Leveraging nanochannels for universal, zero-order drug delivery in vivo
Leveraging nanochannels for universal, zero-order drug delivery in vivo
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DOI：
10.1016/j.jconrel.2013.09.028
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发表时间：
2013-12-28
影响因子：
10.8
通讯作者：
Grattoni, Alessandro
中科院分区：
文献类型：
--
作者：
Ferrati, Silvia;Fine, Daniel;Grattoni, Alessandro
药物递送对于实现有效治疗是必不可少的。在这里，我们报告唯一的植入式纳米通道膜与几何定义的通道小至2.5 nm，实现恒定的药物输送在体内。纳米通道通过物理静电约束被动地控制分子的释放，从而导致恒定的药物扩散。我们利用一种新的设计算法来选择每种治疗剂的最佳纳米通道尺寸。使用小至3.6和20 nm的纳米通道，我们实现了亮丙瑞林、干扰素α-2b、来曲唑、Y-27632、奥曲肽和人生长激素的持续和恒定血浆水平，所有这些药物均以临床相关剂量递送。该装置在狗、大鼠和小鼠中得到了证明，能够维持目标剂量长达70天。为了提供治疗效果的证据，我们成功地将纳米通道递送与RhoA通路抑制剂相结合，以防止大鼠模型中心脏同种异体移植物的慢性排斥反应。我们的研究结果提供了证据表明，纳米通道平台有潜力显着改善慢性疾病的长期治疗。(C)2013爱思唯尔有限公司版权所有。
Drug delivery is essential to achieve effective therapy. Herein we report on the only implantable nanochannel membrane with geometrically defined channels as small as 2.5 nm that achieves constant drug delivery in vivo. Nanochannels passively control the release of molecules by physico-electrostatic confinement, thereby leading to constant drug diffusion. We utilize a novel design algorithm to select the optimal nanochannel size for each therapeutic agent. Using nanochannels as small as 3.6 and 20 nm, we achieve sustained and constant plasma levels of leuprolide, interferon alpha-2b, letrozole, Y-27632, octreotide, and human growth hormone, all delivered at clinically-relevant doses. The device was demonstrated in dogs, rats, and mice and was capable of sustaining target doses for up to 70days. To provide evidence of therapeutic efficacy, we successfully combined nanochannel delivery with a RhoA pathway inhibitor to prevent chronic rejection of cardiac allografts in a rat model. Our results provide evidence that the nanochannel platform has the potential to dramatically improve long-term therapies for chronic conditions. (C) 2013 Elsevier B.V. All rights reserved.