Silk-elastinlike recombinant polymers for gene therapy of head and neck cancer: from molecular definition to controlled gene expression.
Silk-elastinlike protein polymers (SELP's) are block copolymers of silk-like and elastin-like tandem repeats. With appropriate sequence and composition SELPs can be liquid at room temperature and form hydrogels at body temperature. The influence of polymer structure and concentration on biodegradation in vitro and controlled delivery of adenoviruses carrying reporter genes to head and neck tumors in vivo was evaluated using hydrogels made from three SELP analogs. SELP-815K, with eight silk and fifteen elastin units and a lysine (K) modified elastin, was compared to SELP-415K and SELP-47K. Hydrogels with higher silk content and concentration degraded at a slower rate compared to other analogs. Intratumoral injection of adenoviruses with SELPs enhanced gene expression in tumor tissue up to 10 fold compared to viral injection without polymer. Viruses delivered with SELP-815K at 4 wt.% polymer concentration showed the highest level of gene expression. Tumor to liver ratio of expression was up to 55 fold higher for SELP-mediated systems. This study demonstrates the influence of exquisite control over polymer structure using recombinant techniques on spatial and temporal control over adenoviral delivery and establishes the utility of SELP matrices as biodegradable systems for gene therapy of head and neck cancer.
Gustafson
Joshua
J
Department of Bioengineering, University of Utah, Salt Lake City, UT, 84108, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84108, USA.
Greish
Khaled
K
Frandsen
Jordan
J
Cappello
Joseph
J
Ghandehari
Hamidreza
H
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D003432:Cross-Linking Reagents; D004549:Elastin / Q000737:chemistry*; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D020100:Hydrogels; D007763:Lac Operon / Q000235:genetics; D049449:Luminescence; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000737:chemistry; D047011:Silk / Q000737:chemistry*; D013329:Structure-Activity Relationship; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D003432:Cross-Linking Reagents; D020100:Hydrogels; D011994:Recombinant Proteins; D047011:Silk; D004549:Elastin; D001616:beta-Galactosidase