Synthesis and chemical modification of degradable polymers to enhance gene delivery

Poly([beta]-amino ester)s are a class of cationic, degradable polymers that have shown significant promise as gene delivery agents, more effective than the state-of-the-art, commercially available non-viral systems. The main objective of this thesis is to synthesize new poly([beta]-amino ester)s and modify existing ones to further improve their gene delivery properties for clinical applications. This has been accomplished by developing both side- and end-chain chemistries for poly([beta]-amino ester)s. A series of novel poly([beta]-amino ester)s were prepared using a new amine monomer 2-(2-pyridyldithio)-ethylamine. The polymer side chains display fast and selective reactivity towards thiol ligands, as demonstrated using mercaptoethylamine (MEA) and RGDC, a ligand that binds with high affinity to certain integrin receptors on angiogenic endothelial cells. The MEA derivatives in particular, were able to self-assemble with plasmid DNA to form nano-complexes that can partially disassemble in response to intracellular glutathione concentrations. These polymers also displayed low cellular toxicity and were able to mediate transfection at high levels in human hepatocellular carcinoma cells. It is envisioned that the PDA poly([beta]-amino ester)s can serve as cationic, degradable platforms to attach targeting ligands, viral peptides and other molecules to a single chain to improve gene delivery.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2007

Author dc:creator

• Zugates, Gregory Thomas

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/1721.1/38970

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/38970