Improving the delivery and efficacy of molecular medicine via extracellular matrix modulation : insights from intravital microscopy

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.

Department dc:contributor.department

Massachusetts Institute of Technology. Biological Engineering Division.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2005

Author dc:creator

• McKee, Trevor David

Advisor dc:contributor.advisor

• Rakesh K. Jain and Peter T.C. So.

• Biological Engineering Division.

Statement dc:rights

• 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.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/33865

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/33865