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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-02052006-162009 |
| Date | 06 February 2006 |
| Creators | Smith, Ralph Adam |
| Contributors | Todd D. Giorgio, Frederick Haselton, E. Duco Jansen, J. Oliver McIntyre, Ian Tomlinson |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-02052006-162009/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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