4.7 Article

Repurposing Bedaquiline for Effective Non-Small Cell Lung Cancer (NSCLC) Therapy as Inhalable Cyclodextrin-Based Molecular Inclusion Complexes

Journal

Publisher

MDPI
DOI: 10.3390/ijms22094783

Keywords

bedaquiline; sulfobutylether-beta-cyclodextrin; non-small cell lung cancer; inhalation; molecular docking

Funding

  1. College of Pharmacy and Health Sciences, St. John's University, Queens, NY
  2. College of Pharmacy and Health Sciences at St. John's University
  3. American Heart Association (AHA) [18AIREA33960072]
  4. College of Pharmacy and Health Sciences, St. John's University

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Repurposed drugs show promising efficacy against cancer, with bedaquiline being explored in an inhalable cyclodextrin complex formulation for treating non-small cell lung cancer. The complex demonstrates efficient lung deposition and cytotoxicity, indicating potential for NSCLC treatment.
There is growing evidence that repurposed drugs demonstrate excellent efficacy against many cancers, while facilitating accelerated drug development process. In this study, bedaquiline (BDQ), an FDA approved anti-mycobacterial agent, was repurposed and an inhalable cyclodextrin complex formulation was developed to explore its anti-cancer activity in non-small cell lung cancer (NSCLC). A sulfobutyl ether derivative of beta-cyclodextrin (SBE-beta-CD) was selected based on phase solubility studies and molecular modeling to prepare an inclusion complex of BDQ and cyclodextrin. Aqueous solubility of BDQ was increased by 2.8 x 10(3)-fold after complexation with SBE-beta-CD, as compared to its intrinsic solubility. Solid-state characterization studies confirmed the successful incorporation of BDQ in the SBE-beta-CD cavity. In vitro lung deposition study results demonstrated excellent inhalable properties (mass median aerodynamic diameter: 2.9 +/- 0.6 mu m (<5 mu m) and fine particle fraction: 83.3 +/- 3.8%) of BDQ-CD complex. Accelerated stability studies showed BDQ-CD complex to be stable up to 3 weeks. From cytotoxicity studies, a slight enhancement in the anti-cancer efficacy was observed with BDQ-cyclodextrin complex, compared to BDQ alone in H1299 cell line. The IC50 values for BDQ and BDQ-CD complex were found to be similar to 40 mu M in case of H1299 cell line at 72 h, whereas BDQ/BDQ-CD were not found to be cytotoxic up to concentrations of 50 mu M in A549 cell line. Taken together, BDQ-CD complex offers a promising inhalation strategy with efficient lung deposition and cytotoxicity for NSCLC treatment.

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