Degree Type

Dissertation

Date of Award

2011

Degree Name

Doctor of Philosophy

Department

Chemical and Biological Engineering

First Advisor

Balaji Narasimhan

Abstract

There are several challenges associated with current strategies for drug and vaccine delivery. These include the need for multiple-dose administrations, which can hinder patience compliance, the requirements for specific storage conditions due to the fragile structure of protein-based molecules, and the need for additional excipients to enhance protein stability or adjuvant the immune response. This work has focused on the development of a high throughput, combinatorial approach to optimize degradable polymeric biomaterials, specifically polyanhydrides, to overcome these challenges associated with drug and vaccine delivery. We have developed high throughput techniques to rapidly fabricate polymer film and nanoparticle libraries to carry out detailed investigations of protein/biomaterial, cell/biomaterial, and host/biomaterial interactions. By developing and employing a highly sensitive fluorescence-based assay we rapidly identified that protein release kinetics are dictated by polymer chemistry, pH, and hydrophobicity, and thus can be tailored for the specific application to potentially eliminate the need for multiple-dose treatments. Further investigation of protein/biomaterial interactions identified polymer chemistry, pH, hydrophobicity, and temperature to be integral factors controlling protein stability during fabrication of the delivery device, storage, and delivery. Amphiphilic polymer chemistries were specifically identified to preserve the structure of both robust and fragile proteins from device fabrication to release. Our investigations of cell/biomaterial interactions revealed that all nanoparticle and polymer film chemistries studied were non-toxic at concentrations expected for human use. Furthermore, cellular activation studies were carried out with antigen presenting cells co-incubated with the polymer libraries which indicated that polymer films do not possess immune stimulating properties; however, the nanoparticles do, in a chemistry dependent manner. Combining these insights with informatics analysis, we discovered the molecular basis of the "pathogen-mimicking" behavior of amphiphilic polyanhydride nanoparticles. Specific molecular descriptors that were identified for this pathogen-mimicking behavior include alkyl ethers, % hydroxyl end groups, backbone oxygen content, and hydrophobicity. These findings demonstrated the stealth properties of polyanhydride films for tissue engineering and the pathogen-mimicking adjuvant properties of the nanoparticles for vaccine delivery. Finally, host/biomaterial interactions were studied, which indicated that polymer chemistry and administration route affect nanoparticle biodistribution and mucoadhesion. Amphiphilic nanoparticles were identified to reside longest at parenteral administration routes and adhere best to mucosal surfaces. These results point to their ability to provide a long-term antigen depot in vivo. In summary, the studies described in this thesis have created a rational design paradigm for materials selection and optimization for use as drug delivery vehicles and vaccine adjuvants, which will overcome the challenges associated with administration frequency, protein instability, and insufficient immune stimulation.

Copyright Owner

Latrisha Kay Petersen

Language

en

Date Available

2012-04-30

File Format

application/pdf

File Size

344 pages

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