Functional extracellular vesicles engineered with lipid-grafted hyaluronic acid effectively reverse cancer drug resistance
Functional extracellular vesicles engineered with lipid-grafted hyaluronic acid effectively reverse cancer drug resistance
复制标题
用脂质移植透明质酸改造的功能性细胞外囊泡可有效逆转癌症耐药性
DOI：
10.1016/j.biomaterials.2019.119475
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发表时间：
2019-12-01
期刊：
影响因子：
14
通讯作者：
Wang, Zheng
中科院分区：
文献类型：
--
作者：
Liu, Jia;Ye, Zhilan;Wang, Zheng
多药耐药（MDR）是导致肿瘤化疗无效的关键问题。已经开发了许多多功能纳米载体来增加药物递送功效和抑制药物外排以克服癌症耐药性。然而，由于纳米载体复杂的多步制备过程及其不良的副作用和潜在的免疫原性，在临床上取得的成功有限。在这里，产生透明质酸（HA）功能化的细胞外囊泡（EV）作为天然载体以有效地递送阿霉素（DOX）和逆转MDR。从非癌性HEK 293 T细胞（hEV）分离的EV降低耐药MCF 7/ADR细胞中的P-糖蛋白（P-gp）表达。为了获得肿瘤靶向能力，通过简单的孵育用拟脂链接枝的HA（lipHA）修饰hEV。由于CD 44介导的癌症特异性靶向和P-gp抑制能力，HA功能化的hEV（lipHA-hEV）显著促进耐药乳腺癌细胞中的细胞内DOX积累。在临床前MDR肿瘤模型中，lipHA-hEV深入肿瘤组织并有效地将DOX运输到肿瘤局部，同时消除DOX的全身毒性。重要的是，DOX@ lipHA-hEV将MDR肿瘤生长抑制了89%，并将动物存活时间延长了约50%。因此，我们的工程肿瘤靶向hEV是克服癌症MDR的有希望的天然载体。
Multidrug resistance (MDR) is a key issue accounting for ineffectiveness of cancer chemotherapy. Numerous multifunctional nanocarriers have been developed to increase drug delivery efficacy and inhibit drug efflux for overcoming cancer drug resistance. However, limited success has been achieved in clinic because of nanocarriers complicated multi-step fabrication procedures and their undesired side toxicity as well as potential immunogenicity. Here, hyaluronic acid (HA) functionalized extracellular vesicles (EVs) are generated as natural vehicles to efficiently deliver doxorubicin (DOX) and reverse MDR. The EVs isolated from noncancerous HEK293T cells (hEVs) reduce P-glycoprotein (P-gp) expression in drug resistant MCF7/ADR cells. To acquire tumor-targeting capability, hEVs are modified with lipidomimetic chains-grafted HA (lipHA) by a simple incubation. Owing to CD44-mediated cancer-specific targeting and P-gp suppressive capability, the HA-functionalized hEVs (lipHA-hEVs) remarkably promote the intracellular DOX accumulation in drug resistant breast cancer cells. In preclinical MDR tumor models, lipHA-hEVs deeply penetrate into tumor tissue and effectively transport DOX into tumor local, while eliminating DOX's systemic toxicity. Importantly, DOX@lipHA-hEVs inhibited MDR tumor growth by 89% and extend animal survival time by approximately 50%. Thus, our engineered tumor-targeting hEVs are promising natural carriers for overcoming cancer MDR.