Date of Award

2025

Document Type

Dissertation

Degree Name

Pharmaceutical Sciences (Ph.D.)

Department

Pharmaceutical Sciences

First Advisor

Nitesh Kumar Kunda

Second Advisor

Abu Serajuddin

Third Advisor

Ketan Patel

Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, with conventional treatments such as surgery, radiotherapy, and chemotherapy often limited by significant side effects and suboptimal targeting of primary tumor tissues. The poor solubility of existing anticancer drugs further compromises therapeutic efficacy. Consequently, there is an urgent need for targeted therapies to specifically target oncogenic mutations by enhancing therapeutic efficacy while minimizing off-target toxicities. In my dissertation, we focused on exploring nifuroxazide (NIF) as a promising anticancer agent and in novel combination therapy with gefitinib (GEF) to improve therapeutic outcomes, mitigate drug resistance, and reduce adverse effects in NSCLC therapy. Nifuroxazide has significantly inhibited cancer cell proliferation and tumor growth in several NSCLC cell lines. To overcome the limitation of poor solubility and to improve anti-cancer efficacy, NIF-loaded solid lipid nanoparticles (NIF-SLNs) were formulated. NIF-SLNs demonstrated improvement in in vitro tumor cytotoxicity confirming the significance of nanocarriers for improved therapeutic efficacy. Moreover, combining GEF with NIF has shown significant synergistic effects at a 1:2 drug ratio against GEF-resistant cells, resensitizing them to GEF treatment. To deliver this combination effectively, SLNs co-encapsulating GEF and NIF were prepared using ultrasonication followed by spray-drying with an inert carrier, L-Leucine, to create inhalable nanocomposite microparticles. Developing these nanocomposites combined the merits of both nano- and microparticles, ensuring deep lung deposition and efficient uptake into tumor tissue. In addition to efficient drug loading, dry powder nanocomposites have enhanced stability, prevented drug leakage, and provided sustained drug release. Further, the dry powder particles displayed suitable aerosolization characteristics for efficient lung deposition (MMAD 1-5 µm and FPF >75%). Lastly, treatment with dry powder nanocomposites resulted in a 2.5-fold decrease in 3D tumor spheroid size, confirming significant inhibition of tumor growth. Our study's findings were further supported by the fluorescence staining of nanocomposites-treated spheroids, which clearly showed a reduction of live cells. This provided strong evidence that developed inhalable dry powder nanocomposites with novel drug combination can be a promising strategy for NSCLC treatment at a reduced dose, potentially revolutionizing NSCLC treatment.

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