Exosomes for the Enhanced Tissue Bioavailability and Efficacy of Curcumin
Exosomes for the Enhanced Tissue Bioavailability and Efficacy of Curcumin
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DOI：
10.1208/s12248-017-0154-9
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发表时间：
2017-11-01
期刊：
影响因子：
4.5
通讯作者：
Gupta, Ramesh
中科院分区：
文献类型：
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作者：
Aqil, Farrukh;Munagala, Radha;Gupta, Ramesh
外泌体是具有30-100 nm粒径的细胞外微泡，并且携带蛋白质、脂质、RNA和DNA的货物。它们在细胞中穿梭的特性表明这些颗粒可以作为纳米药物载体。在这份手稿中，我们表明姜黄素可以使用乳源性外泌体有效地递送。当姜黄素在10%乙醇：乙腈（1：1）的存在下与外泌体混合时，提供18- 24%的载药量，并且根据粒度分析、载药量和抗增殖活性确定，该制剂在-80摄氏度下储存6个月是稳定的。癌细胞对外来体的摄取涉及小窝/网格蛋白介导的内吞作用。在Sprague-Dawley大鼠中口服施用外泌体姜黄素（ExoCUR）在各种器官中的水平比游离试剂高3-5倍。与游离姜黄素相比，ExoCUR对多种癌细胞系（包括乳腺癌、肺癌和宫颈癌）显示出增强的抗增殖活性。ExoCUR在人肺癌和乳腺癌细胞中显示出显著更高的抗炎活性，测量为NF-κ B活化。为了确定体内抗肿瘤活性，将携带宫颈CaSki肿瘤异种移植物的裸鼠用ExoCUR通过口服管饲、姜黄素饮食、单独的外来体和PBS作为对照进行处理。虽然通过饮食途径的姜黄素未能引起任何效果，但外来体具有适度（25-30%）的肿瘤生长抑制。然而，ExoCUR显示出对宫颈肿瘤异种移植物的显著抑制（61%; p < 0.01）。在给予外来体或ExoCUR的大鼠中未观察到总体或全身毒性。这些结果表明，外泌体可以被开发为用于递送姜黄素的潜在纳米载体，否则姜黄素在过去会遇到显著的组织生物利用度问题。
Exosomes are extracellular microvesicles with a particle size of 30-100 nm and carry a cargo of proteins, lipids, RNA, and DNA. Their properties of shuttling in-and-out of the cells suggest that these particles can be exploited as a nano drug carrier. In this manuscript, we show that curcumin can be delivered effectively using milk-derived exosomes. Curcumin when mixed with exosomes in the presence of 10% ethanol:acetonitrile (1:1) provided a drug load of 18-24%, and the formulation stored at - 80A degrees C was stable for 6 months as determined by particle size analysis, drug load, and antiproliferative activity. The uptake of exosomes by cancer cells involved caveolae/clathrin-mediated endocytosis. Oral administration of exosomal curcumin (ExoCUR) in Sprague-Dawley rats demonstrated 3-5 times higher levels in various organs versus free agent. ExoCUR showed enhanced antiproliferative activity against multiple cancer cell lines including, breast, lung, and cervical cancer compared with the free curcumin. ExoCUR showed significantly higher anti-inflammatory activity measured as NF-kappa B activation in human lung and breast cancer cells. To determine in vivo antitumor activity, nude mice bearing the cervical CaSki tumor xenograft were treated with ExoCUR by oral gavage, curcumin diet, exosomes alone, and PBS as controls. While curcumin via dietary route failed to elicit any effect, exosomes had a modest (25-30%) tumor growth inhibition. However, ExoCUR showed significant inhibition (61%; p < 0.01) of the cervical tumor xenograft. No gross or systemic toxicity was observed in the rats administered with the exosomes or ExoCUR. These results suggest that exosomes can be developed as potential nano carriers for delivering curcumin which otherwise has encountered significant tissue bioavailability issues in the past.