研究动态
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封装在新型 CD25 靶向纳米脂质体中的 Foxp3 抑制肽可促进小鼠肿瘤的有效消退。

Foxp3 inhibitory peptide encapsulated in a novel CD25-targeted nanoliposome promotes efficient tumor regression in mice.

发表日期:2024 Jul 29
作者: Alejandro Serrano, Noelia Casares, Iñaki F Trocóniz, Teresa Lozano, Juan J Lasarte, Sara Zalba, María J Garrido
来源: ACTA PHARMACOLOGICA SINICA

摘要:

P60 是一种 Foxp3 抑制肽,可以阻碍调节性 T 细胞 (Treg) 活性并损害肿瘤增殖。但全身稳定性低、特异性差,导致需要每日给药才能达到治疗效果。因此,本研究旨在通过将 P60 封装在靶向在 Tregs 中组成型表达的 CD25 的脂质体中来提高 P60 的稳定性和特异性递送。将用 DSPE-PEG750 或 DSPE-PEG2000 配制的 P60 脂质体与缀合至抗 CD25 的 Fab' 片段的 DSPE-PEG2000-马来酰亚胺胶束一起孵育,以开发两种靶向制剂或免疫脂质体 (IL):IL-P602000(仅限 DSPE-PEG2000)和IL-P60750(结合 DSPE-PEG750 和 DSPE-PEG2000)。无论 PEG 链长如何,P60 封装效率均为 50%-60%。在体外测定中,与 IL-PEG2000 和非靶向脂质体相比,IL-PEG750 的 Treg 摄取分别高出 2.5 倍和 14 倍。事实上,IL-P60750 允许 CD8 T 细胞在 Treg 存在的情况下离体增殖,剂量比游离 P60 低 10-20 倍。在 MC38 和 LLCOVA 荷瘤小鼠中评估了 P60 和 IL-P60750 单一疗法以及与抗 PD-1 联合疗法的抗肿瘤反应。在 MC38 模型中,IL-P60750 单一疗法诱导 40% 的小鼠肿瘤完全消退,而抗 PD-1 组合疗法则达到 100%。这种效应与肿瘤中活化的 CD8 T 细胞的显着增加有关。值得注意的是,IL-P60750 还在离体测定中抑制人 Treg,显示了该制剂的翻译能力。总之,用不同的PEG链长度配制的IL-P60750通过选择性抑制Treg活性表现出抗肿瘤功效,并增强抗PD1的效果。总而言之,这种新型 IL 代表了一个有前途的癌症免疫疗法纳米平台。© 2024。作者。
P60, a Foxp3 inhibitory peptide, can hinder the regulatory T cell (Treg) activity and impair tumor proliferation. However, low systemic stability and poor specificity have led to daily dosing to achieve therapeutic effect. Therefore, this study aims to improve P60 stability and specific delivery through its encapsulation in liposomes targeting CD25, constitutively expressed in Tregs. P60 liposomes formulated with DSPE-PEG750 or DSPE-PEG2000 were incubated with DSPE-PEG2000-Maleimide micelles conjugated to Fab' fragments of anti-CD25 to develop two targeted formulations or immunoliposomes (IL): IL-P602000 (DSPE-PEG2000 only) and IL-P60750 (combining DSPE-PEG750 and DSPE-PEG2000). P60 encapsulation efficiency was 50%-60% irrespective of PEG chain length. Treg uptake was 2.5 and 14 times higher for IL-PEG750 compared with IL-PEG2000 and non-targeted liposomes, respectively, in in-vitro assays. In fact, IL-P60750 allowed CD8+  T cells ex-vivo proliferation in presence of Treg at doses 10-20 times lower than for free P60. Antitumor response of P60 and IL-P60750 in monotherapy and combined with anti-PD-1 was evaluated in MC38 and LLCOVA tumor bearing mice. In MC38 model, IL-P60750 monotherapy induced total tumor regression in 40% of mice reaching 100% for anti-PD-1 combination. This effect was associated with a significant increase in activated CD8+ T cells in tumors. Notably, IL-P60750 also inhibited human Treg in ex-vivo assay, showing the translational capability of this formulation. In conclusion, IL-P60750 formulated with different PEG chain lengths, has demonstrated antitumor efficacy by selective inhibition of Treg activity and enhances the effect of anti-PD1. Altogether, this novel IL represents a promising nanoplatform for cancer immunotherapies.© 2024. The Author(s).