Author

Jingga Morry

Date

10-2016

Document Type

Dissertation

Degree Name

Ph.D.

Department

Department of Biomedical Engineering

Abstract

The increased production of reactive oxygen species (ROS) is a hallmark of fibrosis and cancer. In fibrosis, the release of ROS along with secretion of pro-fibrotic cytokines by the immune cells during the inflammatory phase has been known to promote the activation of fibroblasts and induce collagen deposition. In cancer, ROS also plays a crucial role in various signaling cascades involved in cellular survival, proliferation, resistance to apoptosis, angiogenesis, as well as metastasis. However, the results from clinical studies involving antioxidant therapies in patients have been disappointing, mostly due to the low bioavailability of the conventional antioxidant therapies.

Nanoparticles with intrinsic antioxidant properties have great potential to be used for attenuating oxidative stress in various oxidative-induced diseases including fibrosis and cancer. Our group has recently developed and optimized a polymer-coated mesoporous silica nanoparticle (NP) for siRNA and drug delivery. The platform consists of a 50-nm mesoporous silica nanoparticle (MSNP) core coated layer-by-layer with bioreducible cross-linked 10-kDa polyethyleneimine (PEI) for effective siRNA binding and endosomal escape, and polyethylene glycol (PEG) for preventing nanoparticle aggregation, minimizing enzyme degradation of siRNAs, shielding the toxic effect of PEI, and preventing recognition by the immune system.

In this dissertation, I sought to evaluate the antioxidant activity and siRNA delivery efficiency of our NP platform for the treatment of fibrosis and cancer metastasis. In my first project, I investigated the intrinsic antioxidant property of our NPs and assessed the added benefit of silencing heat shock protein 47 (HSP47) as a gene target in a skinfibrosis model. HSP47 is a collagen-specific molecular chaperone responsible for proper assembly of collagen molecule and its overexpression has been observed in numerous fibrotic diseases. To this end, I have made the novel discovery on the antioxidant property of our nanoparticle which is attributed by its MSNP core. I also found that the nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (-SMA), and collagen type I (COL I), as well as skin thickness of the mice.

In my second project, I explored the therapeutic potential of the nanoparticle platform for treating metastatic breast cancer. PLK1 was identified as the top therapeutic target for TNBC cells and tumor initiating cells in a kinome-wide screen. NP inhibited cancer migration and invasion in TNBC cells owing to its ROS and NOX4 modulating properties. In vivo, siPLK1-NP knocked down 80% of human PLK1 mRNA expression in metastatic breast cancer cells residing in mice lungs, inhibited distant metastasis from lung to other organs, and reduced overall tumor burden. Long term treatment delayed the onset of death in mice by 36 days and improved the overall survival.

In conclusion, in this dissertation I have shown that our NP platform has great potential for the treatment of fibrosis and cancer. Given the most optimal gene target, our nanoparticles will be able to provide combinatorial treatment not only for fibrosis and cancer, but also for other types of oxidative-induced inflammatory diseases.

Identifier

doi:10.6083/M4PV6JGT

School

School of Medicine

Available for download on Monday, November 18, 2019

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