Head and neck squamous cell carcinoma (HNSCC) is an ominous cancer with more than 48,000 new cases diagnosed annually in the US. Gene-directed enzyme prodrug therapy (GDEPT) using adenovirus with herpes simplex virus thymidine kinase (Ad.HSVtk) in conjunction with ganciclovir (GCV) is effective in HNSCC tumor management, however transient gene expression, dissemination of viruses to non-target organs, and multiple injections required for both the virus and drug limit therapeutic utility. Matrix-mediated delivery of adenoviruses by silk-elastinlike protein polymer (SELP) hydrogels increase transfection efficiency in tumors, localize transgene expression, and enhance therapeutic efficacy. Matrix metalloproteinases (MMPs) are known to degrade and remodel the tumor extracellular matrix. By introducing MMP responsive amino acid sequences at precise locations in SELPs, it is possible to control the degradation of SELPs and release of both adenoviruses and GCV. The following Specific Aims will be addressed: 1) Synthesize and characterize silk- elastinlike polymers containing MMP degradable sequences in the backbone. 2) Evaluate the influence of MMP responsive sequences on degradation properties of SELP hydrogels and adenoviral release in vitro. 3) Evaluate the influence of MMP degradable sequences on improvement of transfection efficiency, duration of transgene expression, biodistribution, therapeutic efficacy, and toxicity in vivo. The new polymers are designed to enhance the efficacy of GDEPT while reducing toxicity and the need for multiple injections of both the virus and the drug, ultimately enhancing therapeutic outcome for patients with HNSCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107621-09
Application #
8590110
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Fu, Yali
Project Start
2004-04-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2014
Total Cost
$285,923
Indirect Cost
$84,271
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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
Poursaid, Azadeh; Jensen, Mark Martin; Huo, Eugene et al. (2016) Polymeric materials for embolic and chemoembolic applications. J Control Release 240:414-433
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
Jung, Se-Hui; Choi, Joung-Woo; Yun, Chae-Ok et al. (2014) Sustained local delivery of oncolytic short hairpin RNA adenoviruses for treatment of head and neck cancer. J Gene Med 16:143-52
Price, Robert; Poursaid, Azadeh; Cappello, Joseph et al. (2014) Effect of shear on physicochemical properties of matrix metalloproteinase responsive silk-elastinlike hydrogels. J Control Release 195:92-8
Frandsen, Jordan L; Ghandehari, Hamidreza (2012) Recombinant protein-based polymers for advanced drug delivery. Chem Soc Rev 41:2696-706

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