Graduation Date

Fall 12-14-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupicky

Abstract

Acute kidney injury (AKI) is a major kidney disease associated with high mortality and morbidity. Long-term AKI may lead to chronic kidney disease and end-stage renal disease. Several clinical trials failed due to lack of efficacy and undesired side effects. Studies showed that macromolecular delivery systems would be a promising method to target kidney, however, little is known about how physicochemical properties affects the polymers deposition in ischemia-reperfusion (I/R) AKI.

Gene therapy has been well studied as a promising therapeutic agent for several diseases, including cancer and AKI. Although small interfering RNA (siRNA) has been commonly used to treat AKI through hydrodynamic injection, this method has some disadvantages.

The expression of CXCR4 increases in response to AKI. Emerging evidence shows that CXCR4/SDF-1 axis is implicated in regulating trafficking and invasion of inflammatory cells in the injured kidneys. The inhibition of the axis appears to exert beneficial therapeutic effect in AKI.

First, to understand how physicochemical properties affects renal accumulation in AKI, we synthesized a panel of 9 fluorescently labeled polymers with a range of size and different net charge. By testing biodistribution in unilateral I/R animal model, we found negatively charged pMAA-5 and neutral pHPMA-36 had greatest potential for accumulating in I/R kidneys as compared with sham-operated kidneys. The polymers passed through glomerulus and sustained in proximal tubular cells for up to 24 hours after injection. We also confirmed the consistency of bilateral and unilateral I/R animal model by confirming biodistribution of pAPMA-30 and pHPMA-16 in bilateral I/R animal model. This study demonstrated for the first time that polymers with specific physical characteristics exhibit promising enhanced ability to accumulate in AKI kidney.

Second, to explore the potential of CXCR4/SDF-1 axis in the treatment of AKI, we formulated polyplexes with our previously synthesized polymeric CXCR4 antaganist (PCX). Biodistribution study indicated that the majority of injected polyplexes can accumulated in injured renal rubule cells. Transfection effect of the polyplexes in unilateral I/R injury mouse model showed a better silencing effect complared with hydrodynamic injection, which providing a novel dual-functional pharmacological method for treatment of AKI.

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