Degree Type

Dissertation

Date of Award

2011

Degree Name

Doctor of Philosophy

Department

Chemical and Biological Engineering

First Advisor

Balaji Narasimhan

Abstract

In this work, a transdisciplinary approach that combines concepts from biomaterials, nanotechnology, carbohydrate and protein chemistry, molecular biology, immunology and computational analysis has been applied to rationally design and engineer novel vaccine platforms that encompass passive and active targeting strategies.

First, the intrinsic properties of the polyanhydride systems utilized in these studies were tailored to achieve the stability of proteins with the potential to be used as antigens and/or therapeutic agents. Amphiphillic polyanhydride chemistries showed the most optimal properties to preserve structural integrity and functionality of different proteins. The surface chemistry of polyanhydride particles was also identified as an important attribute that directs the adjuvant properties of these carriers. In this context, this work revealed changes in particle uptake and activation phenotype of antigen presenting cells as a consequence of chemistry-dependent surface adsorption of serum proteins.

Active targeting strategies were also designed to improve and direct the adjuvant properties of polyanhydride particles. In this work, two approaches were taken: adjuvant and antigen modifications. Carbohydrate-functionalization of polyanhydride nanoparticles results in the development of "pathogen-like" particles with the ability to induce and enhance APC activation by specific interactions with the mannose receptor. Finally, antigenic modification with alpha-Gal residues in combination with polyanhydride particles as vaccine delivery vehicles results in the production of high antibody titers with high avidity and with the ability to recognize protective epitopes in vivo.

In summary, the studies provide key insights into the rational design of targeted platforms to enhance the induction of antigen-specific immune responses and to facilitate the design of protective targeted therapeutic treatments and vaccines.

Copyright Owner

Brenda Rocio Carrillo-conde

Language

en

Date Available

2012-04-28

File Format

application/pdf

File Size

343 pages

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