Abstract
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.
Highlights
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide and has drawn significant attention from researchers in the field [1]
We developed bedaquiline-cyclodextrin inclusion complex to improve aqueous solubility of BDQ which further assists in achieving enhanced anti-tumoral effectiveness
The band of -OH group of SBE-β-CD at 3380 cm−1 was observed to be smoothened, which may be due to involvement in intermolecular hydrogen bonding with BDQ molecules during complexation, indicating BDQ’s successful encapsulation inside the hydrophobic cavity of SBE-β-CD molecule. These results provide an insight about incorporation of several functional groups of BDQ in the cavity of SBE-βCD molecule during inclusion process
Summary
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide and has drawn significant attention from researchers in the field [1]. With increased resistance to conventional anti-cancer therapeutics and severe systemic toxicities observed with newer treatment modalities, there is a dire need to discover and develop new therapeutics and delivery systems to achieve safe and efficacious medications [2]. To overcome this emerging challenge, repurposing of old drugs has gained much traction and has led to the identification of some promising FDA-approved drugs for lung cancer treatment [3,4]. Diaryl quinolines demonstrating cytotoxic activity against different cancer types lead to the identification of anti-cancer efficacy of bedaquiline (BDQ) [8,9]
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