Date of Award

2021

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Vivek Gupta

Second Advisor

Lin Mantell

Third Advisor

Abu Serajuddin

Abstract

New drug and dosage form development faces significant challenges, especially in oncology, due to longer development cycle and associated scale-up complexities. Repurposing of existing drugs with potential anti-cancer activity into new therapeutic regimens provides a feasible alternative. In this project, amodiaquine (AQ), an anti-malarial drug, has been explored for its anti-cancer efficacy through formulating inhalable nanoparticulate systems using high-pressure homogenization (HPH) with scale-up feasibility and high reproducibility. A 32 multifactorial design was employed to better understand critical processes and formulation parameters so as to ensure product quality with improved anticancer efficacy in non-small cell lung cancer (NSCLC). Optimized AQ loaded nanoparticles (AQ NP) were evaluated for physicochemical properties, stability profile, in-vitro aerosol deposition behavior, cytotoxic potential against NSCLC cells in-vitro and in 3D simulated tumor spheroid model while the results confirming the significance of nanoparticle encapsulation for an enhanced anti-cancer efficacy. Furthermore, targeting potential of transferrin ligand conjugated AQ-loaded nanoparticles (Tf-AMQ NPs) was investigated, also evaluated for their physicochemical properties. Tf-AMQ NP (liquid state) exhibited an aerodynamic diameter of 4.4±0.1 µm and fine particle fraction of 83.2±3.0%, indicating drug deposition in the respirable airways. Cytotoxicity studies in NSCLC cell line with overexpressed transferrin receptors revealed significant reduction in IC50 values with Tf-decorated AQ-loaded nanoparticles compared to plain drug or non-targeted NPs, along with significant apoptosis induction (caspase assay) and reduced % colony growth in A549 and H1299 cells with Tf-AMQ NP. Moreover, 3D simulated spheroid studies (~ 7-fold reduction in spheroid volume compared to AMQ NPs) revealed efficacy of conjugated nanoparticles in penetration to tumor core, and growth inhibition. AQ’s autophagy inhibition ability significantly increased with nanoparticle encapsulation and transferrin conjugation. Further, another ligand folic acid has been explored for its ability to be conjugated to nanoparticles and to enhance anti-cancer efficacy and were found to exhibit superior anti-cancer efficacy in multiple cancer types such as breast cancer and cervical cancer. To conclude, amodiaquine can be a promising candidate for repurposing to treat NSCLC while delivering inhalable transferrin conjugated nanoparticles developed using a scalable HPH process to the target site, thus reducing the dose, side effects.

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