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Gankyrin is an oncoprotein responsible for the development of numerous cancer types. It regulates the expression levels of multiple tumor suppressor proteins (TSPs) in liver cancer; however, gankyrin's regulation of these TSPs in breast and lung cancers has not been thoroughly investigated. Additionally, no small-molecule gankyrin inhibitor has been developed which demonstrates potent anti-proliferative activity against gankyrin overexpressing breast and lung cancers. Herein, we are reporting the structure-based design of gankyrin-binding small molecules which potently inhibited the proliferation of gankyrin overexpressing A549 and MDA-MB-231 cancer cells, reduced colony formation, and inhibited the growth of 3D spheroids in an

Aim: This study was designed to develop and test nintedanib-loaded niosomes as inhalable carriers for enhancing its therapeutic efficacy via localized drug accumulation and addressing issues such as low bioavailability and severe toxicity. Methods: Niosomes were prepared by thin-film hydration method and were evaluated for in vitro therapeutic effectiveness in lung cancer cells. Results: The optimized niosomal formulation displayed optimized vesicle size, controlled and extended release of drug, and efficient aerodynamic properties indicating its suitability as an aerosolized formulation. In vitro studies revealed significantly superior cytotoxicity of nintedanib-loaded niosomes which was further validated by 3D spheroids. Conclusion: These findings establish the effectiveness of niosomes as inhalable delivery carriers which could serve as a promising strategy for delivery of nintedanib to treat several lung cancers.

Applicability of hydrogels as drug delivery systems is on the rise due to their highly tunable degree of polymeric crosslinking to attain varying rates of payload release. Sustaining the release of therapeutic payloads at certain physiological sites has been the need of the hour to treat disorders such as peritoneal or pleural malignancies. These disorders can be targeted

Nelfinavir (NFV), a FDA approved antiretroviral drug, has been reported to exhibit cancer cells growth inhibition and increased apoptosis. However, it requires a higher dose leading to toxicity, thus limiting its potential clinical translation. We aim to develop biodegradable (poly (lactic-co-glycolic acid)) PLGA nanoparticles of nelfinavir and determine their efficacy to treat non-small cell lung cancer (NSCLC). HIV protease inhibitor, NFV, was loaded into PLGA nanoparticles by double emulsion/solvent evaporation method; and nanoparticles were characterized for physicochemical characteristics including morphology and intracellular uptake. Their anti-cancer efficacy in NSCLC was assessed by in vitro assays including cytotoxicity, cellular migration, colony formation; and 3D spheroid culture mimicking in-vivo tumor microenvironment. Studies were also conducted to elucidate effects on molecular pathways including apoptosis, autophagy, and endoplasmic stress. NFV loaded PLGA nanoparticles (NPs) were found to have particle size: 191.1 ± 10.0 nm, zeta potential: −24.3 ± 0.9 mV, % drug loading: 2.5 ± 0.0%; and entrapment efficiency (EE): 30.1 ± 0.5%. NFV NP inhibited proliferation of NSCLC cells compared to NFV and exhibited significant IC50 reduction. From the caspase-dependent apoptosis assays and western blot studies (upregulation of ATF3), it was revealed that NFV NP significantly induced ER stress marker ATF3, cleaved PARP and further caused autophagy inhibition (LC3BII upregulation) leading to increased cellular death. In addition, NFV NP were found to be more efficacious in penetrating solid tumors in ex-vivo studies compared to plain NFV. Nelfinavir, a lead HIV protease inhibitor can be repositioned as a NSCLC therapeutic through nanoparticulate delivery. Given its ability to induce apoptosis and efficient tumor penetration capability, NFV loaded PLGA nanoparticulate systems provide a promising delivery system in 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 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 (&lt, 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.