Targeted drug delivery by novel polymer-drug conjugates containing linkers cleavable by disease-associated enzymes

We have conceptualized a new class of polymer-linker-drug conjugates to achieve targeted drug delivery for the systemic treatment of cancer and other inflammatory diseases. The physiochemical properties of the polymer allow the conjugate to circulate longer in the body by minimizing renal and hepatic clearance, thereby improving the pharmacokinetics of the attached drugs. Traditionally, linkers are degraded by acidity or by some ubiquitous intracellular enzymes. We incorporate linkers that are sensitive to a specific extracellular enzyme whose overexpression is co-localized with the diseased tissue. The drug molecules remain inactive when attached to the polymer, thus preventing normal tissues from harmful side effects. When the conjugate is transported to the diseased area where there is a high level of the target enzyme, the linkers are cleaved to release the drugs at the specific site. As an example, we designed and synthesized two generations of novel polymer-peptide-drug conjugates for the tumor-targeted delivery of chemotherapeutics. To allow for passive targeting and enhanced permeation and retention (EPR), dextran with a size greater than 6 nm was selected as the polymeric carrier. This biocompatible and biodegradable carrier was chemically modified to allow for conjugation with doxorubicin and methotrexate, two common chemotherapeutics with undesirable side effects.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2005

Author dc:creator

• Chau, Ying

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/1721.1/32332
• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Identifier URI

http://dspace.mit.edu/handle/1721.1/32332

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/32332