Sustained local delivery of oncolytic short hairpin RNA adenoviruses for treatment of head and neck cancer.

Abstract

BACKGROUND:

Oncolytic adenovirus (Ad)-mediated gene therapy is a promising approach for suppression of primary tumors. Therapeutic efficacy of Ad-mediated gene therapy has been limited by immunogenicity, rapid dissemination of viral progenies into systemic circulation and short duration of biological activity. Polymeric sustained local delivery can overcome many of these challenges to produce a viable therapy with improved outcomes.

METHODS:

Silk-elastinlike protein polymer (SELP) hydrogels were used for matrix-mediated delivery of oncolytic Ad, containing short hairpin RNA (shRNA) targeted to C-Met (sh-C-Met), to solid tumors in a nude mouse model of human head and neck cancer. The biological activity of Ad released from SELP hydrogels was examined as a function of time to investigate protective effects on viral activity. Antitumor efficacy and viral distribution were investigated for 3 weeks in tumor-bearing mice.

RESULTS:

The encapsulation of Ad with SELP hydrogels sustained biological activity longer than Ad alone. Ad in SELP matrix showed 1.5-fold greater antitumor efficacy compared to that of naked Ad in human xenograft tumor models. Histological analysis demonstrated that treatment with Ad in a SELP matrix resulted in apoptosis in a wider area of tumor tissue and higher density of Ad infection compared to Ad administered alone.

CONCLUSIONS:

Matrix-mediated delivery of Ad-containing shRNA with SELP hydrogels enhances therapeutic efficacy by tumor-selective infection, spatiotemporal control and preservation of biologic activity.

• Authors: Se-Hui Jung, Joung-Woo Choi, Chae-Ok Yun, Ji Young Yhee, Robert Price, Sun Hwa Kim, Ick Chan Kwon, Hamidreza Ghandehari
• Journal: The journal of gene medicine (J Gene Med) 2014 May-Jun Vol. 16 Issue 5-6 Pg. 143-52 ISSN: 1521-2254 [Electronic] England
• PMID: 24962819 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 John Wiley & Sons, Ltd.

Chemical References

• Hydrogels
• Polymers
• RNA, Small Interfering
• Vascular Endothelial Growth Factor A
• Proto-Oncogene Proteins c-met

Topics

• Adenoviruses, Human (genetics)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Genetic Vectors (genetics)
• Head and Neck Neoplasms (genetics, therapy)
• Humans
• Hydrogels
• Oncolytic Virotherapy
• Oncolytic Viruses (genetics)
• Polymers
• Proto-Oncogene Proteins c-met (genetics)
• RNA Interference
• RNA, Small Interfering (genetics)
• Transduction, Genetic
• Vascular Endothelial Growth Factor A (genetics)