Exosome-liposome hybrid nanoparticle codelivery of TP and miR497 conspicuously overcomes chemoresistant ovarian cancer.
Exosome-liposome hybrid nanoparticle codelivery of TP and miR497 conspicuously overcomes chemoresistant ovarian cancer.
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DOI：
10.1186/s12951-022-01264-5
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发表时间：
2022-01-25
影响因子：
10.2
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Li L;He D;Guo Q;Zhang Z;Ru D;Wang L;Gong K;Liu F;Duan Y;Li H
虽然以顺铂为基础的化疗已被作为卵巢癌（OC）的一线治疗方法，但在治疗过程中，肿瘤细胞对顺铂产生耐药性，导致卵巢癌患者预后不良。研究表明，磷脂酰肌醇3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）通路的过度激活参与肿瘤化疗耐药，microRNA-497 （miR497）的过度表达可能通过抑制mTOR通路来克服OC化疗耐药。然而，miR497转录效率低，化学性质不稳定，限制了其临床应用。此外，雷公藤甲素（TP）被证实对顺铂耐药细胞系具有优越的杀伤作用，部分原因是通过抑制mTOR途径。尽管如此，TP严重的全身毒性和较弱的水溶性限制了其临床应用。本文研究了miR497和TP联合应用是否能通过协同抑制mTOR信号通路进一步克服OC化学耐药。通过将表达cd47的肿瘤外泌体与crgd修饰的脂质体（miR497/TP- henps）融合形成生物激发的杂交纳米颗粒，以共同递送miR497和TP。体外实验结果表明，纳米颗粒被肿瘤细胞有效吸收，从而显著促进肿瘤细胞凋亡。同样，混合纳米颗粒在肿瘤区域有效富集，并发挥显著的抗癌活性，而在体内没有任何负面影响。在机制上，它们促进了过度激活的PI3K/AKT/mTOR信号通路的去磷酸化，促进了活性氧（ROS）的产生，并上调了巨噬细胞从M2到M1的极化。总的来说，我们的发现可能为克服顺铂耐药OC提供了一种转化策略，并为治疗其他顺铂耐药肿瘤提供了一种潜在的解决方案。在线版本包含补充材料，可在10.1186/s12951-022-01264-5获得。
Although cisplatin-based chemotherapy has been used as the first-line treatment for ovarian cancer (OC), tumor cells develop resistance to cisplatin during treatment, causing poor prognosis in OC patients. Studies have demonstrated that overactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is involved in tumor chemoresistance and that overexpression of microRNA-497 (miR497) may overcome OC chemotherapy resistance by inhibiting the mTOR pathway. However, the low transcriptional efficiency and unstable chemical properties of miR497 limit its clinical application. Additionally, triptolide (TP) was confirmed to possess a superior killing effect on cisplatin-resistant cell lines, partially through inhibiting the mTOR pathway. Even so, the clinical applications of TP are restricted by serious systemic toxicity and weak water solubility. Herein, whether the combined application of miR497 and TP could further overcome OC chemoresistance by synergically suppressing the mTOR signaling pathway was investigated. Bioinspired hybrid nanoparticles formed by the fusion of CD47-expressing tumor exosomes and cRGD-modified liposomes (miR497/TP-HENPs) were prepared to codeliver miR497 and TP. In vitro results indicated that the nanoparticles were efficiently taken up by tumor cells, thus significantly enhancing tumor cell apoptosis. Similarly, the hybrid nanoparticles were effectively enriched in the tumor areas and exerted significant anticancer activity without any negative effects in vivo. Mechanistically, they promoted dephosphorylation of the overactivated PI3K/AKT/mTOR signaling pathway, boosted reactive oxygen species (ROS) generation and upregulated the polarization of macrophages from M2 to M1 macrophages. Overall, our findings may provide a translational strategy to overcome cisplatin-resistant OC and offer a potential solution for the treatment of other cisplatin-resistant tumors. The online version contains supplementary material available at 10.1186/s12951-022-01264-5.
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影响因子：
5.7
作者：
Musa F;Alard A;David-West G;Curtin JP;Blank SV;Schneider RJ
通讯作者：
Schneider RJ
热敏外泌体-脂质体混合纳米颗粒介导的化学免疫疗法可改善转移性腹膜癌的治疗
DOI：
10.1002/advs.202000515
发表时间：
2020-09
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
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作者：
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影响因子：
12.4
作者：
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Gao W
影响因子：
2.3
作者：
Chen, Yuan-Wu;Lin, Gu-Jiun;Sytwu, Huey-Kang
通讯作者：
Sytwu, Huey-Kang
影响因子：
11.2
作者：
Mukherjee, Anirban;Van Huynh;Vasquez, Karen M.
通讯作者：
Vasquez, Karen M.