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Title page for ETD etd-11222014-171529

Type of Document Dissertation
Author McFadden, Ian David
URN etd-11222014-171529
Title Folate-targeted proteolytic nanobeacons: towards selective, imaged delivery in solid tumors
Degree PhD
Department Interdisciplinary Materials Science
Advisory Committee
Advisor Name Title
J. Oliver McIntyre Committee Co-Chair
Todd D. Giorgio Committee Co-Chair
Barbara Fingleton Committee Member
Craig Duvall Committee Member
Thomas Yankeelov Committee Member
Wellington Pham Committee Member
  • drug delivery
  • solid tumors
  • folate-targeting
  • nanotechnology
  • optical imaging
  • cancer
  • FRET
Date of Defense 2014-11-17
Availability unrestricted
Cancer, a diagnosis that encompasses over 200 different disease states classified as malignant neoplasms, is poised to become the leading cause of death in the United States. Many of these diseases arise in the form of solid tumors that are very challenging to treat due to heterogeneity between tissues of origin, between individuals, and even between cells within a single tumor. Common factors among many solid tumor malignancies include elevated concentrations of matrix metalloproteinases (MMPs) and overexpression of the α-isoform of the folate receptor (FR), each of which has been correlated with tumor progression to metastatic disease. We hypothesized that combined targeting of proteolytically-activated nanobeacons to tumor-associated MMP activity and FR expression could provide a delivery vehicle that allows imaging of selective delivery to tumor cells. Furthermore, this dual-targeting strategy was hypothesized to result in more selective delivery to tumor cells than either targeting mechanism alone. This dissertation presents the development, troubleshooting, and optimization of techniques to synthesize and characterize folate-targeted proteolytic nanobeacons (FTPNBs) suitable for testing these hypotheses.

Solid phase peptide synthesis (SPPS) was utilized to produce folic acid-coupled, fluorescently labeled MMP substrate peptides with functional chemistry for bionconjugation with nanoparticles. Such peptides were coupled to poly(amido amine) dendrimer nanoparticles to produce functional FTPNBs. In a set of pilot validation experiments, intact and MMP-cleaved FTPNBs were shown to be internalized by MDA-MB-231 human metastatic breast cancer cells via a mechanism that was inhibited by the inclusion of free folic acid to compete for FR.

Future implications of this work include: elucidation of the intracellular fate of folate conjugates classified by valency of FR binding; development of dual-targeted constructs tailored to the activity of other proteases and targeting ligands; and modification of the presented design to include imaging agents that would allow in vivo imaging of protease activity in humans. The last of these could constitute theranostic agents with excellent potential for translation to the clinic, wherein delivery of tumoricidal compounds to tumor cells could be easily monitored.

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