The overall goal of this proposal is to develop a novel local drug delivery system for cancer radiotherapy by direct intratumoral administration of a thermally sensitive macromolecule conjugated to a therapeutic radionuclide of interest. Thermally sensitive elastin-like polypeptides (ELPs) that spontaneously undergo a soluble-insoluble phase transition between room temperature and body temperature leading to the formation of a coacervate, "gel-like" phase will be designed and optimized at the molecular level via genetic engineering methods. Two innovative strategies to increase the retention of the ELPs in solid tumors beyond that provided by thermal coacervation will also be investigated: (1) Zn-mediated reversible crosslinking of ELP coacervates, and (2) binding of ELPs and their proteolytic fragments to extracellular matrix proteins. These genetically engineered ELPs will be conjugated to 131I, a therapeutic radioisotope, and infused into a tumor to spontaneously form a radioactive depot within the tumor with long in vivo retention (>1 week) at the injection site. These polymers will be evaluated for therapeutic efficacy and immunogenic properties. We hypothesize that this local delivery approach for the targeted irradiation of solid tumors from the "inside-out" will enhance therapeutic efficacy by providing enhanced exposure of the radionuclide to the tumor while minimizing exposure of healthy tissues, thereby reducing systemic toxicity. Furthermore, the clinical significance of the proposed research is that it will lead to a novel, genetically engineered, nonimmunogenic injectable radionuclide deposition system that is an improvement over current brachytherapy methods.

Public Health Relevance

Cancer is the second leading cause of death in the US. This project will develop a new local delivery method to improve the efficacy of different drugs to many different types of solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA138784-03
Application #
8193068
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Prasanna, Pat G
Project Start
2009-05-17
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$323,700
Indirect Cost
$116,200
Name
Duke University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Asai, Daisuke; Xu, Donghua; Liu, Wenge et al. (2012) Protein polymer hydrogels by in situ, rapid and reversible self-gelation. Biomaterials 33:5451-8
Liu, Wenge; MacKay, J Andrew; Dreher, Matthew R et al. (2010) Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model. J Control Release 144:2-9