Multifunctional Neomycin-Triazine-Based Cationic Lipids for Gene Delivery with Antibacterial Properties,Bioconjugate Chemistry

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Multifunctional Neomycin-Triazine-Based Cationic Lipids for Gene Delivery with Antibacterial Properties
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2021-01-20 , DOI: 10.1021/acs.bioconjchem.0c00616
Chiara Pennetta ₁ , Nina Bono ₁ , Federica Ponti _{1,

2} , Maria Cristina Bellucci ₃ , Fiorenza Viani ₄ , Gabriele Candiani ₁ , Alessandro Volonterio _{1,

4}

Affiliation

Cationic lipids (CLs) have gained significant attention among nonviral gene delivery vectors due to their ease of synthesis and functionalization with multivalent moieties. In particular, there is an increasing request for multifunctional CLs having gene delivery capacity and antibacterial activity. Herein, we describe the design and synthesis of a novel class of aminoglycoside (AG)-based multifunctional vectors with high transfection efficiency and noticeable antibacterial properties. Specifically, cationic amphiphiles were built on a triazine scaffold, allowing for an easy derivatization with up to three potentially different substituents, such as neomycin (Neo) that serves as the polar head and one or two lipophilic tails, namely stearyl (ST) and oleyl (OL) alkyl chains and cholesteryl (Chol) tail. With the aim to shed more light on the effect of different types and numbers of lipophilic moieties on the ability of CLs to condense and transfect cells, the performance of Neo–triazine-based derivatives as gene delivery vectors was evaluated and compared. The ability of Neo–triazine-based derivatives to act as antimicrobial agents was evaluated as well. Neo–triazine-based CLs invariably exhibited excellent DNA condensation ability, even at a low charge ratio (CR, +/−). Besides, each derivative showed very good transfection performance at its optimal CR on two different cell lines, along with negligible cytotoxicity. CLs bearing symmetric two-tailed OL proved to be the most effective in transfection. Interestingly, Neo–triazine-based derivatives, used as either free lipids or lipoplexes, exhibited strong antibacterial activity against Gram-negative bacteria, especially in the case of CLs bearing one or two aliphatic chains. Altogether, these results highlight the potential of Neo–triazine-based derivatives as effective multifunctional nonviral gene delivery vectors.

中文翻译：

具有抗菌特性的用于基因传递的多功能新霉素-三嗪基阳离子脂质

阳离子脂质 (CLs) 在非病毒基因递送载体中获得了极大的关注，因为它们易于合成和具有多价部分的功能化。特别是，对具有基因传递能力和抗菌活性的多功能 CL 的需求越来越大。在此，我们描述了一类新型基于氨基糖苷 (AG) 的多功能载体的设计和合成，该载体具有高转染效率和显着的抗菌特性。具体而言，阳离子两亲物建立在三嗪支架上，允许使用多达三个可能不同的取代基轻松衍生化，例如用作极性头部的新霉素 (Neo) 和一两个亲脂尾部，即硬脂基 (ST) 和油基(OL) 烷基链和胆固醇 (Chol) 尾。为了更多地了解不同类型和数量的亲脂性部分对 CL 凝聚和转染细胞能力的影响，评估和比较了基于新三嗪的衍生物作为基因递送载体的性能。还评估了基于新三嗪的衍生物作为抗菌剂的能力。即使在低电荷比（CR，+/-）下，基于新三嗪的 CL 也始终表现出出色的 DNA 缩合能力。此外，每种衍生物在两种不同细胞系的最佳 CR 下都显示出非常好的转染性能，并且细胞毒性可忽略不计。带有对称双尾 OL 的 CL 被证明是最有效的转染。有趣的是，基于新三嗪的衍生物，用作游离脂质或脂质复合物，对革兰氏阴性菌表现出很强的抗菌活性，特别是在带有一或两条脂肪链的 CL 的情况下。总之，这些结果突出了基于新三嗪的衍生物作为有效的多功能非病毒基因递送载体的潜力。

更新日期：2021-01-20

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