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Surface Modified Vascular Tissue for Targeted Delivery

Deglau, Timothy Edward (2005) Surface Modified Vascular Tissue for Targeted Delivery. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Thrombosis and restenosis are common problems associated with intravascular procedures such as anastomoses, balloon angioplasty, and carotid endarterectomies. Application of a molecular barrier at the site of injury to inhibit platelet deposition would be advantageous. Additional therapeutic benefit could be achieved if the modified surface provided a target for delivery of pharmaceuticals, vectors, or cells. This dissertation focuses on the development of an intravascular modification and targeted delivery system that possesses numerous potential applications in the treatment of vascular injury.Polyethylene glycol is commonly used for modification of molecules and surfaces to increase biocompatibility, reduce immunogenicity, and provide stealth characteristics. Protein-reactive polyethylene glycols could be used to modify vascular surfaces forming a molecular barrier. In addition, the polymer could be used as a target for delivery of agents by applying a recognizable tag to the terminus. Agents could be targeted to modified vascular tissue using, for instance, the biotin/avidin recognition system.The ability to modify vascular surfaces with protein-reactive polyethylene glycols was confirmed using quantitative flow cytometry and epi-fluorescence microscopy. Furthermore, in vitro perfusion studies with cultured cells and scrape-damaged arteries demonstrated preferential delivery of microspheres and cells to polyethylene glycol-biotin modified vascular surfaces.An in vivo rabbit model provided a more rigorous assessment of the polymer modification and targeted delivery system. Polymer modification of balloon injured rabbit femoral arteries persisted for a minimum of 72 hours. Targeted microspheres preferentially adhered to healthy and injured arteries modified with the reactive polymer as opposed to untreated controls. Furthermore, the ability to target microspheres to the modified arteries persisted for a minimum of 72 hours.In conclusion, it was shown that it is possible to modify vascular tissue with a protein-reactive polyethylene glycol and that this modification with signaling molecules can also provide a target for the site-specific delivery of vascular-infused agents. An intravascular targeted delivery system such as this might find numerous applications in the treatment of intravascular injury that is associated with angioplasty, stenting, and endarterectomy procedures.


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    Item Type: University of Pittsburgh ETD
    Creators/Authors:
    CreatorsEmailORCID
    Deglau, Timothy Edwardtedst9@pitt.edu
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairWagner, William Rwagnerwr@upmc.edu
    Committee MemberRussell, Alan Jarussell@pitt.edu
    Committee MemberBeckman, Eric Jbeckman@pitt.edu
    Committee MemberVillanueva, Flordeliza Svillanuevafs@upmc.edu
    Committee MemberBorovetz, Harvey Sborovetzhs@upmc.edu
    Title: Surface Modified Vascular Tissue for Targeted Delivery
    Status: Unpublished
    Abstract: Thrombosis and restenosis are common problems associated with intravascular procedures such as anastomoses, balloon angioplasty, and carotid endarterectomies. Application of a molecular barrier at the site of injury to inhibit platelet deposition would be advantageous. Additional therapeutic benefit could be achieved if the modified surface provided a target for delivery of pharmaceuticals, vectors, or cells. This dissertation focuses on the development of an intravascular modification and targeted delivery system that possesses numerous potential applications in the treatment of vascular injury.Polyethylene glycol is commonly used for modification of molecules and surfaces to increase biocompatibility, reduce immunogenicity, and provide stealth characteristics. Protein-reactive polyethylene glycols could be used to modify vascular surfaces forming a molecular barrier. In addition, the polymer could be used as a target for delivery of agents by applying a recognizable tag to the terminus. Agents could be targeted to modified vascular tissue using, for instance, the biotin/avidin recognition system.The ability to modify vascular surfaces with protein-reactive polyethylene glycols was confirmed using quantitative flow cytometry and epi-fluorescence microscopy. Furthermore, in vitro perfusion studies with cultured cells and scrape-damaged arteries demonstrated preferential delivery of microspheres and cells to polyethylene glycol-biotin modified vascular surfaces.An in vivo rabbit model provided a more rigorous assessment of the polymer modification and targeted delivery system. Polymer modification of balloon injured rabbit femoral arteries persisted for a minimum of 72 hours. Targeted microspheres preferentially adhered to healthy and injured arteries modified with the reactive polymer as opposed to untreated controls. Furthermore, the ability to target microspheres to the modified arteries persisted for a minimum of 72 hours.In conclusion, it was shown that it is possible to modify vascular tissue with a protein-reactive polyethylene glycol and that this modification with signaling molecules can also provide a target for the site-specific delivery of vascular-infused agents. An intravascular targeted delivery system such as this might find numerous applications in the treatment of intravascular injury that is associated with angioplasty, stenting, and endarterectomy procedures.
    Date: 13 October 2005
    Date Type: Completion
    Defense Date: 05 July 2005
    Approval Date: 13 October 2005
    Submission Date: 25 July 2005
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-07252005-130509
    Uncontrolled Keywords: angioplasty; endothelial cells; intravascular; microspheres; polyethylene glycol; targeted delivery
    Schools and Programs: Swanson School of Engineering > Bioengineering
    Date Deposited: 10 Nov 2011 14:53
    Last Modified: 04 Jun 2012 12:38
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-07252005-130509/, etd-07252005-130509

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