Multivalent polyrotaxane vectors as adaptive cargo complexes for gene therapy,Polymer Chemistry

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Multivalent polyrotaxane vectors as adaptive cargo complexes for gene therapy
Polymer Chemistry ( IF 4.1 ) Pub Date : 2017-09-07 00:00:00 , DOI: 10.1039/c7py01256j
Rodinel Ardeleanu _{1,

2,

3,

4} , Andrei I. Dascalu _{1,

2,

3,

4} , Andrei Neamtu _{1,

2,

3,

4,

5} , Dragos Peptanariu _{1,

2,

3,

4} , Cristina M. Uritu _{1,

2,

3,

4} , Stelian S. Maier _{1,

2,

3,

4,

6} , Alina Nicolescu _{1,

2,

3,

4} , Bogdan C. Simionescu _{1,

2,

3,

4,

7} , Mihail Barboiu _{8,

9,

10,

11,

12} , Mariana Pinteala _{1,

2,

3,

4}

Affiliation

This paper describes the philosophy to design, and a procedure to construct polyrotaxane-type gene carriers, together with the proof of their ability to conjunctively cooperate in order to generate cargo-complexes with dsDNA, able to efficiently transfect cultured cells. The main feature of these entities is their functionality as a cargo-complex that chemomimic the histones, and morphomimic the nucleosome. The polyrotaxane contains a PEG axle end-capped with silatrane cages, allowing the threading of nine cyclodextrin units, functionalized with polyethylenimines (PEI, 2 kDa). The obtained ROT-PEI multivalent architecture is similar to a giant PEI polycation, but devoid of the toxicity of large PEIs. To increase the cargo-complexes’ versatility and to reduce their cytotoxicity, the study has been complemented with two other types of carriers: (i) including a mixture of PEI and short PEG molecules (ROT-PEI-PEG₇₅₀), and (ii) with PEI branches post-decorated with guanidine or arginine (ROT-PEI-G; ROT-PEI-Arg). The molecular geometry and the overall interactions of the synthesized carriers were investigated in silico. The experimental DNA binding capacity of these carriers in relationship with size, morphology and electrical charge was evaluated. The in vitro tests, showing the cytotoxicity and transfection efficiency of the investigated carriers, provided new information on gene vector design.

中文翻译：

多价聚轮烷载体作为基因治疗的适应性货物复合物

本文描述了设计原理，以及构建聚轮烷型基因载体的过程，并证明了它们能够协同合作以生成与dsDNA形成货物复合物的能力，从而能够有效地转染培养的细胞。这些实体的主要特征是它们的功能是作为货物复合物，对组蛋白进行化学处理，对核小体进行形态学处理。聚轮烷包含一个用硅烷基笼子封端的PEG轴，允许穿入9个用聚乙烯亚胺（PEI，2 kDa）功能化的环糊精单元。所获得的ROT-PEI多价结构类似于巨型PEI聚阳离子，但没有大型PEI的毒性。为了增加货物复合物的多功能性并降低其细胞毒性，该研究还补充了两种其他类型的载体：₇₅₀），和（ii）用胍或精氨酸（ROT-PEI-G; ROT-PEI-Arg）后装饰的PEI分支。合成载体的分子几何和整体相互作用进行了计算机研究。评价了这些载体的实验DNA结合能力与大小，形态和电荷的关系。在体外试验中，示出了所研究的载流子的细胞毒性和转染效率，设置在基因载体设计的新信息。

更新日期：2017-09-14

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