Enhanced Delivery of Plasmid Encoding Interleukin-12 Gene by Diethylene Triamine Penta-Acetic Acid (DTPA)-Conjugated PEI Nanoparticles
Enhanced Delivery of Plasmid Encoding Interleukin-12 Gene by Diethylene Triamine Penta-Acetic Acid (DTPA)-Conjugated PEI Nanoparticles
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DOI：
10.1007/s12010-016-1991-1
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发表时间：
2016-05-01
影响因子：
3
通讯作者：
Sheikhsaran, Fatemeh
中科院分区：
文献类型：
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作者：
Dehshahri, Ali;Sadeghpour, Hossein;Sheikhsaran, Fatemeh
重组治疗蛋白被认为是一类治疗各种疾病的有效药物。尽管重组治疗性蛋白有效，但仍有一些报道指出重组治疗性蛋白的全身不良反应限制了其广泛的临床应用。在用于肿瘤免疫治疗的多种细胞因子中，白细胞介素12(IL-12)作为一种强大的抗肿瘤和抗血管生成因子显示出巨大的潜力。然而，全身注射IL-12后的显著毒性反应促使研究人员寻找替代方法，如在肿瘤组织内传递和局部表达IL-12基因。为了将IL-12基因的编码基因转移到载体上，用二乙三胺五乙酸(DTPA)对聚乙烯亚胺(PEI)进行了修饰，以调节聚合物的疏水-亲水平衡及其毒性。DTPA偶联的PEI衍生物能够形成100-180 nm的复合体，具有很强的缩合能力和对酶降解的保护作用。在接合度为0.1%时，DTPA偶联的PEI的基因转移能力最强，IL-12的产生水平是未修饰PEI的两倍。研究结果表明，通过调节PEI的表面正电荷和改善聚合物的疏水平衡，可以认为是开发安全有效的纳米载体的一种成功策略。
Recombinant therapeutic proteins have been considered as an efficient category of medications used for the treatment of various diseases. Despite their effectiveness, there are some reports on the systemic adverse effects of recombinant therapeutic proteins limiting their wide clinical applications. Among different cytokines used for cancer immunotherapy, interleukin-12 (IL-12) has shown great ability as a powerful antitumor and antiangiogenic agent. However, significant toxic reactions following the systemic administration of IL-12 have led researchers to seek for alternative approaches such as the delivery and local expression of the IL-12 gene inside the tumor tissues. In order to transfer the plasmid encoding IL-12 gene, the most extensively investigated polycationic polymer, polyethylenimine (PEI), was modified by diethylene triamine penta-acetic acid (DTPA) to modulate the hydrophobic-hydrophilic balance of the polymer as well as its toxicity. DTPA-conjugated PEI derivatives were able to form complexes in the size range around 100-180 nm with great condensation ability and protection of the plasmid against enzymatic degradation. The highest gene transfer ability was achieved by the DTPA-conjugated PEI at the conjugation degree of 0.1 % where the level of IL-12 production increased up to twofold compared with that of the unmodified PEI. Results of the present study demonstrated that modulation of the surface positive charge of PEI along with the improvement of the polymer hydrophobic balance could be considered as a successful strategy to develop safe and powerful nanocarriers.