A Quantitative Pharmacology Model of Exosome-Mediated Drug Efflux and Perturbation-Induced Synergy.
A Quantitative Pharmacology Model of Exosome-Mediated Drug Efflux and Perturbation-Induced Synergy.
复制标题
外泌体介导的药物外排和扰动诱导的协同作用的定量药理学模型。
DOI：
10.3390/pharmaceutics13070997
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发表时间：
2021-06-30
期刊：
影响因子：
5.4
通讯作者：
Au JL
中科院分区：
文献类型：
--
作者：
Wang J;Yeung BZ;Wientjes MG;Cui M;Peer CJ;Lu Z;Figg WD;Woo S;Au JL
外泌体是由细胞分泌的天然存在的囊泡，正在作为药物载体进行开发。我们使用实验和计算研究来研究细胞内外泌体加工和外泌体介导的药物外排的动力学以及外泌体抑制的影响。实验使用了四种人类乳腺癌或卵巢癌细胞，一种细胞毒性药物紫杉醇（PTX），两种外泌体抑制剂，（奥美拉唑（OME），其抑制外来体释放，和GW 4869（GW），其抑制外来体形成所需的鞘脂神经酰胺的合成），外来体中PTX水平的LC-MS/MS分析，和共聚焦显微镜研究内吞转运（使用荧光纳米颗粒和内吞细胞器标记物监测）。在所有四种细胞中，外泌体产生被PTX增强，但被OME或GW减弱（p < 0.05）; PTX增强被OME或GW完全逆转。与OME或GW的共处理同时减少了外来体中的PTX量，并增加了外来体-供体细胞中的PTX量和细胞毒性（对应于>2倍的协同作用，如曲线偏移和不确定性包络分析所示）。这种协同作用与先前的报道一致，即OME共施用显著增强了荷瘤小鼠和患有三阴性转移性乳腺癌的患者中的紫杉烷活性。实验结果被用来开发定量药理学模型;模型模拟揭示了两种外泌体抑制剂对细胞内PTX加工和亚细胞分布的不同影响。
Exosomes, naturally occurring vesicles secreted by cells, are undergoing development as drug carriers. We used experimental and computational studies to investigate the kinetics of intracellular exosome processing and exosome-mediated drug efflux and the effects of exosome inhibition. The experiments used four human-breast or ovarian cancer cells, a cytotoxic drug paclitaxel (PTX), two exosome inhibitors (omeprazole (OME), which inhibits exosome release, and GW4869 (GW), which inhibits synthesis of sphingolipid ceramide required for exosome formation), LC-MS/MS analysis of PTX levels in exosomes, and confocal microscopic study of endocytic transport (monitored using fluorescent nanoparticles and endocytic organelle markers). In all four cells, exosome production was enhanced by PTX but diminished by OME or GW (p < 0.05); the PTX enhancement was completely reversed by OME or GW. Co-treatment with OME or GW simultaneously reduced PTX amount in exosomes and increased PTX amount and cytotoxicity in exosome-donor cells (corresponding to >2-fold synergy as indicated by curve shift and uncertainty envelope analyses). This synergy is consistent with the previous reports that OME co-administration significantly enhances the taxane activity in tumor-bearing mice and in patients with triple negative metastatic breast cancer. The experimental results were used to develop a quantitative pharmacology model; model simulations revealed the different effects of the two exosome inhibitors on intracellular PTX processing and subcellular distribution.
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影响因子：
50.3
作者：
Hu G;Chong RA;Yang Q;Wei Y;Blanco MA;Li F;Reiss M;Au JL;Haffty BG;Kang Y
通讯作者：
Kang Y
DOI：
10.1016/j.apsb.2016.02.001
发表时间：
2016-07
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Ha D;Yang N;Nadithe V
通讯作者：
Nadithe V
影响因子：
16.1
作者：
Li, Yinghuan;Wang, Jie;Wientjes, M. Guillaume;Au, Jessie L. -S.
通讯作者：
Au, Jessie L. -S.
影响因子：
46.2
作者：
Behzadi S;Serpooshan V;Tao W;Hamaly MA;Alkawareek MY;Dreaden EC;Brown D;Alkilany AM;Farokhzad OC;Mahmoudi M
通讯作者：
Mahmoudi M
影响因子：
16.1
作者：
Au JL;Yeung BZ;Wientjes MG;Lu Z;Wientjes MG
通讯作者：
Wientjes MG