Nanoparticle-Enhanced Drug Delivery: Delivering Small Nucleic Acid Therapeutics to Combat Disease at the Gene Expression Level

Alden, Nicholas

Nanoparticle-Enhanced Drug Delivery: Delivering Small Nucleic Acid Therapeutics to Combat Disease at the Gene Expression Level

Restricted

Author:: Alden, Nicholas
Graduate Program:: Bioengineering
Degree:: Doctor of Philosophy
Document Type:: Dissertation
Date of Defense:: June 27, 2023
Committee Members:: Daniel Hayes, Program Head/Chair
Adam Glick, Outside Unit & Field Member
Pak Kin Wong, Major Field Member
Yong Wang, Major Field Member
Scott Medina, Major Field Member
Daniel Hayes, Chair & Dissertation Advisor
Keywords:: Plasmonic Nanoparticles
Near-Infrared
Diels-Alder
Synthetic miRNA Mimics
Head & Neck Cancer
Lung Cancer
Poly-Beta(Amino Esters)
Nanoparticles
Drug Delivery Systems
Abstract:: Small ribonucleic acids (sRNAs) such as micro-RNAs (miRNAs) have recently gained attraction for their prognostic and therapeutic capabilities in treating cancer. Efficient and effective delivery of specific anti-tumorigenic miRNA whose target genes are differentially expressed in tumors compared to surrounding tissue promotes the foundation for innovative gene-level therapies. Dysregulated gene pathways critical to the uncontrolled proliferation of cancer cells could be targeted by miRNA through controlled delivery techniques to disrupt tumors while leaving healthy cells intact. Although, nucleic acid delivery methods currently available have not yet achieved efficient, non-toxic, translational delivery of miRNAs with tumor-specific selectivity. In the studies set forth herein, small nucleic acid delivery systems based on organic and inorganic nanoparticle vectors carrying therapeutic miRNA mimics into human cancer cells were evaluated through rigorous in vitro and in vivo analyses are presented. These nanoparticles were specifically engineered to deliver these small nucleic acid therapeutics with precise spatiotemporal control, in an effort to demonstrate the medicinal capacity miRNA mimics may contribute to the modern infrastructure in cancer intervention. To achieve these feats, these nanoparticles leverage various thermo-chemical properties such as pH distortion or photothermal heating under external stimuli sources for controlled chemical cleavage and release of cargo, synthetic miRNA mimics with sequence specificity to carcinogenic pathways heavily implicated among the models that were evaluated. Lastly, the stimulated release of miRNA mimics from the nanoparticles and the therapeutic efficacy of successfully delivered miRNA mimics delivery were examined in vivo, with significant results in disrupting cancer cells, and even tumor growth under various in vitro and in vivo settings. These results demonstrate the potential of our precision-controlled nanoparticle delivery system designed to effectively administer synthetic miRNA mimics and induce tumor regression.

Tools