Li Yawen, Shawgo Rebecca S, Tyler Betty, Henderson Paul T, Vogel John S, Rosenberg Aron, Storm Phillip B, Langer Robert, Brem Henry, Cima Michael J
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
J Control Release. 2004 Nov 24;100(2):211-9. doi: 10.1016/j.jconrel.2004.08.018.
A drug delivery microelectromechanical systems (MEMS) device was designed to release complex profiles of multiple substances in order to maximize the effectiveness of drug therapies. The device is based on micro-reservoirs etched into a silicon substrate that contain individual doses of drug. Each dose is released by the electrochemical dissolution of the gold membrane that covers the reservoir. The first in vivo operation of this device was reported in this study. Subcutaneous release was demonstrated in rats using two tracer molecules, fluorescein dye and radiolabeled mannitol, and one radiolabeled chemotherapeutic agent, carmustine (BCNU). BCNU was chosen because of the need to improve the direct delivery of chemotherapy to malignant tumors. The spatial profile of fluorescein dye release from the drug delivery device was evaluated by fluorimetry, the temporal profile of 14C labeled mannitol release was evaluated by liquid scintillation counting, and the temporal profile of 14C labeled BCNU release was evaluated by accelerator mass spectrometry (AMS). Release profiles obtained from injected controls were compared with those from activated devices. The in vivo dye release results showed high concentration of fluorescein in the flank tissue surrounding the devices 1 h after activation. The 14C labeled mannitol released from the drug delivery devices was rapidly cleared (1 day) from the rat urine. In vivo release of 14C labeled BCNU from activated devices showed slightly slower kinetics than the injected and in vitro controls, and the time to reach the steady-state plasma 14C concentration was on the order of 1 h. All these results demonstrated the capability of this drug delivery device to achieve localized delivery of various compounds with well-defined temporal profiles.
一种药物递送微机电系统（MEMS）装置被设计用于释放多种物质的复杂释放曲线，以最大化药物治疗的效果。该装置基于蚀刻在硅衬底中的微储库，这些微储库包含单剂量的药物。每个剂量通过覆盖储库的金膜的电化学溶解来释放。本研究报道了该装置的首次体内操作。使用两种示踪分子（荧光素染料和放射性标记的甘露醇）以及一种放射性标记的化疗药物卡莫司汀（BCNU）在大鼠中证明了皮下释放。选择BCNU是因为需要改善化疗对恶性肿瘤的直接递送。通过荧光法评估了从药物递送装置释放的荧光素染料的空间分布，通过液体闪烁计数评估了14C标记的甘露醇释放的时间分布，通过加速器质谱（AMS）评估了14C标记的BCNU释放的时间分布。将从注射对照获得的释放曲线与从激活装置获得的释放曲线进行比较。体内染料释放结果显示，激活后1小时，装置周围胁腹组织中荧光素浓度很高。从药物递送装置释放的14C标记的甘露醇从大鼠尿液中迅速清除（1天）。激活装置中14C标记的BCNU的体内释放显示出比注射对照和体外对照稍慢的动力学，达到稳态血浆14C浓度的时间约为1小时。所有这些结果都证明了这种药物递送装置能够以明确的时间分布实现各种化合物的局部递送。
