M2-Like Tumor-Associated Macrophage-Targeted Codelivery of STAT6 Inhibitor and IKKβ siRNA Induces M2-to-M1 Repolarization for Cancer Immunotherapy with Low Immune Side Effects.,ACS Central Science

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M2-Like Tumor-Associated Macrophage-Targeted Codelivery of STAT6 Inhibitor and IKKβ siRNA Induces M2-to-M1 Repolarization for Cancer Immunotherapy with Low Immune Side Effects.
ACS Central Science ( IF 12.7 ) Pub Date : 2020-07-01 , DOI: 10.1021/acscentsci.9b01235
Hong Xiao _{1,

2} , Yu Guo ₃ , Bo Li ₂ , Xiaoxia Li ₂ , Yong Wang _{1,

2} , Shisong Han ₂ , Du Cheng ₂ , Xintao Shuai _{1,

2}

Affiliation

Tumor-associated macrophages (TAMs) usually display the tumor-promoting M2 phenotype rather than the tumoricidal M1 phenotype. Thus, M2-to-M1 repolarization of TAMs has emerged as a promising strategy for tumor immunotherapy nowadays. However, immune side effects remain a great challenge, because phenotypic conversion of macrophages into the proinflammatory M1 phenotype may also be induced in normal tissue. Here, aiming at repolarizing TAMs without altering the M1/M2 polarization balance in healthy organs, we develop a micellar nanodrug with M2-targeting peptides (M2peptide) hidden in the pH-sheddable PEG corona so that an active targeting of M2-like macrophages is triggered only in the acidic tumor microenvironment (TME). The smart nanodrug effectively functions M2-to-M1 repolarization via M2-targeted codelivery of IKKβ siRNA and STAT6 inhibitor AS1517499 (AS), which suppresses the tumor growth and metastasis. Moreover, immune side effects are reduced because the neutral-pH environment in healthy organs does not trigger a “stealth-to-nonstealth” conversion of the nanodrug essential for M2-targeted drug delivery.

中文翻译：

STAT6抑制剂和IKKβsiRNA的与M2肿瘤相关的巨噬细胞靶向的Codelivery诱导癌症免疫治疗的M2至M1重极化，且免疫副作用低。

肿瘤相关的巨噬细胞（TAM）通常显示促进肿瘤的M2表型，而不是具有杀伤性的M1表型。因此，如今，TAM的M2到M1复极化已成为一种有前景的肿瘤免疫疗法策略。但是，免疫副作用仍然是一个巨大的挑战，因为在正常组织中也可能诱导巨噬细胞向促炎性M1表型的表型转化。在这里，为了在不改变健康器官中M1 / M2极化平衡的情况下使TAM复极化，我们开发了一种胶束纳米药物，该胶束纳米药物具有可在pH下降的PEG电晕中隐藏的M2靶向肽（M2肽），因此可以主动靶向M2类巨噬细胞仅在酸性肿瘤微环境（TME）中触发。智能纳米药物通过IKKβsiRNA的M2靶向转运和STAT6抑制剂AS1517499（AS）有效地发挥M2至M1复极化的功能，从而抑制了肿瘤的生长和转移。此外，由于健康器官中的pH值环境不会触发对M2靶向药物输送必不可少的纳米药物的“隐身-非隐身”转化，因此降低了免疫副作用。

更新日期：2020-07-22

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