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20Mar31 Dissertation_FINAL.pdf (6.39 MB)

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MMP-Degradable Biosensors: Applications in Drug Delivery and Personalized Medicine

Deshmukh, Ameya
http://rave.ohiolink.edu/etdc/view?acc_num=osu1585925271421393

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Biomedical Engineering.
Matrix metalloproteinases (MMPs) are the primary regulators of matrix degradation and reorganization through which they control key physiological processes such as wound healing and embryogenesis. Aberrant MMP activity contributes to the progression of several disease states, including cancer, in which it has been extensively characterized. To directly measure the activity of MMPs in cancer, researchers have developed MMP-degradable, fluorescent peptide biosensors. However, the peptide sequences used in these biosensors are often characterized in-solution using recombinant or purified enzymes, which are not representative of cell-mediated processes. To overcome this limitation, we have adapted MMP-degradable biosensors to the development of fluorescent peptide zymography. By covalently conjugating the peptide to the polyacrylamide backbone, this technique was able to measure a wider range of MMPs and displayed improved sensitivity compared to traditional zymography. Fluorescent peptide zymography was then used in combination with other MMP-sensing technologies to design a MMP-sensitive hydrogel drug delivery platform targeting liposarcoma, in vitro. Liposarcoma cell lines exhibiting elevated MMP activity stimulated drug release by selectively degrading a stably incorporated peptide-drug conjugate. The drug delivery platform can complement traditional surgical methods for the treatment of locally recurrent liposarcoma. Finally, we adapted a peptide-conjugated poly (ethylene glycol) (PEG) hydrogel to study the effects of dimensionality on drug treatment-induced MMP activity in breast cancer. Culture conditions regulated cellular MMP activity in response to drug treatment, where cells developed a chemoresistant phenotype in three-dimensional culture. This work motivated us to evaluate the feasibility of directly encapsulating tissue samples in the PEG hydrogels to predict patient-specific drug response. Ex vivo breast tissue dissections were >85% viable in PEG hydrogels after 24 hours, and MMP and metabolic activity could be measured simultaneously. In the future, we plan to perform a drug screen on encapsulated patient tissue samples to measure changes in cellular MMP activity, which will be validated with a xenograft mouse model. Our eventual goal is to use this technology to inform personalized treatment decisions.
Jennifer Leight, Ph.D. (Advisor)
Keith Gooch, Ph.D. (Committee Member)
Daniel Stover, M.D. (Committee Member)
150 p.
Biomedical Engineering
Matrix metalloproteinases; MMPs; MMP-degradable peptides; biosensors; biomaterials; local drug delivery; de-differentiated liposarcoma; zymography; substrate zymography; cancer; tissue engineering; personalized medicine

Recommended Citations

Citations

  • Deshmukh, A. (2020). MMP-Degradable Biosensors: Applications in Drug Delivery and Personalized Medicine [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1585925271421393

    APA Style (7th edition)

  • Deshmukh, Ameya. MMP-Degradable Biosensors: Applications in Drug Delivery and Personalized Medicine. 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1585925271421393.

    MLA Style (8th edition)

  • Deshmukh, Ameya. "MMP-Degradable Biosensors: Applications in Drug Delivery and Personalized Medicine." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1585925271421393

    Chicago Manual of Style (17th edition)

osu1585925271421393
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