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Title page for ETD etd-02052006-162009


Type of Document Dissertation
Author Smith, Ralph Adam
URN etd-02052006-162009
Title Development of a Nanoparticle-Based System for Imaging and Targeted Therapeutic Delivery to Tumor Cells
Degree PhD
Department Biomedical Engineering
Advisory Committee
Advisor Name Title
Todd D. Giorgio Committee Chair
E. Duco Jansen Committee Member
Frederick Haselton Committee Member
Ian Tomlinson Committee Member
J. Oliver McIntyre Committee Member
Keywords
  • MMP-7
  • surface modification
  • Nanoparticles
  • Drug targeting
  • flow cytometry
  • proteolysis
  • quantum dot
  • CD13
  • NGR
  • Drug delivery systems
Date of Defense 2005-11-14
Availability unrestricted
Abstract
Selective targeting of damaged or diseased cells is a concept with great potential to revolutionize the efficacy of systemically administered agents. Successful targeting preferentially delivers imaging agents and/or therapies to specific tissues, enhancing detection and diagnosis as well as therapies minimizing damage to nontarget cells. However, the current generation of targeted therapies has not yet generally achieved highly specific targeting of tumors and emerging neoplasia through a single recognition mechanism.

Effective performance of targeted systems depends upon recognition of unique characteristics on the cellular surface. HT-1080 cells in vitro present 3,840,000 ± 70,000 CD13 receptors per cell, a level presumably suitable for effective targeting. Receptor presentation can be further modulated by exposure to factors such as ionizing radiation and various cytokines, presenting opportunities to modify receptor expression for optimized delivery of targeted constructs.

Single modality targeted nanoscale quantum dots (QDs) were synthesized to enable specific interaction with target cells. Nonspecific interaction was limited by functionalizing the QD surface with a passive PEG coating. To facilitate specific binding to target receptors, QDs were surface-functionalized with targeting peptides. The resulting constructs (QD-PEG-NGR) bound to the surface of HT-1080 cells at a level of 15,410 ± 980/cell, enabling high contrast imaging and the potential for significant therapeutic delivery.

To overcome specific limitations that plague current single-modality targeting technologies, a multifunctional QD-based proximity-activated (PA) targeting system was developed. QDs were functionalized with a proteolytically sensitive PA coating designed to mask an underlying targeting ligand. Specific matrix metalloprotease-7 (MMP-7) activity resulted in maximal cleavage of 90.9 ± 15.4% of the available PA structures from the QD surface. Effective cleavage was measured at exposure times and enzyme concentrations consistent with estimated in vivo conditions.

Multifunctional NPs offer opportunities unavailable with molecular structures or current single-modality targeted constructs. Effective targeting, imaging, and delivery to specific cells can be achieved with the two-component targeting methodology detailed in this work. Application of these targeting methodologies may offer a powerful system to significantly improve cancer treatment.

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