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dc.contributor.advisorRam Sasisekharan.en_US
dc.contributor.authorEavarone, David A. (David Alan)en_US
dc.contributor.otherHarvard University--MIT Division of Health Sciences and Technology.en_US
dc.date.accessioned2010-09-03T18:34:23Z
dc.date.available2010-09-03T18:34:23Z
dc.date.copyright2009en_US
dc.date.issued2009en_US
dc.identifier.urihttp://hdl.handle.net/1721.1/58393
dc.descriptionThesis (Ph. D. in Biomedical Engineering)--Harvard-MIT Division of Health Sciences and Technology, 2009.en_US
dc.descriptionCataloged from PDF version of thesis.en_US
dc.descriptionIncludes bibliographical references.en_US
dc.description.abstractIn the continuing search for effective treatments for cancer, the emerging model is the combination of traditional chemotherapy with anti-angiogenesis agents that inhibit blood vessel growth. However, the implementation of this strategy has faced two major obstacles. First, the long-term shutdown of tumor blood vessels by the anti-angiogenesis agent can prevent the tumor from receiving a therapeutic concentration of the chemotherapy agent. Second, inhibiting blood supply drives the formation of intra-tumoral hypoxia, or a lack of oxygen, which has been correlated with increased tumor invasiveness and resistance to chemotherapy. In this thesis we report the disease-driven engineering of a drug delivery system, a 'nanocell', which overcomes these barriers unique to solid tumors. The nanocell comprises a nuclear nanoparticle encapsulated within a lipid membrane and is preferentially taken up by the tumor. The nanocell delivers a temporal release of two drugs within the tumor core: the outer lipid envelope first releases an anti-angiogenesis agent, causing a vascular shutdown; the inner nanoparticle, which is trapped inside the tumor, then releases a chemotherapy agent. This focal release within the tumor targets cells most at risk for hypoxia and results in improved therapeutic index with reduced toxicity. The technology can be extended to additional agents, so as to target multiple signaling pathways or distinct tumor compartments, enabling the model of an 'integrative' approach in cancer therapy.en_US
dc.description.abstract(cont.) In the second part of the thesis we report new tools for the optimization of nanocell formulations. We present a new, three-dimensional, voxel-based computational model for Monte Carlo simulations of nanoparticle delivery systems that enables direct investigation of the entire vehicle during particle degradation and drug release. Use of this model in combination with emerging mechanistic understandings of nanoparticle drug release will facilitate optimization of nanocell combination therapy release profiles. We additionally report the generation and characterization of a set of carbohydrate-based chemotherapeutic agents that have the potential for use in nanocells as reduced toxicity alternatives to traditional chemotherapy agents.en_US
dc.description.statementofresponsibilityby David A. Eavarone.en_US
dc.format.extent121 p.en_US
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsM.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/7582en_US
dc.subjectHarvard University--MIT Division of Health Sciences and Technology.en_US
dc.titleA novel nanoscale delivery system for spatio-temporal delivery of combination chemotherapyen_US
dc.typeThesisen_US
dc.description.degreePh.D.in Biomedical Engineeringen_US
dc.contributor.departmentHarvard University--MIT Division of Health Sciences and Technology.en_US
dc.contributor.departmentHarvard University--MIT Division of Health Sciences and Technology
dc.identifier.oclc650349524en_US


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