Characterization and real-time imaging of gene expression of adenovirus embedded silk-elastinlike protein polymer hydrogels
Characterization and real-time imaging of gene expression of adenovirus embedded silk-elastinlike protein polymer hydrogels
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DOI：
10.1021/mp800054w
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发表时间：
2008-09-01
影响因子：
4.9
通讯作者：
Ghandehari, Hamidreza
中科院分区：
文献类型：
--
作者：
Cresce, Arthur von Wald;Dandu, Ramesh;Ghandehari, Hamidreza
与腺病毒载体相关的瞬时表达水平、载体传播和毒性已促使基质用于局部和受控的基因传递。两个重组丝蛋白-弹性蛋白聚合物类似物，SELP-47K和SELP-415K，由不同长度和比例的丝蛋白和弹性蛋白单元组成，先前被证明是能够通过基质介导的可控腺病毒基因传递的可注射水凝胶。本文报道了在头颈癌人肿瘤异种移植模型中，利用全动物成像技术研究了这些SELP类似物对腺病毒基因表达的时空控制性。病毒表达水平的实时图像表明，聚合物浓度和聚合物结构是影响病毒释放和病毒转染性的主要因素。聚合物浓度的降低和聚合物弹性蛋白含量的增加会导致更大的释放，这可能是由于水凝胶网络结构的变化。为了更好地理解这一关系，用动态力学分析(DMA)和透射电子显微镜(TEM)分析了水凝胶的宏观和微观结构。结果证实，蛋白质聚合物的浓度和弹性蛋白含量通过改变SELP纤维网络的物理约束和SELP纤维的水化程度来影响水凝胶的孔径。使用可通过微创技术注射到肿瘤内的SELP水凝胶载体来调节病毒释放的可能性为治疗性病毒的传递带来了巨大的希望。
Transient expression levels, vector dissemination and toxicities associated with adenoviral vectors have prompted the usage of matrices for localized and controlled gene delivery. Two recombinant silk-elastinlike protein polymer analogues, SELP-47K and SELP-415K, consisting of different lengths and ratios of silk and elastin units, were previously shown to be injectable hydrogels capable of matrix-mediated controlled adenoviral gene delivery. Reported here is a study of spatiotemporal control over adenoviral gene expression with these SELP analogues in a human tumor xenograft model of head and neck cancer using whole animal imaging. Real-time images of viral expression levels indicate that polymer concentration and polymer structure are predominant factors that affect viral release and, thus, viral transfection. Decrease in polymer concentration and increase in polymer elastin content results in greater release, probably due to changes in the network structure of the hydrogel. To better understand this relationship, macro- and microstructural properties of the hydrogels were analyzed using dynamic mechanical analysis (DMA) and transmission electron microscopy (TEM). The results confirm that the concentration and the elastin content of the protein polymer affect the pore size of the hydrogel by changing the physical constraints of the SELP fibril network and the degree of hydration of the SELP fibrils. The potential to modulate viral release using SELP hydrogel delivery vehicles that can be injected intratumorally by minimally invasive techniques holds significant promise for the delivery of therapeutic viruses.