西班牙纳瓦拉健康研究所María J. Garrido等研究人员合作发现，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。这一研究成果发表在2024年7月29日出版的国际学术期刊《中国药理学报》上。

研究人员旨在通过将P60包裹在靶向CD25的脂质体中来提高P60的稳定性和特异性传递，因为CD25在调节性T细胞（Treg）中持续表达。研究人员将P60脂质体与DSPE-PEG₇₅₀或DSPE-PEG₂₀₀₀配制，随后与结合了抗-CD25 Fab片段的DSPE-PEG₂₀₀₀-马来酰亚胺胶束共孵育，开发了两种靶向配方或免疫脂质体（IL）：IL-P60₂₀₀₀（仅含DSPE-PEG₂₀₀₀）和IL-P60₇₅₀（结合了DSPE-PEG₇₅₀和DSPE-PEG₂₀₀₀）。无论PEG链长度如何，P60的包封效率为50%–60%。在体外实验中，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。实际上，IL-P60₇₅₀允许CD8+ T细胞在Treg存在下的体外增殖，其剂量比自由P60低10–20倍。

通过MC38和LLCOVA肿瘤小鼠模型，研究人员评估了P60和IL-P60₇₅₀在单药治疗和与抗-PD-1联合治疗下的抗肿瘤反应。在MC38模型中，IL-P60₇₅₀单药治疗使40%的小鼠肿瘤完全消退，而与抗-PD-1联合治疗的消退率达到100%。这一效果与肿瘤中激活的CD8+ T细胞显著增加相关。值得注意的是，IL-P60₇₅₀在体外实验中也抑制了人类Treg，从而展示了该配方的转化潜力。总之，IL-P60₇₅₀通过选择性抑制Treg活性并增强抗-PD1的效果展示了抗肿瘤效能。总的来说，这种新型IL代表了一种有前途的癌症免疫治疗纳米平台。

据悉，P60是一种Foxp3抑制肽，可以抑制Treg的活性并抑制肿瘤增殖。然而，低系统稳定性和较差的特异性导致需要每日给药才能达到治疗效果。

附：英文原文

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

Author: Serrano, Alejandro, Casares, Noelia, Trocniz, Iaki F., Lozano, Teresa, Lasarte, Juan J., Zalba, Sara, Garrido, Mara J.

Issue&Volume: 2024-07-29

Abstract: 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.

DOI: 10.1038/s41401-024-01338-0

Source: https://www.nature.com/articles/s41401-024-01338-0