Theranostic dendrimer-based lipid nanoparticles containing PEGylated BODIPY dyes for tumor imaging and systemic mRNA delivery in vivo.
Theranostic dendrimer-based lipid nanoparticles containing PEGylated BODIPY dyes for tumor imaging and systemic mRNA delivery in vivo.
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DOI：
10.1016/j.jconrel.2020.06.030
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发表时间：
2020-09-10
期刊：
影响因子：
--
通讯作者：
Siegwart DJ
中科院分区：
文献类型：
--
作者：
Xiong H;Liu S;Wei T;Cheng Q;Siegwart DJ
基于mRNA的疗法已经成为治疗癌症的有希望的方法。然而，创建既递送mRNA又同时检测癌症的治疗诊断策略是一个重要的未满足的目标。在这里，我们报告了治疗诊断的树状聚合物为基础的脂质纳米颗粒（DLNP）系统的发展，含有聚乙二醇化的BODIPY染料（PBD）的mRNA的交付和近红外（NIR）成像在体外和体内。在体外，用pH响应性PBD-脂质配制的DLNP产生的功能性蛋白质是用传统PEG-脂质配制的对照DLNP的5至35倍，并且当用含有BODIPY核心、吲哚接头和1000至5000 g/mol的PEG长度的PBD-脂质配制时，在0.1 mg kg−1的低剂量下能够实现更高的体内mRNA递送效力。此外，我们发现肝脏中mRNA表达的强度与DLNP的pKa相关，表明pKa接近6.3的DLNP通常可以在肝脏中产生更多的蛋白质。值得注意的是，4A 3-SC8&PEG2k5d配制的DLNP成功地介导了肿瘤中的mRNA表达，并同时通过pH响应性NIR成像照射肿瘤。所描述的结合了联合收割机mRNA递送和NIR成像的治疗诊断脂质纳米颗粒有望成为同时检测和治疗癌症的适用的未来方法。治疗诊断纳米医学具有检测癌症和提供治疗活性药物的潜力。本文中，开发了含有PBD-脂质的治疗诊断DLNP系统，用于有效的mRNA递送和非侵入性NIR成像。PDB-脂质与DLNP的这种独特组合增强了癌细胞中的mRNA产生，介导了肿瘤中的mRNA表达，并同时通过pH响应性NIR成像照亮了肿瘤。
mRNA-based therapeutics have emerged as a promising approach to treat cancer. However, creation of theranostic strategies to both deliver mRNA and simultaneously detect cancer is an important unmet goal. Here, we report the development of theranostic dendrimer-based lipid nanoparticle (DLNP) system containing PEGylated BODIPY dyes (PBD) for mRNA delivery and near-infrared (NIR) imaging in vitro and in vivo. DLNPs formulated with a pH-responsive PBD-lipid produced 5- to 35-fold more functional protein than control DLNPs formulated with traditional PEG-lipid in vitro and enabled higher mRNA delivery potency in vivo at a low dose of 0.1 mg kg−1 when formulated with a PBD-lipid containing a BODIPY core, indole linker, and PEG length between 1000 and 5000 g/mol. Moreover, we found the intensity of mRNA expression in the liver correlated with the pKa of DLNPs, indicating that DLNPs with a pKa close to 6.3 could generally produce more protein in livers. Notably, 4A3-SC8&PEG2k5d formulated DLNPs successfully mediated mRNA expression in tumors and simultaneously illuminated tumors via pH-responsive NIR imaging. The described theranostic lipid nanoparticles that combine mRNA delivery and NIR imaging hold promise as an applicable future approach to simultaneously detect and treat cancer. Theranostic nanomedicines have the potential to both detect cancer and provide therapeutically active drugs. Herein, a theranostic DLNP system containing PBD-lipids is developed for effective mRNA delivery and non-invasive NIR imaging. This unique combination of PDB-lipids with DLNPs enhanced mRNA production in cancer cells, mediated mRNA expression in tumors, and simultaneously illuminated tumors via pH-responsive NIR imaging.
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