Silk-elastinlike protein polymers improve the efficacy of adenovirus thymidine kinase enzyme prodrug therapy of head and neck tumors

摘要

Background: Adenoviral-directed enzyme prodrug therapy is a promising approach for head and neck cancer gene therapy. The challenges faced by this approach, however, comprise transient gene expression and dissemination of viruses to distant organs. Methods: We used recombinant silk-elastinlike protein polymer (SELP) matrices for intratumoral delivery of adenoviruses containing both thymidine kinase-1 and luciferase genes in a nude mouse model of JHU-022 head and neck tumor. Hydrogels made from two SELP analogues (47K and 815K), with similar silk to elastinlike block ratios but different block lengths, were studied for intratumoral viral delivery. Tumor-bearing mice were followed up for tumor progression and luciferase gene expression concomitantly for 5 weeks. Polymer safety was evaluated through body weight change, blood count, and liver and kidney functions, in addition to gross and microscopic histological examination. Results: SELP-815K analogues efficiently controlled the duration and extent of transfection in tumors for up to 5 weeks with no detectable spread to the liver. An approximately five-fold greater reduction in tumor volume was obtained with matrix-mediated delivery compared to intra-tumoral injection of adenoviruses in saline. SELP matrix proved safe in all injected mice compared to the control group. Conclusions: The SELP-controlled gene delivery approach could potentially improve the anticancer activity of virus-mediated gene therapy at the same time as limiting viral spread to normal organs.