Khare Purva, Edgecomb Sara X, Hamadani Christine M, Conway James F, Tanner Eden E L, S Manickam Devika
Graduate School of Pharmaceutical Sciences, Duquesne University 600 Forbes Avenue, 453 Mellon Hall Pittsburgh PA 15282 USA
Department of Chemistry and Biochemistry, The University of Mississippi MS USA.
Nanoscale Adv. 2023 Dec 5;6(7):1853-1873. doi: 10.1039/d3na00699a. eCollection 2024 Mar 26.
Lipidoid nanoparticles (LNPs) have transformed the field of drug delivery and are clinically used for the delivery of nucleic acids to liver and muscle targets. Post-intravenous administration, LNPs are naturally directed to the liver due to the adsorption of plasma proteins like apolipoprotein E. In the present work, we have re-engineered LNPs with ionic liquids (ILs) to reduce plasma protein adsorption and potentially increase the accumulation of LNPs in hard-to-deliver central nervous system (CNS) targets such as brain endothelial cells (BECs) and neurons. We have developed two approaches to re-engineer LNPs using a choline -2-hexenoate IL: first, we have optimized an IL-coating process using the standard LNP formulation and in the second approach, we have incorporated ILs into the LNPs by replacing the PEG-lipid component in the standard formulation using ILs. IL-coated as well as IL-incorporated LNPs were colloidally stable with morphologies similar to the standard LNPs. IL-coated LNPs showed superior uptake into mouse BECs and neurons and demonstrated reduced mouse plasma protein adsorption compared to the standard LNPs. Overall, our results (1) demonstrate the feasibility of re-engineering the clinically approved LNP platform with highly tunable biomaterials like ILs for the delivery of therapeutics to CNS targets like BECs and neurons and (2) suggest that the surface properties of LNPs play a critical role in altering their affinity to and uptake into hard-to-deliver cell types.
类脂纳米颗粒（LNPs）已经改变了药物递送领域，并在临床上用于将核酸递送至肝脏和肌肉靶点。静脉注射后，由于载脂蛋白E等血浆蛋白的吸附作用，LNPs会自然地被导向肝脏。在本研究中，我们用离子液体（ILs）对LNPs进行了重新设计，以减少血浆蛋白吸附，并有可能增加LNPs在难以递送的中枢神经系统（CNS）靶点（如脑内皮细胞（BECs）和神经元）中的积累。我们开发了两种使用胆碱-2-己烯酸离子液体重新设计LNPs的方法：第一，我们使用标准的LNP配方优化了离子液体涂层工艺；在第二种方法中，我们通过用离子液体取代标准配方中的聚乙二醇脂质成分，将离子液体掺入LNPs中。离子液体涂层和掺入离子液体的LNPs在胶体上是稳定的，其形态与标准LNPs相似。与标准LNPs相比，离子液体涂层的LNPs在小鼠BECs和神经元中的摄取效果更好，并且血浆蛋白吸附减少。总体而言，我们的结果（1）证明了用离子液体等高度可调的生物材料对临床批准的LNP平台进行重新设计，以将治疗药物递送至BECs和神经元等CNS靶点的可行性，（2）表明LNPs的表面性质在改变其对难以递送的细胞类型的亲和力和摄取方面起着关键作用。
