Dual receptor recognizing liposomes containing paclitaxel and hydroxychloroquine for primary and metastatic melanoma treatment via autophagy‐dependent and independent pathways
Dual receptor recognizing liposomes containing paclitaxel and hydroxychloroquine for primary and metastatic melanoma treatment via autophagy‐dependent and independent pathways
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DOI：
10.1016/j.jconrel.2018.08.015
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发表时间：
2018-10
影响因子：
10.8
通讯作者：
Sheng Yin;C. Xia;Yashi Wang;Dandan Wan;Jingdong Rao;Xian Tang;Jiaojie Wei;Xuhui Wang;Man Li
中科院分区：
文献类型：
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作者：
Sheng Yin;C. Xia;Yashi Wang;Dandan Wan;Jingdong Rao;Xian Tang;Jiaojie Wei;Xuhui Wang;Man Li
自噬作为恶性肿瘤的一种细胞保护机制，从而维持恶性肿瘤的生存，促进恶性肿瘤的增殖和转移。最近的研究表明，自噬抑制剂可以增强化疗药物的抗肿瘤生长功效。然而，化疗药物联合自噬抑制剂的抗肿瘤转移作用及其可能机制尚未得到深入研究。在此，我们制备了R8-dGR肽修饰的紫杉醇（PTX）和羟氯喹（HCQ）共载脂质体（PTX/HCQ-R8-dGR-Lip），用于通过识别B16 F10黑色素瘤细胞上的整合素αvβ3受体和神经纤毛蛋白-1受体来增强递送。我们的研究结果表明，R8-dGR修饰的脂质体（R8-dGR-Lip）增强肿瘤靶向递送在体外和体内。此外，PTX/HCQ-R8-dGR-Lip在体外对B16 F10细胞的迁移、侵袭和抗失巢凋亡能力表现出最佳的抑制作用，在体内对抑制原发性肿瘤生长和减少肺转移的效率也表现出增强。同时，抗转移机制研究证实，化疗药物PTX和自噬抑制剂HCQ的组合进一步抑制桩蛋白的降解、MMP 9和MMP 2的表达。HCQ通过干扰CXCR 4/CXCL 12轴，以非自噬的方式诱导恶性黑色素瘤的侵袭和转移。
Autophagy acts as a cytoprotective mechanism for malignant tumors, thus maintaining the survival and promoting proliferation and metastasis of malignant tumors. Recent studies have showed that autophagy inhibitors can enhance the chemotherapeutic efficacy of anti-tumor growth. However, the antimetastasis effects and the possible mechanisms of chemotherapeutics combined with autophagy inhibitors have not been thoroughly explored. Here, we prepared R8-dGR peptide modified paclitaxel (PTX) and hydroxychloroquine (HCQ) co-loaded liposomes (PTX/HCQ-R8-dGR-Lip) for enhanced delivery by recognizing integrin αvβ3 receptors and neuropilin-1 receptors on B16F10 melanoma cells. Our results showed that R8-dGR modified liposomes (R8-dGR-Lip) enhanced tumor-targeting delivery in vitro and in vivo. Besides, PTX/HCQ-R8-dGR-Lip exhibited the optimum inhibitory effects on migration, invasion and anoikis resistance of B16F10 cells in vitro, and showed enhanced efficiency on inhibiting primary tumor growth and reducing lung metastasis in vivo. Meanwhile, the antimetastasis mechanism studies confirmed that the combination of the chemotherapeutic PTX and the autophagy inhibitor HCQ further suppressed the degradation of paxillin, the expression of MMP9 and MMP2. Moreover, HCQ disturbed the CXCR4/CXCL12 axis which could induce invasion and metastasis of malignant melanoma in an autophagy-independent way.