Department of Health Technology, Section for Biotherapeutic Engineering and Drug Targeting, Technical University of Denmark, Produktionstorvet Building 423, DK 2800 Lyngby, Denmark; Center for Nanomedicine and Theranostics, Technical University of Denmark, DK 2800 Lyngby, Denmark.
Department of Health Technology, Section for Biotherapeutic Engineering and Drug Targeting, Technical University of Denmark, Produktionstorvet Building 423, DK 2800 Lyngby, Denmark; Center for Nanomedicine and Theranostics, Technical University of Denmark, DK 2800 Lyngby, Denmark.
J Control Release. 2022 Feb;342:337-344. doi: 10.1016/j.jconrel.2021.12.033. Epub 2021 Dec 29.
Systemic administration of toll-like receptor (TLR) agonists have demonstrated impressive preclinical results as an anti-cancer therapy due to their potent innate immune-stimulatory properties. The clinical advancement has, however, been hindered by severe adverse effects due to systemic activation of the immune system. Liposomal drug delivery systems may modify biodistribution, cellular uptake, and extend blood circulation, and thus, potentially enable systemic administration of TLR agonists at therapeutic doses. In this study, we investigated potential barriers for the administration of TLR agonists formulated in polyethylene glycosylated (PEGylated) liposomes with regards to liposome formulation, TLR agonist, administration route, administration schedule, biodistribution, blood clearance, and anti-PEG antibodies. We found that administration of TLR agonists formulated in PEGylated liposomes led to high anti-PEG antibody titers, which upon multiple intravenous administrations, resulted in accelerated blood clearance and acute hypersensitivity reactions. The latter was found to be associated with anti-PEG IgG antibody and not anti-PEG IgM antibody opsonization. This study highlights the need to carefully design and evaluate nanoparticle delivery systems for immunotherapy as anti-nanoparticle immune responses may challenge the therapeutic application.
由于 Toll 样受体 (TLR) 激动剂具有强大的固有免疫刺激特性，全身给药已在癌症治疗的临床前研究中取得了令人瞩目的成果。然而，由于免疫系统的全身激活，其临床应用受到严重不良反应的阻碍。脂质体药物递送系统可以改变生物分布、细胞摄取并延长血液循环，从而有可能使 TLR 激动剂以治疗剂量进行全身给药。在这项研究中，我们研究了 PEG 化脂质体给药的 TLR 激动剂在脂质体配方、TLR 激动剂、给药途径、给药方案、生物分布、血液清除和抗 PEG 抗体方面的潜在障碍。我们发现，PEG 化脂质体给药的 TLR 激动剂会引起高抗 PEG 抗体滴度，多次静脉给药后，会导致血液清除加速和急性过敏反应。后者被发现与抗 PEG IgG 抗体而非抗 PEG IgM 抗体调理有关。本研究强调了需要仔细设计和评估免疫治疗用的纳米颗粒递送系统，因为针对纳米颗粒的免疫反应可能会挑战其治疗应用。
