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Zent Thesis v11_FINAL.pdf (13.01 MB)

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Tools for Investigating Pericellular Matrix Metalloproteinase Activity and Applications in Drug Development

Zent, Joshua Michael
http://rave.ohiolink.edu/etdc/view?acc_num=osu1650304900046765

Abstract Details

2022, Doctor of Philosophy, Ohio State University, Biomedical Engineering.
Pericellular degradation of the extracellular matrix is predominantly mediated by a family of enzymes called matrix metalloproteinases (MMPs). In many malignancies, MMP activity is increased in the tumor microenvironment and appears to correlate with tumor growth and metastasis. However, previous clinical attempts to treat cancer by directly targeting MMPs have failed, with new evidence suggesting this is partly because the relationship between elevated MMP activity and disease progression is less direct and more context dependent than originally assumed. Alternatively, MMP-activated prodrugs have been developed using well-established chemotherapeutics which have demonstrated potential to improve the concentration of active drug at tumor sites while lowering overall systemic concentration and thus deleterious side effects. However, improved design of these peptide-drug conjugates requires investigation of how MMP-activity fluctuates at the level of individual cells and whether differences in activity can be used to target drug delivery not only to the tumor microenvironment but also to the specific cells and cell types most important to driving disease progression. As ideal tools for such an investigation do not exist, we worked to design a method for microscopic imaging of pericellular MMP-activity using biosensor-laden hydrogels and develop image-analysis software for quantification of this activity. In the process of investigating our hydrogel system, we discovered that the biosensor signal for pericellular MMP activity could not be separated from other manipulations of local hydrogel. As a result, we were unable to use our image-analysis software for quantification of pericellular MMP activity. However, our initial approach in software design led us to the successful development of a new preprocessing framework called Segmentation Area Restriction by Neighborhood (SARN) which can define local regions around individual cells that improves their subsequent segmentation by commonly used intensity-based thresholding methods. Finally, we describe work on the development of a synthesis method for a doxorubicin-peptide conjugate designed to covalently bind into hydrogels until released by MMP-mediated cleavage. While we were unable to synthesize a product with sufficient yield to use in biological experimentation, we were able to detail a strategy for successful synthesis and report on new chemical phenomena discovered in the process.
Jennifer Leight (Advisor)
Keith Gooch (Committee Member)
Samir Ghadiali (Committee Member)
Rizwan Ahmad (Committee Member)
147 p.
Biomedical Engineering
matrix metalloproteinases; cellular segmentation; peptide-drug conjugates

Recommended Citations

Citations

  • Zent, J. M. (2022). Tools for Investigating Pericellular Matrix Metalloproteinase Activity and Applications in Drug Development [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1650304900046765

    APA Style (7th edition)

  • Zent, Joshua. Tools for Investigating Pericellular Matrix Metalloproteinase Activity and Applications in Drug Development. 2022. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1650304900046765.

    MLA Style (8th edition)

  • Zent, Joshua. "Tools for Investigating Pericellular Matrix Metalloproteinase Activity and Applications in Drug Development." Doctoral dissertation, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu1650304900046765

    Chicago Manual of Style (17th edition)

osu1650304900046765
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