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

Autor: Aaron Muth, Mimansa Goyal, Rasha Elbatanony, Srikanth Kolluru, Tejashri Chavan, Vineela Parvathaneni, Nathan Vega, Vivek Gupta, Nitesh K. Kunda
Rok vydání: 2021
Předmět:
Models
Molecular
0301 basic medicine
Lung Neoplasms
Antitubercular Agents
non-small cell lung cancer (NSCLC)
02 engineering and technology
Pharmacology
chemistry.chemical_compound
Carcinoma
Non-Small-Cell Lung
Biology (General)
bedaquiline
Diarylquinolines
Solubility
Cytotoxicity
Spectroscopy
chemistry.chemical_classification
inhalation
Drug Carriers
Antibiotics
Antineoplastic
Inhalation
Cyclodextrin
beta-Cyclodextrins
General Medicine
021001 nanoscience & nanotechnology
Computer Science Applications
Chemistry
0210 nano-technology
QH301-705.5
sulfobutylether-β-cyclodextrin
Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
Cell Line
Tumor
Administration
Inhalation
medicine
Humans
Physical and Theoretical Chemistry
QD1-999
Molecular Biology
non-small cell lung cancer
A549 cell
Organic Chemistry
Drug Repositioning
molecular docking
medicine.disease
In vitro
030104 developmental biology
chemistry
A549 Cells
Bedaquiline
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 4783, p 4783 (2021)
Volume 22
Issue 9
ISSN: 1422-0067
Popis: 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 β-cyclodextrin (SBE-β-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 × 103-fold after complexation with SBE-β-CD, as compared to its intrinsic solubility. Solid-state characterization studies confirmed the successful incorporation of BDQ in the SBE-β-CD cavity. In vitro lung deposition study results demonstrated excellent inhalable properties (mass median aerodynamic diameter: 2.9 ± 0.6 µm (<
5 µm) 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 ~40 µM in case of H1299 cell line at 72 h, whereas BDQ/BDQ-CD were not found to be cytotoxic up to concentrations of 50 µM in A549 cell line. Taken together, BDQ-CD complex offers a promising inhalation strategy with efficient lung deposition and cytotoxicity for NSCLC treatment.
Databáze: OpenAIRE
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