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Access Type
WSU Access
Date of Award
January 2022
Degree Type
Thesis
Degree Name
M.S.
Department
Pharmaceutical Sciences
First Advisor
Arun A. Iyer
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common primary malignant neoplasm of the pancreas as it accounts for more than 90% of all pancreatic cancer types. The PDAC microenvironment is made up of malignant cells that are surrounded by desmoplastic stroma, which hinders tumor infiltration by immune cells, thus making PDAC immunologically inert (cold) tumor, which is unresponsive to immunotherapy. Treatment with CD40 agonists and Metformin have been shown to break the desmoplastic ECM to a great extent. However, use of soluble CD40 ligand has been shown to cause systemic toxicity due to non-specific activation of peripheral immune cells. Main goal of the project is to develop ‘pHe-triggered, tumor/stromal cell -adhesive nanoliposomes (pHTANL)’ loaded with CD40 agonist antibody that could be directly cytotoxic to tumor cells and alter the desmoplastic stroma, while also enhancing tumor immune infiltration and activation in PDAC with minimal systemic toxicity. Dynamic light scattering (DLS) and Transmission electron microscopy (TEM) were used to characterization of NLs size and morphology. Subsequently, a fluorescence imaging study using NLs was performed by loading the NLs with FITC dye to confirm the adhesion of to CD40 receptor on the surface of macrophage cells. Efficacy and safety studies of pHTANL-CD40a were performed in vitro/vivo.The TEM/DLS analysis showed well-defined spherical vesicles (pHTANL-CD40a) with a small size of ~100-180 nm that allows tumor targeting by the EPR effect. Furthermore, the choice of lipids in the formulation revealed better NLs adhesion to tumor cells at acidic pH (~5.5-6.5) in comparison to physiological pH (~7.4). The zeta potential determination estimated the surface charges to be -14.7 mV and 37.17 mV at pH 7.4 and pH 6.5, respectively, indicating that the NL preparations were physically stable at physiologic pH. pHTANL-CD40a have achieved sustained release of CD40a in acidic condition, like that in the tumor ECM. pHTANL-CD40a was more effective than free CD40a in activating macrophages in vitro, as determined by the expression of antigen-presentation and co-stimulatory/activation markers MHC class II, CD86 and CD11c. Treatment of Panc02 transplanted C57Bl6 mice with free CD40a significantly reduced the growth of tumor, but the tumors grew rapidly after the treatment was stopped and there was no survival benefit compared to the control groups. Whereas treatment with pHTANL-CD40a further inhibited the tumor growth with a treatment efficacy of 63% with survival up to 30 days, compared to 22 and 24 days in the control and free CD40a, respectively. pHTANL-CD40a delivery can an open new avenue for selectively activating tumor-killing immune cells with less systematic side effects.
Recommended Citation
Althobaiti, Salma, "Reprogramming The Tumor Microenvironment In Pancreatic Cancer By Tme-Targeted Cd40a Nanoliposome" (2022). Wayne State University Theses. 896.
https://digitalcommons.wayne.edu/oa_theses/896