Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
J Gene Med. 2010 Jul;12(7):572-9. doi: 10.1002/jgm.1469.
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.
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.
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.
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.
腺病毒导向酶前药治疗是头颈部癌症基因治疗的一种很有前途的方法。然而，这种方法面临的挑战包括瞬时基因表达和病毒向远处器官的传播。
我们使用重组丝弹性蛋白样蛋白聚合物（SELP）基质，在 JHU-022 头颈部肿瘤裸鼠模型中进行肿瘤内传递含有胸苷激酶-1 和荧光素酶基因的腺病毒。研究了两种 SELP 类似物（47K 和 815K）的水凝胶，它们具有相似的丝弹性蛋白样嵌段比，但嵌段长度不同，用于肿瘤内病毒传递。通过肿瘤进展和荧光素酶基因表达同时监测 5 周，对携带肿瘤的小鼠进行随访。除了大体和显微镜组织学检查外，还通过体重变化、血细胞计数以及肝肾功能评估聚合物的安全性。
SELP-815K 类似物可有效地控制肿瘤内转染的持续时间和程度，长达 5 周，且未检测到向肝脏扩散。与在盐水中瘤内注射腺病毒相比，通过基质介导的传递可使肿瘤体积减少约五倍。与对照组相比，所有注射小鼠的 SELP 基质均安全。
SELP 控制的基因传递方法有可能在限制病毒向正常器官传播的同时，提高病毒介导基因治疗的抗癌活性。
