Date of Award

2022

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Vivek Gupta

Second Advisor

Vijaya Korlipara

Third Advisor

Abu Serajuddin

Abstract

Malignant Mesothelioma (MM) is a rare malignancy affecting the mesothelial cells lining major physiological tissues. There is currently no cure for MPM and there is a growing need to bolster the therapeutic arsenal for MPM management. With that in mind, multiple small molecules were screened against MPM models, in-vitro, and it was revealed that Niclosamide (Niclo), an anthelmintic drug, was the most potent against MPM (IC50 values between 1.2-2.2 M) with the ability to inhibit colony formation in MPM cells and is efficacious against 3D tumor models. However, small molecule systemic therapy has resulted in negligible improvement in patient survival relative to a local therapy. So, to develop a localized depot therapy for MPM, a hydrogel-based delivery system is being proposed. Using a design of experiment approach, hydrogel formulation was optimized to yield two formulations with low gelling time, high bio adhesion and a sustained release of small molecules. Further, optimized hydrogels were tested for their potential to carry hydrophilic and hydrophobic therapeutic payloads by loading Doxorubicin hydrochloride (DOX) and Niclo. Developed hydrogels sustained the release of DOX over a period of 12 days, indicating an excellent potential to be a local depot therapy. Therapeutic testing on 2D and 3D MPM tumor models revealed enhanced potency of DOX loaded hydrogels, as compared to plain DOX (p<0.0001). On the other spectrum, for loading Niclo on hydrogels, a carrier assisted loading was tested, using a pre-optimized lipid nano emulsion. Physical characterization of lipid nano emulsion loaded hydrogels revealed a significant increase in bio adhesion for hydrogels (p<0.0001), which can be attributed to the loading of lipid nano emulsion. Release of lipid nano emulsion from hydrogels was extremely slow with 33% release over 12 days. Therapeutic testing of Niclo loaded hydrogels revealed excellent efficacy against 2D and 3D MPM tumor models, indicating that loading nano carriers in hydrogels for efficient hydrophobic drug delivery is possible and yields excellent efficacy, in-vitro. This study tries to re-invent malignant pleural mesothelioma therapeutics by repurposing Niclo and by developing a local non-invasive therapy for MPM using hydrogels.

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