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.

Public Health Relevance

Design of new gene delivery systems will improve the efficacy of treatment, reduce toxicity and improve quality of life for head and neck cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107621-08
Application #
8410479
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
2013-01-01
Budget End
2013-12-31
Support Year
8
Fiscal Year
2013
Total Cost
$299,030
Indirect Cost
$88,584
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
Price, Robert; Poursaid, Azadeh; Ghandehari, Hamidreza (2014) Controlled release from recombinant polymers. J Control Release 190:304-13
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
Price, Robert; Gustafson, Joshua; Greish, Khaled et al. (2012) Comparison of silk-elastinlike protein polymer hydrogel and poloxamer in matrix-mediated gene delivery. Int J Pharm 427:97-104
Anumolu, Rajasekhar; Gustafson, Joshua A; Magda, Jules J et al. (2011) Fabrication of highly uniform nanoparticles from recombinant silk-elastin-like protein polymers for therapeutic agent delivery. ACS Nano 5:5374-82
Greish, Khaled; Frandsen, Jordan; Scharff, Stephanie et al. (2010) Silk-elastinlike protein polymers improve the efficacy of adenovirus thymidine kinase enzyme prodrug therapy of head and neck tumors. J Gene Med 12:572-9
Gustafson, Joshua A; Price, Robert A; Greish, Khaled et al. (2010) Silk-elastin-like hydrogel improves the safety of adenovirus-mediated gene-directed enzyme-prodrug therapy. Mol Pharm 7:1050-6
Dinerman, Adam A; Cappello, Joseph; El-Sayed, Mohamed et al. (2010) Influence of solute charge and hydrophobicity on partitioning and diffusion in a genetically engineered silk-elastin-like protein polymer hydrogel. Macromol Biosci 10:1235-47
Hwang, David; Moolchandani, Vikas; Dandu, Ramesh et al. (2009) Influence of polymer structure and biodegradation on DNA release from silk-elastinlike protein polymer hydrogels. Int J Pharm 368:215-9
Hwang, Wonseok; Kim, Bo-Hyun; Dandu, Ramesh et al. (2009) Surface Induced Nanofiber Growth by Self-Assembly of a Silk-Elastin-like Protein Polymer. Langmuir :

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