Targeted and stimuli-responsive polymers as chemotherapeutic delivery systems

Successful administration of chemotherapeutic agents for cancer treatment requires a balance between the efficacy and the safety of the drug. This often limits physicians to a very narrow therapeutic window. To avoid the harmful side-effects, chemotherapeutic agents may be administered at a suboptimal dose. This is not only a less effective treatment, but can lead to the development of drug resistance by cancerous cells. The therapeutic window can be increased through targeted, stimuli-responsive delivery, which increases the drug concentration at the diseased site, and releases or activates the drug only when it reaches the target. Cancer is a highly variable disease occurring in many organs. There is a need for delivery systems that are easily adaptable for a number of targets in different forms of cancers, and that can accommodate various cytotoxic drugs. The motivation of this project was to develop flexible synthesis procedures for the targeted delivery of chemotherapeutic agents. In this work, we have synthesized and tested three drug delivery systems. The first system is a dextran-based polymer conjugate designed to preferentially deliver doxorubicin to hepatocytes. Doxorubicin has been conjugated to dextran of different molecular weights, with varying degrees of galactose substitution. The degree of doxorubicin substitution was maintained by performing the conjugation of doxorubicin and galactose in two sequential steps. The synthesis scheme was simple, efficient and easily adaptable to other therapeutic agents and targeting moieties with free amine groups. In cell culture studies on target hepatocytes, the dextran-doxorubicin-galactose (DDG) conjugates showed lower toxicity compared to doxorubicin, increased toxicity with higher molecular weight polymers, and greater toxicity with higher degree of galactose substitution.

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

• Zaman, Noreen Tasneem

Advisor dc:contributor.advisor

• Jackie Y. Ying.

• 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/1721.1/43217

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/43217