Redox-responsive nanoassembly restrained myeloid-derived suppressor cells recruitment through autophagy-involved lactate dehydrogenase A silencing for enhanced cancer immunochemotherapy.
Redox-responsive nanoassembly restrained myeloid-derived suppressor cells recruitment through autophagy-involved lactate dehydrogenase A silencing for enhanced cancer immunochemotherapy.
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DOI：
10.1016/j.jconrel.2021.05.034
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发表时间：
2021-05
期刊：
影响因子：
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通讯作者：
C. Xia;Man Li;Guangyao Ran;Xuhui Wang;Zhengze Lu;Ting Li;Xian Tang;Zhirong Zhang;Qin He
中科院分区：
文献类型：
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作者：
C. Xia;Man Li;Guangyao Ran;Xuhui Wang;Zhengze Lu;Ting Li;Xian Tang;Zhirong Zhang;Qin He
髓源性抑制细胞（MDSC）是协助肿瘤生存和抑制抗肿瘤免疫的主要帮凶，可被肿瘤源性细胞因子如粒细胞集落刺激因子（G-CSF）和粒细胞巨噬细胞集落刺激因子（GM-CSF）招募。糖酵解过程中大量的乳酸脱氢酶 A (LDHA) 通常伴随着丰富的肿瘤源性 G-CSF 和 GM-CSF，进一步促进 MDSC 的募集和免疫抑制。为了实现强大的抗肿瘤免疫，开发了一种基于氧化还原响应纳米组件（R-mPDV/PDV/DOX/siL）的免疫化疗方案，该方案整合了通过LDHA沉默抑制细胞因子介导的MDSC募集和通过蒽环类（DOX）引发的免疫原性细胞死亡（ICD）效应增强肿瘤免疫原性的联合策略。这种氧化还原响应纳米组件由三种谷胱甘肽（GSH）响应聚合物自组装而成，其采用聚（δ-戊内酯）（PVL）作为疏水链段和3, 3'-二硫代二丙酸（DA）作为连接亲水链段的键。 DOX 封装在核心中，LDHA siRNA (siL) 被阳离子 PAMAM 有效压缩。 c(RGDfk) (RGD) 配体对整合素 (αvβ3) 的特异性识别增强了细胞内化和肿瘤归巢。 R-mPDV/PDV/DOX/siL从内涵体/溶酶体逃逸后，通过GSH引发的DA裂解而崩解，实现药物的爆发释放和高效的LDHA沉默。 LDHA 表达减少可抑制 G-CSF 和 GM-CSF 细胞因子的产生，抑制 MDSC 的募集并增强抗肿瘤免疫。最终，这种 DOX 和 siL 在 R-mPDV/PDV/DOX/siL 纳米组件上的治疗方案对 4 T1 原位肿瘤实现了强大的抗肿瘤效率，为免疫化疗开辟了新的视野。
Myeloid-derived suppressor cells (MDSCs) are the chief accomplices for assisting tumor's survival and suppressing anti-tumor immunity, which can be recruited by tumor-derived cytokines, such as granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF). The plentiful lactate dehydrogenase A (LDHA) in glycolysis is usually accompanied by abundant tumor-derived G-CSF and GM-CSF, further promoting MDSCs recruitment and immunosuppression. Herein, with the aim to achieve powerful anti-tumor immunity, an immunochemotherapy regimen basing on a redox-responsive nanoassembly (R-mPDV/PDV/DOX/siL) is developed, which integrates the combined strategy of restraining cytokines-mediated MDSCs recruitment through LDHA silencing and reinforcing tumor immunogenicity through anthracycline (DOX)-elicited immunogenic cell death (ICD) effects. This redox-responsive nanoassembly is self-assembled by three glutathione (GSH)-responsive polymers, which employ poly(δ-valerolactone) (PVL) as hydrophobic segment and 3, 3′-dithiodipropionic acid (DA) as linkage to connect hydrophilic segment. DOX is encapsulated in the core and LDHA siRNA (siL) is effectively compressed by cationic PAMAM. The cellular internalization and tumor-homing are strengthened by the specific recognition on integrin (αvβ3) by c(RGDfk) (RGD) ligand. After escaping from endosomes/lysosomes, R-mPDV/PDV/DOX/siL is disintegrated through GSH-elicited cleavage of DA, realizing burst release of drugs and high-efficient LDHA silencing. The reduced expression of LDHA suppresses the generation of G-CSF and GM-CSF cytokines, restrains MDSCs recruitment and reinforces anti-tumor immunity. Eventually, this therapeutic regimen of DOX and siL on R-mPDV/PDV/DOX/siL nanoassembly achieved powerful anti-tumor efficiency on 4 T1 orthotopic tumor, opening the new horizons for immunochemotherapy.