Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering (ENAS)

First Advisor

Saltzman, W. Mark

Abstract

Techniques such as polymeric nanoparticle formulation and nontraditional drug delivery modalities have been developed to address complex delivery challenges associated with aggressive diseases. In this dissertation, polymeric nanoparticle formulations are demonstrated to encapsulate small molecule drugs and coupled with direct local delivery methods to avoid the weaknesses associated with systemic delivery towards two different applications. Firstly, glioblastoma (GBM) is the most deadly and common brain cancer and little progress has been made in improving the standard of care for nearly 17 years. Current therapies suffer from dose limiting toxicities, low penetration into the brain, and tumors resistant to chemotherapies that inevitably recur. The focus of investigations has shifted to combination therapies that are more likely to devastate the tumors and overcome resistance mechanisms. Furthermore, alternative drug delivery modalities such as Convection Enhanced Delivery (CED) have emerged to bypass the blood brain barrier and nanoparticles (NPs) have demonstrated the ability to protect and sustain a variety of cargo within the brain microenvironment. The work presented here establishes the potency of a novel inhibitor of the ATR pathway as a chemosensitizer for alkylating agents such as lomustine, demonstrates the ability to formulate nanoparticles (NPs) with a novel poly(ethylene glycol)-co-poly(ethylene brassylate-co-dioxanone) (PEG-EB-co-DO) polymer, thoroughly investigates the synergy between ATR inhibition and lomustine in vitro, and further successfully elucidates this synergistic effect in mice with either flank or intracranial mouse tumors. Animals administered ATR inhibitors and lomustine exhibited greatly reduced tumor volume in both flank and intracranial models and further demonstrated survival benefit over their single agent counterparts. Furthermore, CED was used to administer the ATR inhibitory NPs to overcome the BBB and improve tissue penetration in the brain. A single dose of ATR inhibitory NPs and free drug was able to induce significant tumor size decreases and survival benefit in combination with lomustine. Secondly, the COVID-19 pandemic has initiated a flurry of investigations into treatments for the different phases of the disease. Such treatments include antiviral drugs to combat cell penetration and replication of the virus, anti-inflammatory drugs to treat the devastating later stage immunologic symptoms, and myriad nucleic acid-based vaccines to prevent the spread of disease altogether. Some of the early small molecules that exhibited promise, such as Remdesivir, were limited due to systemic dose toxicity and thus direct lung administration has become a desirable route to achieve appropriate drug delivery of higher therapeutic doses. The associated work herein uses a novel set of poly(N-substituted carbonate) (PNSC)-based polymeric NPs to encapsulate and slowly release Remdesivir and Ibudilast, an anti-inflammatory drug. Furthermore, the ability to safely deliver these NPs to lung cells and to mouse lungs is established. Deprotected PEG-PLA-PNSC NPs demonstrated high cell uptake compared to their protected counterpart. Both NPs were retained in the lungs for at least 48 hours after intratracheal administration without evidence of leaching into the bloodstream. Furthermore, differences in NP biodistribution were observed after systemic administration such that the deprotected polymer exhibited a lower blood half-life than the protected polymer. Though both projects were focused on different diseases with different organ targets, both relied on novel polymeric NP systems and direct local delivery modalities in order to gain a better understanding of their respective challenges. These results provide evidence of an enhanced method for addressing the limitations of current GBM therapies and a useful set of tunable polymers for direct delivery to the lung. It is hopeful that such strategies will be expanded in the future and eventually contribute to advances in the clinic for both sets of diseases.

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