? The long-term goal of this research is to engineer polymeric delivery systems that improve the efficacy and reduce the toxicity of head and neck cancer gene therapy. The purpose of this project is to engineer silk-elastinlike polymeric (SELP) matrices for minimally invasive controlled delivery of adenovirus constructs carrying the RB94 tumor suppressor gene (Ad-RB94). The rationale is that by genetic engineering of SELPs, it is possible to tailor-make delivery systems that are liquid at room temperature, mixed under mild conditions with adenoviral tumor suppressor gene therapy vectors, form vector-laden hydrogels at body temperature after a single intratumoral injection, release viable vectors at the site of tumor over a desired period of time, and kill the tumor cells with minimum systemic toxicity and maximum efficacy. The following Specific Aims will be addressed: 1) To synthesize and characterize SELP hydrogels for localized and controlled adenoviral gene delivery. Linear SELP copolymer analogs containing silk-like and elastin-like repeating units with various sequences and lengths will be biosynthesized and characterized using recombinant techniques. Hydrogels will be formed from the linear polymers. The degree of swelling of the hydrogels will be examined as a function of polymer structure and initial polymer concentration at physiological temperature, pH, and ionic strength. 2) To examine the influence of polymer and adenoviral composition on the degree of swelling, adenoviral particle release and bioactivity in vitro. Model adenoviruses will be incorporated in the hydrogels. The degree of swelling will be evaluated in the presence of adenoviral particles. The amount released will be evaluated over time as a function of polymer structure and concentration. Release will be correlated with the bioactivity of the particles in relevant in vitro models. From the results of model adenoviral release and in vitro gene transfer, appropriate polymer and Ad-RB94 compositions will be used to examine the bioactivity of the released therapeutic tumor suppressor gene. 3) To evaluate the influence of polymer composition on transduction efficiency, duration of transgene expression, biodistribution, therapeutic efficacy, and toxicity of adenoviral-containing SELP hydrogels in vivo. A nude mouse tumor xenograft model of head and neck cancer will be used to evaluate these parameters by intratumoral administration of SELP hydrogels containing Ad-GFP (Adenoviruses containing green fluorescent protein gene as markers of gene transfer) and Ad-RB94. In the future phases, the proposed matrix-mediated adenoviral .gene therapy approach using genetically engineered polymers can be used for the development of clinically acceptable systems for gene therapy of head and neck cancer. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA107621-04
Application #
7408013
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Fu, Yali
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2008-08-01
Budget End
2010-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$281,835
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Isaacson, Kyle J; Jensen, Mark Martin; Watanabe, Alexandre H et al. (2018) Self-Assembly of Thermoresponsive Recombinant Silk-Elastinlike Nanogels. Macromol Biosci 18:
Isaacson, Kyle J; Martin Jensen, M; Subrahmanyam, Nithya B et al. (2017) Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression. J Control Release 259:62-75
Poursaid, Azadeh; Jensen, Mark Martin; Nourbakhsh, Ida et al. (2016) Silk-Elastinlike Protein Polymer Liquid Chemoembolic for Localized Release of Doxorubicin and Sorafenib. Mol Pharm 13:2736-48
Jeon, Hye-Yoon; Jung, Se-Hui; Jung, Young Mee et al. (2016) Array-Based High-Throughput Analysis of Silk-Elastinlike Protein Polymer Degradation and C-Peptide Release by Proteases. Anal Chem 88:5398-405
Poursaid, Azadeh; Jensen, Mark Martin; Huo, Eugene et al. (2016) Polymeric materials for embolic and chemoembolic applications. J Control Release 240:414-433
Jung, Bo-Kyeong; Lee, Yeon Kyung; Hong, JinWoo et al. (2016) Mild Hyperthermia Induced by Gold Nanorod-Mediated Plasmonic Photothermal Therapy Enhances Transduction and Replication of Oncolytic Adenoviral Gene Delivery. ACS Nano 10:10533-10543
Jung, Se-Hui; Choi, Joung-Woo; Yun, Chae-Ok et al. (2015) Direct observation of interactions of silk-elastinlike protein polymer with adenoviruses and elastase. Mol Pharm 12:1673-9
Price, Robert; Poursaid, Azadeh; Cappello, Joseph et al. (2015) In vivo evaluation of matrix metalloproteinase responsive silk-elastinlike protein polymers for cancer gene therapy. J Control Release 213:96-102
Poursaid, Azadeh; Price, Robert; Tiede, Andrea et al. (2015) In situ gelling silk-elastinlike protein polymer for transarterial chemoembolization. Biomaterials 57:142-52
Price, Robert; Poursaid, Azadeh; Ghandehari, Hamidreza (2014) Controlled release from recombinant polymers. J Control Release 190:304-13

Showing the most recent 10 out of 30 publications