Non-viral drug delivery systems for immune modulation

Biodegradable polymer particles have diverse applications in drug delivery. The main objective of this thesis was to apply these delivery systems to modulating the immune system. We optimized particle formulations for the delivery of three novel immune modulating compounds, small inhibiting RNA, immunostimulatory RNA, and 3-1,6-glucan. Because microparticles formulated from PLGA and Poly(3-amino-ester) have been shown to target and transfect DNA in antigen presenting cells we studied their ability to knock down genes with siRNA. We discovered ways to improve particle morphology, encapsulation efficiency, and buffer the acidic microenvironment of degrading microparticles, all significant challenges with siRNA. We next used fluorescent nanoparticles as imaging agents to study these siRNA delivery challenges. Cationic polymers were deposited on the surface of fluorescent core-shell silica nanoparticles electrostatically; the resulting particles were complexed with a nucleic acid and delivered to cells. We screened a library of 60 unique formulations to identify an optimal protocol for DNA transfection demonstrating efficiency equal to PEI. We screened a library of 30 unique formulations for siRNA delivery and demonstrated knockdown of 25%. Confocal imaging showed that polymer coating increased localization of the nanoparticles to the cell membrane, endosomes and nucleus. Polycation surface-modification seemed broadly extendable to a biodegradable polymer particle delivery system for siRNA. Cationic lipids or lipidoids were promising polycations to apply to biodegradable particle surface-modification because they efficiently deliver siRNA. We screened 30 lipidoid formulations for optimal knockdown in P388-D1 macrophage cells, and isolated formulations that demonstrated up to 40% knockdown in P388-D1, 80% knockdown in primary macrophage, and 65% knockdown in mouse macrophage in vivo.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2008

Author dc:creator

• Fuller, Jason E., Ph. D. Massachusetts Institute of Technology

Advisor dc:contributor.advisor

• Robert Langer.

• Chemical Engineering.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/43202

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/43202