Self-propelled Gemini-like LMWH-scaffold nanodrugs for overall tumor microenvironment manipulation via macrophage reprogramming and vessel normalization.
Self-propelled Gemini-like LMWH-scaffold nanodrugs for overall tumor microenvironment manipulation via macrophage reprogramming and vessel normalization.
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DOI：
10.1021/acs.nanolett.9b04024
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发表时间：
2019-12
期刊：
影响因子：
10.8
通讯作者：
Cheng Xu;Shan Yang;Zhijie Jiang;Jianping Zhou;Jing Yao
中科院分区：
文献类型：
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作者：
Cheng Xu;Shan Yang;Zhijie Jiang;Jianping Zhou;Jing Yao
血管生成是黑色素瘤的标志，其培育肿瘤微环境（TME）用于快速肿瘤进展。血管正常化可以通过TME重建受益于黑色素瘤治疗，而其有限的持续时间和范围仍然是阻力。本文中，两种外观类似的纳米药物，称为Gemini样纳米药物（GLnano），分别用抗血管生成低分子量肝素（LMWH）的相同支架构建，并在体内给药时混合。例如，将多柔比星（DOX）封装到具有DSPE-PEG-茴香酰胺装饰（D-LCA）的LMWH-白杨素纳米药物（LCY）中，用于对黑素瘤细胞的主动靶向和直接细胞杀伤。另一方面，将基质金属蛋白酶（MMPs）敏感肽与LMWH缀合以包封塞来昔布（Cel）（C-Lpep），在TME中被MMPs分解并释放Cel用于肿瘤相关巨噬细胞的M2至M1重编程。我们的研究结果表明，GLnano可以显着延长血管正常化窗口长达12天，最高周细胞覆盖率接近75%，而LCY单药治疗仅需4天。此外，GLnano可以自发地形成“治疗-递送”环，以促进纳米药物向肿瘤深部区域转移，从而产生有效的肿瘤抑制、转移预防和整体TME改善。
Angiogenesis is the hallmark of melanoma that nurtures the tumor microenvironment (TME) for rapid tumor progression. Vessel normalization could benefit melanoma treatment through TME reconstruction, while its limited duration and extent are still the drag. Herein, two kinds of look-like nanodrugs, called Gemini-like nanodrugs (GLnano), were constructed separately with the same scaffold of antiangiogenic low molecular weight heparin (LMWH) and mixed upon administration in vivo. For one, doxorubicin (DOX) was encapsulated into LMWH-chrysin nanodrug (LCY) with DSPE-PEG-anisamide decoration (D-LCA) for active targeting and direct cell killing towards melanoma cells. For another, matrix metalloproteinases (MMPs)-sensitive peptide was conjugated to LMWH to encapsulate celecoxib (Cel) (C-Lpep), disassembling in TME by MMPs and releasing Cel for M2-to-M1 reprogramming of tumor-associated macrophages. Our results showed that GLnano could remarkably elongate the vessel normalization window up to 12 days with the highest pericyte coverage of nearly 75%, compared to only 4 days by LCY monotherapy. Furthermore, GLnano could spontaneously form the "treatment-delivery" loop to promote nanodrugs towards deep tumor regions, leading to a potent tumor inhibition, metastasis prevention, and overall TME improvements.