Development of a lipoplex-type mRNA carrier composed of an ionizable lipid with a vitamin E scaffold and the KALA peptide for use as an ex vivo dendritic cell-based cancer vaccine.,Journal of Controlled Release

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Development of a lipoplex-type mRNA carrier composed of an ionizable lipid with a vitamin E scaffold and the KALA peptide for use as an ex vivo dendritic cell-based cancer vaccine.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-08-03 , DOI: 10.1016/j.jconrel.2019.08.002
Naho Tateshita ₁ , Naoya Miura ₁ , Hiroki Tanaka ₁ , Takeshi Masuda ₂ , Sumio Ohtsuki ₂ , Kota Tange ₃ , Yuta Nakai ₃ , Hiroki Yoshioka ₃ , Hidetaka Akita ₁

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A dendritic cells (DCs)-based vaccine (DC-vaccine) system is an attractive technology for eliciting antigen-specific immune responses that can protect subjects from infectious diseases and for curing various types of cancers. For the insertion of a foreign antigen to DCs, the transfection of an antigen-coding mRNA to the cells is a promising approach. In order to introduce an antigen, a carrier for mRNA transfection is required, since the mRNA molecule per se is unstable in serum-containing medium. We previously reported on an ionizable lipid-like material with vitamin E-scaffolds (ssPalmE) as a material for a lipid nanoparticle (LNP)-based carrier for nucleic acids. In the present study, we report on the development of a lipoplex-type mRNA carrier for use as a DC-vaccine by using a combination of an ssPalmE-LNP and an α-helical cationic peptide "KALA" (ssPalmE-KALA). The transfection of mRNAs complexed with the ssPalmE-KALA achieved a significantly higher protein expression and the production of proinflammatory cytokines from murine bone marrow derived DCs (BMDCs) in comparison with a lipoplex that was prepared with an ssPalm with fatty acid-scaffolds (myristic acid; ssPalmM-KALA). A cellular uptake process and a pH-responsive membrane-destabilization activity cannot explain the preferred protein expression and immune-stimulation caused by the ssPalmE-KALA. Proteomic analyses suggest that transfection with the ssPalmM-KALA stimulates a down-regulatory pathway of translation, while the transfection with the ssPalmE-KALA does not stimulate it. In the vaccination with the BMDCs that were preliminarily transfected with an ovalbumin (OVA)-encoding mRNA elicited the induction OVA specific cytotoxic T-lymphocyte activity in vivo. In parallel, the vaccination induced significant prophylactic anti-tumor effects against a model tumor that stably expressed the OVA protein. Based on the above findings, the ssPalmE-KALA appears to be a potent ex vivo DCs-based RNA vaccine platform.

中文翻译：

由可电离的脂质与维生素E支架和KALA肽组成的脂复合物型mRNA载体的开发，可用作离体树突状细胞癌疫苗。

基于树突细胞（DCs）的疫苗（DC-vaccine）系统是一种引人注目的技术，可引起抗原特异性免疫反应，从而保护受试者免受传染病的侵害并治愈各种类型的癌症。为了将外源抗原插入DC，将编码抗原的mRNA转染至细胞是有前途的方法。为了导入抗原，需要mRNA转染的载体，因为mRNA分子本身在含血清的培养基中不稳定。我们之前曾报道过一种可离子化的类脂质材料，其中维生素E支架（ssPalmE）作为基于脂质纳米颗粒（LNP）的核酸载体的材料。在目前的研究中，我们报道了通过使用ssPalmE-LNP和α-螺旋阳离子肽“ KALA”（ssPalmE-KALA）的组合，用于DC疫苗的脂质复合物型mRNA载体的开发。与用ssPalm和脂肪酸支架（肉豆蔻酸）制备的脂质复合物相比，与ssPalmE-KALA复合的mRNA的转染获得了明显更高的蛋白质表达，并从鼠骨髓来源的DCs（BMDCs）产生了促炎性细胞因子。 ; ssPalmM-KALA）。细胞的吸收过程和pH响应性的膜去稳定活性不能解释ssPalmE-KALA引起的优选蛋白表达和免疫刺激。蛋白质组学分析表明，用ssPalmM-KALA转染可刺激翻译的下调途径，而用ssPalmE-KALA转染不会刺激它。在用预先用卵清蛋白（OVA）编码的mRNA转染的BMDC进行的疫苗接种中，体内诱导了OVA特异性细胞毒性T淋巴细胞的诱导。同时，疫苗接种对稳定表达OVA蛋白的模型肿瘤具有明显的预防性抗肿瘤作用。基于以上发现，ssPalmE-KALA似乎是一种有效的基于离体DC的RNA疫苗平台。

更新日期：2019-08-03

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