Micellar nanoparticles inhibit breast cancer and pulmonary metastasis by modulating the recruitment and depletion of myeloid-derived suppressor cells
Micellar nanoparticles inhibit breast cancer and pulmonary metastasis by modulating the recruitment and depletion of myeloid-derived suppressor cells
复制标题
DOI：
10.1039/d2nr03880c
复制
发表时间：
2022-10-08
期刊：
影响因子：
6.7
通讯作者：
He，Qin
中科院分区：
文献类型：
--
作者：
Lu，Zhengze;Liu，Houqin;He，Qin
骨髓源性抑制细胞（MDSC）因其免疫抑制的病理特征和促癌作用而臭名昭著。它们可以诱导以炎症、免疫抑制和血管渗漏为特征的转移前小生境（PMN）的形成，促进乳腺癌的肺转移。本研究制备了一种肿瘤靶向c（RGDfk）肽修饰的全反式维甲酸低分子肝素（LMWH-ATRA）胶束纳米粒（RLA/DOX/αGC NP），该纳米粒负载化疗药物阿霉素（DOX）和免疫佐剂α-半乳糖神经酰胺（αGC）。亲水性片段LMWH通过与血管内皮细胞表面的P-选择素竞争性结合抑制MDSC的募集，而疏水性片段ATRA通过诱导MDSC分化促进MDSC的耗竭。通过对MDSCs的调控，胶束可以显著改善肺部和肿瘤部位的炎症和免疫抑制微环境，抑制PMN的形成。不仅如此，该胶束还与αGC产生协同效应，有效提高了荷瘤小鼠的抗肿瘤免疫力，为乳腺癌和肺转移提供了一种有前景的治疗策略。
Myeloid-derived suppressor cells (MDSCs) are notorious for their pathological characteristics of immunosuppression and their promoting effect on cancers. They can induce the formation of pre-metastatic niche (PMN) characterized by inflammation, immunosuppression and vascular leakage, and promote pulmonary metastasis of breast cancer. Herein, a tumor targeting c(RGDfk) peptide modified low molecular-weight-heparin-all-trans-retinoic-acid (LMWH-ATRA) micellar nanoparticle loaded with chemotherapeutic drug doxorubicin (DOX) and immune adjuvant α-galactosylceramide (αGC) (RLA/DOX/αGC NP) was developed. The hydrophilic segment LMWH inhibited the recruitment of MDSCs by competitively binding with P-selectin on the surface of vascular endothelial cells (VECs), while the hydrophobic segment ATRA promoted the depletion of MDSCs by inducing their differentiation. Through the modulation of MDSCs, micelles can significantly improve the inflammatory and immunosuppressive microenvironment of the lung and tumor sites, and inhibit the formation of PMN. Not only this, the micelles also produced a synergistic effect with αGC, which effectively improved the anti-tumor immunity of tumor bearing mice and provided a promising therapeutic strategy for breast cancer and pulmonary metastasis.