Date of Degree

9-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Yujia Xu

Advisor

Michael McDevitt

Committee Members

Lynn Francesconi

Michael Drain

Shuiqin Zhou

Brian Zeglis

Subject Categories

Biochemical and Biomolecular Engineering | Biochemistry, Biophysics, and Structural Biology | Biotechnology

Keywords

SGLT2, RNAi, CNC, CNT, VACNT, siRNA, Fibrillar Nanoparticle

Abstract

RNA interference (RNAi) is a powerful tool to manipulate the phenotype of an organism by silencing the expression of specific genes and is viewed as a highly promising platform for treating undruggable targets and disorders where small molecule drugs and antibodies would fail. However, development of RNAi based therapies has faced major barriers including cellular and tissue-specific uptake of the Small Interfering RNA (siRNA). Utilizing different nanoparticles as RNAi excipients, cellular uptake and gene silencing potency can be greatly improved. The research in Dr. McDevitt groups has fibrillar carbon nanotubes (CNT) as carriers for siRNA for gene silencing in vitro and in vivo. Radiolabeled biodistribution of fCNT in mice show renal and hepatic uptake while having fast plasma clearance and excretion in the urine hours after injection. This unique pharmacokinetic profile has been termed Fibrillar Pharmacology due to the fibrillar nature of the nanoparticles that exhibit this behavior.

The hypothesis of my thesis is that other high aspect ratio nanomaterials can also exhibit Fibrillar Pharmacology, and be used as renal specific RNAi based therapeutic agents. During the course of my thesis research, I investigated the application of Vertically Aligned carbon nanotubes (VACNT), and cellulose nanocrystals (CNC) that have been ammonium functionalized and physically characterized. In vivo murine biodistribution of these nanoparticles showed Fibrillar Pharmacology and uptake in the kidneys. With the increased size of the VACNT an increased number of siRNA molecules each particle can carry and propose the prospect of gene delivery via ammonium functionalized VACNT. Additionally, in vivo and in vitro gene knockdown using modified CNC indicate these fibrillar nanoparticles can be a robust platform for gene silencing. Lastly, I investigate the potential of gene silencing in the treatment of Type 2 Diabetes Mellitus by silencing the expression of the glucose transporter, Sodium dependent GLucose coTransporter 2 (SGLT2). Silencing of SGLT2 is expected to lead to excretion of glucose and potentially alleviating hyperglycemia. While it still needs more extensive testing, my work indicated that by combining RNAi with Fibrillar Pharmacology it is possible for renal specific silencing of SGLT2 leading to excretion of glucose and potentially alleviating hyperglycemia.

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