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Zhang, Yifei (2014) TARGETED THERAPY FOR LIVER FIBROSIS AND CANCER. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Liver fibrosis is a chronic disorder that leads to accumulation of excessive amounts of extracellular matrix (ECM), and the first part of my dissertation work is about the effect of microRNA miR-29a in inhibiting the ECM gene expression at post-transcriptional or translational level. Our data indicates that transfection of hepatic stellate cells (HSCs) with miR-29a significantly inhibited the expression of ECM-related genes, which was mediated by the putative targeting sites at their 3’-UTR. We have also found that miR-29a plays a role in mediating the antifibrotic effect of the nuclear receptor Farnesoid X receptor (FXR). In addition, we have uncovered that miR-29b indirectly inhibits ECM synthesis at post-translational level. By targeting the 3'-UTR of Heat shock protein 47 (HSP47) and lysyl oxidase (LOX) which are known to be essential for post-translational modification of ECM proteins, overexpression of miR-29b led to abnormal ECM structure as shown by electron-microscopy.

The second part of my work was to improve the therapeutic outcome via formulation strategy. A drug-interactive motif (Fmoc) was introduced into the PEG5K-VE2 micelle system (PEG-FVE2), and the drug loading capacity was evaluated using paclitaxel (PTX) as a model drug. The Fmoc/PTX physical interaction was demonstrated by a fluorescence quenching assay. PTX-loaded PEG-FVE2 micelles exerted higher antitumor effect than the Taxol formulation both in vitro and in vivo.

As an overall approach, the targeting efficiency of drug carriers was further improved by conjugation with a ligand for the Sigma-2 receptor, which is over-expressed in multiple types of solid tumors. SV119 is a synthetic small molecule which binds to sigma-2 receptors with high affinity and specificity. The final part of my study showed that incorporation of SV119-PEG-DOA significantly increased the cellular uptake of liposomes by tumor cells but not normal cells. This study suggests that SV119-modified liposomes might be another promising drug carrier for tumor targeted drug delivery.

In summary, our study suggests that miR-29 holds potential as a novel therapeutic agent for the treatment of liver fibrosis. In addition, we have developed a novel formulation that enhances the therapeutic efficacy of existing anticancer agents such as paclitaxel.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zhang, Yifeiyiz40@pitt.eduYIZ40
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVenkataramanan, Ramanrv@pitt.eduRV
Thesis AdvisorLi, Songsol4@pitt.eduSOL4
Committee MemberGandhi,
Committee MemberXie, Wenwex6@pitt.eduWEX6
Date: 28 July 2014
Date Type: Publication
Defense Date: 28 May 2014
Approval Date: 28 July 2014
Submission Date: 26 July 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 183
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Pharmaceutical sciences, Molecular biology, Biomedical engineering
Date Deposited: 28 Jul 2014 12:51
Last Modified: 15 Nov 2016 14:22


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