Browsing by Author "Mirab, Fereshteh"
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Item Development, Characterization, and Performance Evaluation of Nanoliposomes with Tunable Rigidity for Delivery Applications(2022-12-13) Mirab, Fereshteh; Litvinov, Dmitri; Mohan, Chandra; Raghunathan, Vijaykrishna; Wu, Tianfu; Majd, SheereenNanoparticle-based delivery systems have emerged as a promising platform for delivery of therapeutics and diagnostics to specific sites in the body. To date, some of the nanocarrier’s physicochemical properties including size, shape, and surface chemistry, are well established as key factors for their delivery performance. Recent studies have suggested that the mechanical properties of nanoparticles can also influence their performance as delivery carriers. This rather new aspect of nanoparticles that may provide new avenues for improving drug delivery, remains unexplored in nanoliposomes -one of the most successful delivery carriers developed to date. The goal of this doctoral project is to develop nanoliposomes with tunable rigidity, characterize their physical and mechanical properties, and investigate the role of nanoliposomes’ rigidity in their cellular interactions to provide an improved understanding of the significance of nanoparticles’ mechanics for their delivery applications. One focus of this study is development and characterization of nanoliposomes with various rigidity levels. To enable tuning the liposomal mechanical properties without changing their other physicochemical properties, we prepared nanoliposomes with cores of hydrogels of various compositions and thus, mechanics. Two biocompatible and biodegradable hydrogels, poly(ethylene glycol) diacrylate (PEGDA) and alginate, were used as the liposome core at various compositions, and the resultant gel-core nanoliposomes (GNLs) were characterized for size distribution, morphology, and surface potential. Next, the mechanical properties of the resultant GNLs was assessed. To this end, we initially evaluated the mechanical properties of bulk hydrogels at different compositions using rheological measurements and compression testing to determine hydrogels’ elastic modulus as a function of their composition. Subsequently, we precisely assessed the mechanical properties of the GNLs in nanoscale using atomic force microscopy (AFM). Upon careful optimization of these experiments, we successfully imaged the GNLs via AFM and determined their Young’s modulus by single particle indentation. Ultimately, we focus on the effect of particles’ rigidity on their cellular interactions including cellular uptake using different cell types (glioblastoma tumor cells, brain endothelial cells, astrocytes, and spleen immune cells) as well as their transport across an in vitro blood-brain-barrier (BBB) model. Briefly, nanoliposomes with more rigidity demonstrated higher cellular uptake compared to their softer counterparts. However, the ability of GNLs to cross the BBB was not affected by their rigidity. Similarly, exocytosis assay of GNLs on endothelial cells indicated this rigidity independency. Further, the effect of particles’ elasticity on their cellular interaction on immune cells was investigated. Particularly, particles with medium rigidity showed the highest cellular uptake on macrophages. The findings of this research can lead to improved nanotherapeutics’ design for enhanced delivery to diseased tissues.Item Preparation of Alginate Encapsulating Nanoliposomes for Drug Delivery(2021-04-01) Patel, Dhriti; Mirab, FereshtehNanomedicine field focuses on the development of nanoscale carriers that can effectively deliver therapeutics to the diseased sites. One of the most promising drug carriers developed to date are the nanoliposomes. Nanoliposomes are accepted in our bodies due to their lipid bilayer structure, which mimics the outer membrane of cells. However, nanoliposomes lack physical stability that limits their success. In contrast, polymeric nanoparticles such as hydrogels have excellent stability and offer tunable mechanical properties. By combining nanoliposomes and polymeric nanoparticles, the hydrogel encapsulated liposomes provide more stability and adjustable mechanical properties for successful drug delivery. In this study, I focus on alginate that is a natural hydrogel and can be crosslinked by calcium ions. I prepare hydrogel encapsulated nanoliposomes using the method of lipid film dehydration and rehydration with the alginic acid solution. Then, I utilize freeze-thaw process and extrusion to form unilamellar vesicles from multilamellar vesicles and adjust their size. Later, the solution is dialyzed to remove non-encapsulated alginate, and then calcium chloride solution is added to the system. The calcium ions diffuse through the lipid membrane and crosslink the alginate. I will study size distribution and zeta potential of these nanoliposomes using dynamic light scattering and laser doppler electrophoresis. Also, I will investigate the mechanical elasticity of alginate hydrogel, using a rheometer instrument, as a function of calcium concentration. This will allow us to control the mechanical properties of hydrogel-filled liposomes, as an important factor for their delivery performance.