Improving the delivery and efficacy of molecular medicine via extracellular matrix modulation : insights from intravital microscopy
Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2006
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| Online Access: | http://hdl.handle.net/1721.1/33865 |
| _version_ | 1811084286721261568 |
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| author | McKee, Trevor David |
| author2 | Rakesh K. Jain and Peter T.C. So. |
| author_facet | Rakesh K. Jain and Peter T.C. So. McKee, Trevor David |
| author_sort | McKee, Trevor David |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005. |
| first_indexed | 2024-09-23T12:48:19Z |
| format | Thesis |
| id | mit-1721.1/33865 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T12:48:19Z |
| publishDate | 2006 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/338652019-04-12T17:26:02Z Improving the delivery and efficacy of molecular medicine via extracellular matrix modulation : insights from intravital microscopy McKee, Trevor David Rakesh K. Jain and Peter T.C. So. Massachusetts Institute of Technology. Biological Engineering Division. Massachusetts Institute of Technology. Biological Engineering Division. Biological Engineering Division. Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005. Includes bibliographical references. The extracellular matrix of tumors is a major barrier to the delivery of molecular medicine. We used fluorescence recovery after photobleaching combined with intravital microscopy to quantitate the transport properties of the tumor interstitium. We found that the presence of fibrillar collagen correlated with hindered diffusion in vivo, and also in vitro, in collagen gels prepared to mimic tumor extracellular matrix. Modification of the tumor collagen matrix directly with purified bacterial collagenase, or indirectly with relaxin treatment, resulted in increased diffusion coefficients of macromolecules within tumors in vivo. In order to quantitate the changes in collagen content and structure induced by relaxin treatment, we adapted and further developed the imaging technique of intravital second harmonic generation microscopy. Using second harmonic generation imaging in combination with a fluorescently labeled gene therapeutic vector, we demonstrated that the spread of these viral vectors within tumors is limited by the fibrillar collagen in the extracellular matrix. Matrix modification via the introduction of bacterial collagenase along with the initial virus injection resulted in a significant improvement in the range of viral distribution within the tumor. (cont.) This resulted in an extended range of infection of cells within the tumor, and improved virus propagation, ultimately leading to enhanced therapeutic outcome. Thus, we show that fibrillar collagen is an important barrier to the distribution of molecular medicine within tumors, and that matrix modifying treatments can significantly enhance both vector distribution, as well as ultimately therapeutic response. by Trevor David McKee. Ph.D. 2006-08-25T18:52:15Z 2006-08-25T18:52:15Z 2005 2005 Thesis http://hdl.handle.net/1721.1/33865 66292724 eng MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 146 leaves 7806206 bytes 7812354 bytes application/pdf application/pdf application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biological Engineering Division. McKee, Trevor David Improving the delivery and efficacy of molecular medicine via extracellular matrix modulation : insights from intravital microscopy |
| title | Improving the delivery and efficacy of molecular medicine via extracellular matrix modulation : insights from intravital microscopy |
| title_full | Improving the delivery and efficacy of molecular medicine via extracellular matrix modulation : insights from intravital microscopy |
| title_fullStr | Improving the delivery and efficacy of molecular medicine via extracellular matrix modulation : insights from intravital microscopy |
| title_full_unstemmed | Improving the delivery and efficacy of molecular medicine via extracellular matrix modulation : insights from intravital microscopy |
| title_short | Improving the delivery and efficacy of molecular medicine via extracellular matrix modulation : insights from intravital microscopy |
| title_sort | improving the delivery and efficacy of molecular medicine via extracellular matrix modulation insights from intravital microscopy |
| topic | Biological Engineering Division. |
| url | http://hdl.handle.net/1721.1/33865 |
| work_keys_str_mv | AT mckeetrevordavid improvingthedeliveryandefficacyofmolecularmedicineviaextracellularmatrixmodulationinsightsfromintravitalmicroscopy |