Shin Kwangsoo, Suh Hee-Won, Grundler Julian, Lynn Anna Y, Pothupitiya Jinal U, Moscato Zoe M, Reschke Melanie, Bracaglia Laura G, Piotrowski-Daspit Alexandra S, Saltzman W Mark
Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
Biomaterials. 2022 Aug;287:121676. doi: 10.1016/j.biomaterials.2022.121676. Epub 2022 Jul 11.
Poly(ethylene glycol) (PEG) is widely employed for passivating nanoparticle (NP) surfaces to prolong blood circulation and enhance localization of NPs to target tissue. However, the immune response of PEGylated NPs-including anti-PEG antibody generation, accelerated blood clearance (ABC), and loss of delivery efficacy-is of some concern, especially for treatments that require repeat administrations. Although polyglycerol (PG), which has the same ethylene oxide backbone as PEG, has received attention as an alternative to PEG for NP coatings, the pharmacokinetic and immunogenic impact of PG has not been studied systematically. Here, linear PG, hyperbranched PG (hPG), and PEG-coated polylactide (PLA) NPs with varying surface densities were studied in parallel to determine the pharmacokinetics and immunogenicity of PG and hPG grafting, in comparison with PEG. We found that linear PG imparted the NPs a stealth property comparable to PEG, while hPG-grafted NPs needed a higher surface density to achieve the same pharmacokinetic impact. While linear PG-grafted NPs induced anti-PEG antibody production in mice, they exhibited minimal accelerated blood clearance (ABC) effects due to the poor interaction with anti-PEG immunoglobulin M (IgM). Further, we observed no anti-polymer IgM responses or ABC effects for hPG-grafted NPs.
聚乙二醇（PEG）被广泛用于纳米颗粒（NP）表面的钝化，以延长血液循环时间并增强纳米颗粒在靶组织中的定位。然而，聚乙二醇化纳米颗粒的免疫反应——包括抗聚乙二醇抗体的产生、加速血液清除（ABC）以及递送效果的丧失——令人担忧，特别是对于需要重复给药的治疗。尽管聚甘油（PG）与PEG具有相同的环氧乙烷主链，作为纳米颗粒涂层中PEG的替代品受到关注，但PG的药代动力学和免疫原性影响尚未得到系统研究。在这里，我们平行研究了具有不同表面密度的线性PG、超支化PG（hPG）以及聚乙二醇包覆的聚丙交酯（PLA）纳米颗粒，以确定PG和hPG接枝的药代动力学和免疫原性，并与PEG进行比较。我们发现，线性PG赋予纳米颗粒与PEG相当的隐身特性，而hPG接枝的纳米颗粒需要更高的表面密度才能实现相同的药代动力学影响。虽然线性PG接枝的纳米颗粒在小鼠中诱导产生抗PEG抗体，但由于与抗PEG免疫球蛋白M（IgM）的相互作用较弱，它们表现出最小的加速血液清除（ABC）效应。此外，我们未观察到hPG接枝的纳米颗粒有抗聚合物IgM反应或ABC效应。
