Radiation-enhanced delivery of plasmid DNA to tumors utilizing a novel PEI polyplex.
Radiation-enhanced delivery of plasmid DNA to tumors utilizing a novel PEI polyplex.
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DOI：
10.1038/s41417-017-0004-z
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发表时间：
2018-08
影响因子：
6.4
通讯作者：
Yeo Y
中科院分区：
文献类型：
--
作者：
Appelbe OK;Kim BK;Rymut N;Wang J;Kron SJ;Yeo Y
围绕基因治疗潜力的兴奋已经减弱，因为到目前为止限制其在临床上成功实施的挑战，如稳定性、转染率和毒性等问题。在本研究中，将低分子量线性聚乙烯亚胺(2.5 kDa)与脂类石胆酸偶联，并与天然多糖硫酸皮肤素(DS)络合，以掩盖修饰后聚合物的额外阳离子电荷。体外实验表明，这些修饰提高了与质粒DNA(PDNA)的复合体的稳定性和转染率。这种新型的三元复合体(pDNA/3e/ds)被用来研究肿瘤靶向放射治疗是否导致荷瘤小鼠体内基因治疗载体的增强积累和滞留。生物分布成像显示，肿瘤照射不仅在pDNA/3e/ds中增加了pDNA的蓄积和滞留，并减少了非靶组织中的pDNA积聚，而且在相关的基于PEI的复合体和商业DNA输送载体中也是如此。在这项研究中开发的含DS的复合体在肿瘤特异性PDNA递送方面显示出最大的增加。这些发现表明，核酸载体设计向前迈进了一步，并通过利用放射治疗作为增强递送的工具，为整体癌症基因治疗提供了一种有前景的方法。
The excitement surrounding the potential of gene therapy has been tempered due to the challenges that have thus far limited its successful implementation in the clinic such as issues regarding stability, transfection efficiency, and toxicity. In this study, low molecular weight linear polyethyleneimine (2.5 kDa) was modified by conjugation to a lipid, lithocholic acid, and complexed with a natural polysaccharide, dermatan sulfate (DS), to mask extra cationic charges of the modified polymer. In vitro examination revealed that these modifications improved complex stability with plasmid DNA (pDNA) and transfection efficiency. This novel ternary polyplex (pDNA/3E/DS) was used to investigate if tumor-targeted radiotherapy led to enhanced accumulation and retention of gene therapy vectors in vivo in tumor-bearing mice. Imaging of biodistribution revealed that tumor irradiation led to increased accumulation and retention as well as decreased off-target tissue buildup of pDNA in not only pDNA/3E/DS, but also in associated PEI-based polyplexes and commercial DNA delivery vehicles. The DS-containing complexes developed in this study displayed the greatest increase in tumor-specific pDNA delivery. These findings demonstrate a step forward in nucleic acid vehicle design as well as a promising approach to overall cancer gene therapy through utilization of radiotherapy as a tool for enhanced delivery.
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影响因子：
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