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

作　　者：Aejandro Serrano Noelia Casares lnaki F.Troconiz Teresa Lozano Juan J.Lasarte Sara Zalba Maria J.Garrido 

机构地区：[1]Department of Pharmaceutical Sciences,School of Pharmacy and Nutrition,University of Navarra,Pamplona,Spain [2]Navarra Institute for Health Research(ldisNA),Pamplona,Spain and 3program of Immunology [3]Immunotherapy,CiMA,Pamplona,Spain

出　　处：《Acta Pharmacologica Sinica》2025年第1期171-183,共13页中国药理学报(英文版)

基　　金：This research was funded by Ministry of Science;Innovation(PID2019-108989RB-100;PID2021-1282830A-00,PLEC2021-008094 MCIN/AEI/10.13039/501100011033);Gobierno de Navarra Industria(0011-1411-2022-000088;SOCRATHES project);Paula and Rodger Riney Foundation and Fundacion Bita;This work was supported by an ADA(University of Navarra)scholarship of Alejandro Serrano.

摘　　要：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-PEG_(750) or DSPE-PEG_(2000) were incubated with DSPE-PEG_(2000)-Maleimide micelles conjugated to Fab'fragments of anti-CD25 to develop two targeted formulations or immunoliposomes(IL):IL-P60_(2000)(DSPE-PEG_(2000) only)and ILP60_(750)(combining DSPE-PEG_(750) and DSPE-PEG_(2000)).P60 encapsulation efficiency was 50%-60%irrespective of PEG chain length.Treg uptake was 2.5 and 14 times higher for IL-PEG_(750) compared with IL-PEG_(2000) and non-targeted liposomes,respectively,in invitro assays.In fact,IL-P6075o allowed CD^(8+)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-P60_(750) in monotherapy and combined with anti-PD-1 was evaluated in MC38 and LLCOVA tumor bearing mice.In MC38 model,IL-P60_(750) 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 CD^(8+)T cells in tumors.Notably,IL-P60_(750) also inhibited human Treg in ex-vivo assay,showing the translational capability of this formulation.In conclusion,IL-P60_(750) 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.

关 键 词：Treg cells CD25 lipid nanoparticle PEG chain lengths post-insertion translation approach 

分 类 号：R73[医药卫生—肿瘤]