Graduation Date

Fall 12-17-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupický, Ph.D.

Second Advisor

Daryl J Murry, Pharm.D.

Third Advisor

Erika I Boesen, Ph.D.

Abstract

Acute kidney injury (AKI) is a major kidney disease that is characterized by a sudden loss of renal function which manifests by a decrease in urine output and an increase in serum creatinine. AKI is a global healthcare burden associated with high morbidity, mortality, and increasing cost. Currently there are no effective pharmacological treatments available. Apoptosis induced by p53 has been demonstrated as an important pathological mechanism for the development of AKI. Meanwhile, CXCR4/SDF-1 axis has been associated with the inflammation during AKI, and CXCR4 is overexpressed on injured tubules. This dissertation hypothesized that polycations with CXCR4 targeting ability could enhance the accumulation of p53 siRNA in injured tubule cells, and simultaneous blockade of CXCR4 would lead to enhanced AKI therapy.

An overview of renal anatomy, pathophysiology and biomarkers of AKI, the application of nanomedicine in AKI is given in Chapter 1.

Chapter 2 reports that PCX can effectively deliver siRNA into the injured renal tubule cells due to the CXCR4 binding effect, and PCX/sip53 showed great anti-apoptosis effect in cisplatin challenged HK-2 cells. Moreover, the in vivo bio-distribution study showed that PCX can enhance the accumulation of siRNA in the injured kidneys, especially the tubules. Renal p53 and CXCR4 expressions were confirmed in two widely used AKI mice models. Finally, the enhanced renal accumulation of PCX/sip53 showed great therapeutic potential in the cisplatin induced AKI (CIS-AKI) mice model.

Chapter 3 reports that modified chitosan (CS) with α-cyclam-p-toluic acid (CPTA) can introduce CXCR4 binding ability. After formulating with siRNA, CPTA modified CS (C-CS) showed improved siRNA protection ability. In vitro studies showed enhanced cellular uptake of C-CS/siRNA and gene knockdown effect. Moreover, in vivo biodistribution showed C-CS/siRNA can effectively accumulate in the injured kidney and retain there for at least 24 hours due to its CXCR4 binding ability. Finally, the treatment with C-CS/sip53 showed great therapeutic potential in ischemia-reperfusion induced AKI (IRI-AKI) mice model.

Chapter 4 reports the synthesis and characterizations of polymeric plerixafor (PP) derivatives. All the polymers showed excellent CXCR4 binding ability in vitro. The hydrophilic moieties modified PP (PP-OH) showed less protein binding, which may benefit for in vivo applications. Finally, the biodistribution study was conducted and PP-OH showed the highest accumulation in injured kidneys, which may provide advanced ideals for the development of CXCR4 binding carriers for drug delivery to injured kidneys.

In chapter 5, conclusions and future directions are given.

Available for download on Tuesday, October 24, 2023

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