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- All Subjects: Nanoparticles
- Creators: Phelan, Patrick
- Creators: Sirianni, Rachael
- Creators: Acharya, Abhinav
Scaled Formulations of Succinate based Polymeric particles for Eventual Testing in Clinical Settings
With an estimated 19.3 million cases and nearly 10 million deaths from cancer in a year worldwide, immunotherapies, which stimulate the immune system so that it can attack and kill cancer cells, are of interest. Tumors are produced from the uncontrolled and rapid proliferation of cells in the body. Cancer cells rely heavily on glutamine for proliferation due to its contribution of nitrogen for nucleotides and amino acids. Glutamine enters the tricarboxylic acid (TCA) cycle as α-ketoglutarate via glutaminolysis, in which glutamine is converted into glutamate by the enzyme glutaminase (GLS). Cancer cell proliferation may be limited by using glutaminase inhibitor CB-839. However, immune cells also rely on these metabolic pathways. Thus, a method for restarting the metabolic pathways in the presence of inhibitors is attractive. Succinate, a key metabolite in the TCA cycle, has been shown to stimulate the immune system despite the presence of metabolic inhibitors, such as CB-839. A delivery method of succinate is through microparticles (MPs) or nanoparticles (NPs) which may be coated in polyethylene glycol (PEG) for improved hydrophilicity. Polyethylene glycol succinate (PEGS) MPs were generated and tested in vivo and were shown to reduce tumor growth and prolong mouse survival. With the success in stimulating the immune system with MPs, NPs were investigated for an improved immune response due to their smaller size. These PES NPs were generated in this study. For clinical settings, it is necessary to scale-up the production of particles. Two methods of scale-up were proposed: (1) a combination of multiple small batches into a mixed batch, and (2) a singular, big batch. Size and release properties were compared to a small batch of PES NPs, and it was concluded that the big batch more closely resembled the small batch compared to the mixed batch. Thus, it was concluded that batch-to-batch variability plays a larger role than volume changes when scaling-up. In clinical settings, it is recommended to produce the particles in a big batch rather than a mixed batch.
In this work, plasmonic nanocomposites have been synthesized and used in laser tissue welding for ruptured porcine intestine ex vivo and incised murine skin in vivo. These laser-responsive nanocomposites improved tissue strength and healing, respectively. Additionally, a spatiotemporal model has been developed for laser tissue welding of porcine and mouse cadaver intestine sections using near-infrared laser irradiation. This mathematical model can be employed to identify optimal conditions for minimizing healthy cell death while still achieving a strong seal of the ruptured tissue using laser welding. Finally, in a model of surgical site infection, laser-responsive nanomaterials were shown to be efficacious in inhibiting bacterial growth. By incorporating an anti-microbial functionality to laser-responsive nanocomposites, these materials will serve as a treatment modality in sealing tissue, healing tissue, and protecting tissue in surgery.
In order to aid future scaling up of the MVA process, the agglomerate size distribution in the MVA system was predicted by utilizing a force balance model coupled with a two-fluid model (TFM) simulation. The particle agglomerate size that was predicted using the computer simulation was validated with experimental data and found to be in good agreement.
Lastly, in order to demonstrate the utility of the MVA system in an air revitalization application, the capture of CO2 was examined. CO2 breakthrough time and adsorption capacities were tested in the MVA system and compared to a vibrating fluidized bed (VFB) system. Experimental results showed that the improved fluidity in the MVA system enhanced CO2 adsorption capacity.