Exosome is a mechanism of intercellular drug transfer: Application of quantitative pharmacology.
Exosome is a mechanism of intercellular drug transfer: Application of quantitative pharmacology.
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DOI：
10.1016/j.jconrel.2017.10.020
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发表时间：
2017-12-28
期刊：
影响因子：
--
通讯作者：
Au JL
中科院分区：
文献类型：
--
作者：
Wang J;Yeung BZ;Cui M;Peer CJ;Lu Z;Figg WD;Guillaume Wientjes M;Woo S;Au JL
胞外体是由细胞分泌到细胞外空间的小膜泡(直径30-100 nm)。本研究评估了化疗药物对外切体产生和/或释放的影响，并量化了外切体对细胞间药物转移和药效学的贡献。用紫杉醇(PTX，2-1000 nM)或阿霉素(DOX，20-1000 nM)处理人乳腺癌细胞(MCF7)、转移性LM2细胞、卵巢A2780细胞和卵巢癌细胞(OVCAR4)24-48小时后，用超速离心法从药物处理后的供体细胞培养上清液中提取外显体，分析乙酰胆碱酯酶活性、总蛋白、药物浓度以及对药物初始受体细胞(受体细胞)的生物学效应(细胞毒性和抗迁移)。这些结果被用来开发计算预测定量药理学模型。处于指数生长期的细胞在培养上清液中释放约220个外切体。PTX和DOX以剂量和时间依赖的方式显著促进外切体的产生和/或释放，对卵巢癌细胞的影响大于对乳腺癌细胞的影响。从供体细胞分离的外切体含有较高的药物水平(100-1000 nM的PTX作用24小时后为2-7 pmole/106细胞)，并能引起细胞毒性和抑制受体细胞的迁移。将细胞内PTX药代动力学与PTX药效学相结合的定量药理学模型成功地预测了外切体对细胞间药物转运的影响、PTX对供体细胞的细胞毒性以及含PTX的外切体对受体细胞的细胞毒性。额外的模型模拟表明，在临床可达到的PTX浓度范围内，外切体对活性药物外流的贡献随着药物浓度的增加而增加，并在后者饱和时超过P-糖蛋白外流。我们的结果表明：(A)化疗药物可刺激外切体的产生或释放，(B)外切体是一种细胞间药物转移机制，有助于邻近细胞的药效学。
Exosomes are small membrane vesicles (30–100 nm in diameter) secreted by cells into extracellular space. The present study evaluated the effect of chemotherapeutic agents on exosome production and/or release, and quantified the contribution of exosomes to intercellular drug transfer and pharmacodynamics. Human cancer cells (breast MCF7, breast-to-lung metastatic LM2, ovarian A2780 and OVCAR4) were treated with paclitaxel (PTX, 2–1000 nM) or doxorubicin (DOX, 20–1000 nM) for 24–48 h. Exosomes were isolated from the culture medium of drug-treated donor cells (Donor cells) using ultra-centrifugation, and analyzed for acetylcholinesterase activity, total proteins, drug concentrations, and biological effects (cytotoxicity and anti-migration) on drug-naïve recipient cells (Recipient cells). These results were used to develop computational predictive quantitative pharmacology models. Cells in exponential growth phase released ~220 exosomes/cell in culture medium. PTX and DOX significantly promoted exosome production and/or release in a dose- and time-dependent manner, with greater effects in ovarian cancer cells than in breast cancer cells. Exosomes isolated from Donor cells contained appreciable drug levels (2–7 pmole/106 cells after 24 h treatment with 100–1000 nM PTX), and caused cytotoxicity and inhibited migration of Recipient cells. Quantitative pharmacology models that integrated cellular PTX pharmacokinetics with PTX pharmacodynamics successfully predicted effects of exosomes on intercellular drug transfer, cytotoxicity of PTX on Donor cells and cytotoxicity of PTX-containing exosomes on Recipient cells. Additional model simulations indicate that within clinically achievable PTX concentrations, the contribution of exosomes to active drug efflux increased with drug concentration and exceeded the p-glycoprotein efflux when the latter was saturated. Our results indicate (a) chemotherapeutic agents stimulate exosome production or release, and (b) exosome is a mechanism of intercellular drug transfer that contributes to pharmacodynamics of neighboring cells.
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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
影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
FEATHERSTONE, RM
影响因子：
16.1
作者：
Au JL;Yeung BZ;Wientjes MG;Lu Z;Wientjes MG
通讯作者：
Wientjes MG
来自吉非替尼治疗的 EGFR 突变肺癌细胞的外泌体通过上调自噬改变顺铂敏感性
影响因子：
--
作者：
Li XQ;Liu JT;Fan LL;Liu Y;Cheng L;Wang F;Yu HQ;Gao J;Wei W;Wang H;Sun GP
通讯作者：
Sun GP
影响因子：
2.9
作者：
DIAZ, JF;ANDREU, JM
通讯作者：
ANDREU, JM