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Title page for ETD etd-06122013-101145


Type of Document Dissertation
Author Sims, Artez Laurant
Author's Email Address artez.l.sims@vanderbilt.edu
URN etd-06122013-101145
Title Development and Application of Dendritic Systems for Targeted Intracellular Delivery
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Eva M. Harth Committee Chair
David Wright Committee Member
James E. Crowe Jr. Committee Member
Timothy Hanusa Committee Member
Keywords
  • colocalization
  • rotavirus treatment
  • dendrimers
Date of Defense 2013-05-17
Availability unrestricted
Abstract
This project reports the synthesis of several dendritic polymers towards applications in intracellular transport. The structures discussed feature variations in core, periphery, and branched units all of which are manipulated to create sophisticated designs of delivery.

One of the dendrimers reported is designed to provide delivery into the cellular cytoplasm. An alternative synthesis for this second generation dendritic transporter is presented and used to attach novel antibodies. In this approach, conjugation of transporter and single-chained antibody is used for viral therapy. Comparatively, the bioconjugate is demonstrated to achieve viral inhibition against cells infected with rotavirus more effectively than antibody alone. The investigation utilizes a novel approach for viral treatment.

To extend the utility of dendrimers a library of third generation dendrimers were also created. As a synthetic advantage, the structures undergo a facile preparation process and demonstrate the potential for creating systems featuring polyvalent peripheries. Using this approach, third generation structures are developed featuring emanating units containing ethyl and hexy alkyl units and guanidine head groups.

Additional application of this synthetic route is used to construct third generation dendrimers for delivery to the mitochondria. The dendrimers are modified with various ratios of lipophilic and cationic functionality at the periphery. Investigation of the construct featuring an equal distribution of perpheritic lipophilic and cationic functional groups demonstrates mitochondria targeting. The findings from these investigations highlight approaches using dendrimers to facilitate cellular delivery for therapeutic application.

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