Silk Lyogels for Sustained Local Delivery of Therapeutic Antibodies.
Guziewicz, Nicholas.
2012
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Abstract: The
medical importance of monoclonal antibody therapeutics continues to grow with over 300
such therapeutics under development and more than 25 already approved. Most such
therapies are delivered systemically through intravenous, intramuscular, or subcutaneous
administration with repeat bolus dosing. Indications in tumor regression,
osteoarthritis, or inflammation would benefit from ... read morethe availability of sustained local
delivery systems. Despite their appeal, sustained local delivery systems for antibodies
are not readily available. Three factors are thought to contribute to the scarcity of
such products: therapeutic protein instability, protein incompatibility with delivery
matrix processing or degradation products, and segregation of protein and matrix
development. A multi-step approach is described in which a therapeutic antibody, a silk
delivery matrix, and silk-antibody interactions are characterized in parallel.
Initially, the solution behavior of a model antibody was evaluated. Low pH insolubility,
structural destabilization between pH 6.0 and 7.0, deamidation, and methionine oxidation
were identified as modes of instability. Second, a novel silk material format, the
antibody-loaded lyogel, was produced by lyophilization of sonication induced silk
hydrogels. The lyophilization process imparted significant sustained release properties
on the lyogel compared to the parent hydrogel material. Third, a complex mechanism
describing antibody release from silk lyogels was defined. The strongest parameter
governing antibody release was hydration behavior of the silk lyogel matrix, which was
controlled by silk matrix density. Secondary ionic repulsions also played a critical
role in antibody recovery and release. While difficult to fully characterize, delivery
systems defined by multi-component release mechanisms are desirable because they offer
many control points for fine tuning release properties. Finally, characterization of
released antibody confirmed a favorable stability profile. No significant changes in
physical stability or biological function were observed. Interaction with the silk
matrix was found to induce antibody methionine oxidation. The parallel development
approach helped identify effective strategies for antibody stability and release
optimization. The improved mechanistic understanding of silk-antibody interactions lead
to the creation of a polysorbate loaded lyogel with improved antibody recovery and a
methionine loaded lyogel which prevented antibody
oxidation.
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Biomedical Engineering.
Advisors: David Kaplan, and Bernardo Perez-Ramirez.
Committee: Fiorenzo Omenetto, and Joshua Kritzer.
Keyword: Biomedical engineering.read less - ID:
- v692tj483
- Component ID:
- tufts:21101
- To Cite:
- TARC Citation Guide EndNote
