Design of abiotic polymer ligand-decorated lipid nanoparticles for effective neutralization of target toxins in the blood
Design of abiotic polymer ligand-decorated lipid nanoparticles for effective neutralization of target toxins in the blood
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DOI：
10.1039/d1bm00515d
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发表时间：
2021-07-09
影响因子：
6.6
通讯作者：
Asai，Tomohiro
中科院分区：
文献类型：
--
作者：
Koide，Hiroyuki;Yamauchi，Ikumi;Asai，Tomohiro
大分子毒素常导致炎性细胞因子的产生、多器官功能障碍和细胞死亡。由几种功能单体合成的聚合物配体(Pls)与目标毒素结合后具有中和作用的潜力，因此，它们作为非生物解毒剂具有重要意义。虽然PLS在血液中几乎没有中和作用，因为它可以立即从血液中清除，但通过将PLS直接修饰到脂质纳米粒(PL-LNPs)上，可以显著提高毒素中和效果。然而，这种直接修饰降低了PL的迁移率，诱导了捕获目标后的LNP聚集，并缩短了LNP的血液循环时间。我们设计了新型的PL-LNPs，以提高PL的迁移率，抑制捕获靶点后的聚集趋势，并延长LNP的血液循环时间，以实现体内高效的毒素中和。具体地说，用聚乙二醇改性LNPs，并用额外的聚乙二醇改性PL修饰的LNPs(PL-PEGLNPs)。以组蛋白为靶毒素，以N-异丙基丙烯酰胺为基础的PLS作为组蛋白捕获剂。静脉注射∼后24 h，聚乙二醇化使血浆LNP水平增加90倍，并抑制组蛋白捕获后的LNP聚集。PL-PEG-LNPs对组蛋白的解离常数(Kd)比PL-LNPs小两倍。虽然PL-LNPs抑制了血液中组蛋白-血小板的相互作用，但由于聚集，大量的组蛋白-PL-LNP复合体聚集在肺中。然而，PL-PEG-LNPs既抑制了组蛋白-血小板的相互作用，也抑制了组蛋白在肺中的积聚。重要的是，与PL-LNP相比，PL-PEG-LNP处理提高了组蛋白处理的小鼠的存活率。这些结果为体内非生物解毒剂纳米粒的开发提供了平台。
Macromolecular toxins often induce inflammatory cytokine production, multiple-organ dysfunction, and cell death. Synthetic polymer ligands (PLs) prepared with several functional monomers have the potential of neutralizing target toxins after binding to them; therefore, they are of significant interest as abiotic antidotes. Although PLs show little toxin neutralization effect in the bloodstream because of immediate elimination from there, the toxin neutralization effect is significantly improved by the direct decoration of PLs onto lipid nanoparticles (PL-LNPs). However, this direct decoration decreases PL mobility, induces LNP aggregation after capturing the target, and decreases LNP blood circulation time. We designed novel PL-LNPs to improve PL mobility, inhibit the aggregation tendency after capturing the target, and increase LNP blood circulation time in order to achieve highly effective toxin neutralization in vivo. Specifically, LNPs were modified with PLs-conjugated polyethylene glycol (PEG), and additional PEG was used to modify the PL-decorated LNPs (PL-PEG-LNPs). Histones were used as target toxins, and N-isopropylacrylamide-based PLs were used for histone capture. PEGylation increased the plasma LNP level 24 h after intravenous injection by ∼90 times and inhibited LNP aggregation after histone capture. The dissociation constant (Kd) of PL-PEG-LNPs against histone was two times smaller compared to that of PL-LNPs. Although PL-LNPs inhibited histone–platelet interaction in the bloodstream, a large amount of histone–PL-LNP complexes accumulated in the lungs because of aggregation. However, PL-PEG-LNPs inhibited both histone–platelet interaction and histone accumulation in the lungs. Importantly, PL-PEG-LNP treatment increased the survival rate of histone-treated mice compared to PL-LNPs. These results provide a platform for the development of abiotic antidote nanoparticles in vivo.