicine
  • Cancer Therapy
  • Drug Delivery

Background:

  • Multidrug resistance (MDR) mediated by high expression of multidrug resistance-associated protein 1 (MRP1) significantly limits paclitaxel (PTX) efficacy in non-small cell lung cancer (NSCLC).
  • Indomethacin (IND), a non-steroidal anti-inflammatory drug (NSAID), is a potential MRP1 inhibitor.
  • Utilizing established drugs avoids additional biosafety concerns.

Purpose of the Study:

  • To design and synthesize a novel carrier-free nanodrug delivery system (nDDs) to overcome PTX resistance in NSCLC.
  • To investigate the self-assembly, stability, and drug release characteristics of the designed nanodrug.
  • To evaluate the efficacy of the nanodrug in reversing MRP1-mediated MDR.

Main Methods:

  • Conjugation of IND and PTX via a disulfide bond (-S-S-) to form IND-S-S-PTX.
  • Self-assembly of the conjugate into nanodrugs (IND-S-S-PTX NPs) with particle size ~160 nm and PDI 0.099.
  • Molecular dynamics (MD) simulations for self-assembly process and density functional theory (DFT) calculations for driving forces.

Main Results:

  • The IND-S-S-PTX NPs exhibited good water dispersibility and stability.
  • The disulfide bond enabled GSH-sensitive drug release in the tumor microenvironment.
  • The nanodrug successfully reversed MDR in A549/taxol cells by downregulating MRP1 expression.

Conclusions:

  • The developed carrier-free IND-S-S-PTX nanodrug is a promising strategy to overcome paclitaxel resistance in NSCLC.
  • The nanodrug leverages the MRP1 inhibitory properties of indomethacin and the anti-cancer effects of paclitaxel.
  • This approach offers a safe and effective alternative for NSCLC chemotherapy.
Keywords:
IndomethacinMultidrug resistance-associated protein 1NanomedicinePaclitaxelSelf-assembled conjugates

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