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Immunopolymer Lipid Nanoparticles for Delivery of Macromolecules to Antigen-Expressing Cells
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2020-11-20 , DOI: 10.1021/acsabm.0c00857 Arvind K Jain 1 , Carole J R Bataille 2 , Sabine Milhas 1 , Ami Miller 1 , Jing Zhang 1 , Terry H Rabbitts 1
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2020-11-20 , DOI: 10.1021/acsabm.0c00857 Arvind K Jain 1 , Carole J R Bataille 2 , Sabine Milhas 1 , Ami Miller 1 , Jing Zhang 1 , Terry H Rabbitts 1
Affiliation
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Macromolecules such as antibodies and antibody fragments have been reported to interfere with intracellular targets, but their use is limited to delivery systems where expression is achieved from vectors such as plasmids or viruses. We have developed PEGylated nanoparticles of poly-lactic acid (PLA), including the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), which are functionalized with monoclonal anti-CD7, anti-CD53, or anti-GPR56 antibodies for receptor-mediated endocytic delivery into T-cell leukemia cell lines. Incorporation of DOTAP as the lipid component of the PLA nanoparticles enhanced the release of the immuno-nanoparticles from the endosomes into the cytosol compared to nanoparticles made from PLA alone. Systemic delivery of these anti-CD7 immuno-nanoparticles into humanized CD7 transgenic mice resulted in localization in the spleen, enhanced uptake into CD7-expressing splenocytes, and release of low amounts of reporter mRNA for translation. These functionalized polymer lipid nanoparticles are the basis for elaboration and optimization for realizing their potential in therapeutic applications to carry specific macromolecules such as mRNAs for translation into therapeutic proteins that can target intracellular proteins which mediate disease.
中文翻译：
用于将大分子递送至抗原表达细胞的免疫聚合物脂质纳米颗粒
据报道，诸如抗体和抗体片段之类的大分子会干扰细胞内靶标，但它们的用途仅限于通过质粒或病毒等载体实现表达的递送系统。我们开发了聚乳酸 (PLA) 的聚乙二醇化纳米粒子，包括阳离子脂质 1,2-二油酰基-3-三甲基铵-丙烷 (DOTAP)，其通过单克隆抗 CD7、抗 CD53 或抗 GPR56 进行功能化用于受体介导的内吞递送至 T 细胞白血病细胞系的抗体。与单独由 PLA 制成的纳米颗粒相比，掺入 DOTAP 作为 PLA 纳米颗粒的脂质成分增强了免疫纳米颗粒从内体释放到胞质溶胶中。将这些抗 CD7 免疫纳米颗粒全身递送至人源化 CD7 转基因小鼠中，导致其在脾脏中的定位，增强对表达 CD7 的脾细胞的摄取，并释放少量用于翻译的报告基因 mRNA。这些功能化的聚合物脂质纳米粒子是详细阐述和优化的基础，以实现其在治疗应用中的潜力，携带特定的大分子，例如 mRNA，翻译成可以靶向介导疾病的细胞内蛋白质的治疗性蛋白质。
更新日期：2020-12-21
中文翻译：
用于将大分子递送至抗原表达细胞的免疫聚合物脂质纳米颗粒
据报道，诸如抗体和抗体片段之类的大分子会干扰细胞内靶标，但它们的用途仅限于通过质粒或病毒等载体实现表达的递送系统。我们开发了聚乳酸 (PLA) 的聚乙二醇化纳米粒子，包括阳离子脂质 1,2-二油酰基-3-三甲基铵-丙烷 (DOTAP)，其通过单克隆抗 CD7、抗 CD53 或抗 GPR56 进行功能化用于受体介导的内吞递送至 T 细胞白血病细胞系的抗体。与单独由 PLA 制成的纳米颗粒相比，掺入 DOTAP 作为 PLA 纳米颗粒的脂质成分增强了免疫纳米颗粒从内体释放到胞质溶胶中。将这些抗 CD7 免疫纳米颗粒全身递送至人源化 CD7 转基因小鼠中，导致其在脾脏中的定位，增强对表达 CD7 的脾细胞的摄取，并释放少量用于翻译的报告基因 mRNA。这些功能化的聚合物脂质纳米粒子是详细阐述和优化的基础，以实现其在治疗应用中的潜力，携带特定的大分子，例如 mRNA，翻译成可以靶向介导疾病的细胞内蛋白质的治疗性蛋白质。
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