In vivo release from a drug delivery MEMS device

Yawen Li; Rebecca S. Shawgo; Betty Tyler; Paul T. Henderson; John S. Vogel; Aron Rosenberg; Phillip B. Storm; Robert Langer; Henry Brem; Michael J. Cima

doi:10.1016/j.jconrel.2004.08.018

In vivo release from a drug delivery MEMS device

Yawen Li, Rebecca S. Shawgo, Betty Tyler, Paul T. Henderson, John S. Vogel, Aron Rosenberg, Phillip B. Storm, Robert Langer, Henry Brem, Michael J. Cima

School of Medicine

Research output: Contribution to journal › Article › peer-review

107 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	211-219
Number of pages	9
Journal	Journal of Controlled Release
Volume	100
Issue number	2
DOIs	https://doi.org/10.1016/j.jconrel.2004.08.018
State	Published - Nov 24 2004

Keywords

Accelerator mass spectrometry (AMS)
Carmustine (BCNU)
Drug delivery
In vivo release kinetics
Microelectromechanical systems (MEMS)

ASJC Scopus subject areas

Pharmaceutical Science

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10.1016/j.jconrel.2004.08.018

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@article{a1d8a8b7dbd64cb6ac62e1995c06e470,

title = "In vivo release from a drug delivery MEMS device",

abstract = "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.",

keywords = "Accelerator mass spectrometry (AMS), Carmustine (BCNU), Drug delivery, In vivo release kinetics, Microelectromechanical systems (MEMS)",

author = "Yawen Li and Shawgo, {Rebecca S.} and Betty Tyler and Henderson, {Paul T.} and Vogel, {John S.} and Aron Rosenberg and Storm, {Phillip B.} and Robert Langer and Henry Brem and Cima, {Michael J.}",

note = "Funding Information: This work was funded by the U.S. National Institute of Health grant no. 1 R24 AI47739-01 and U19-CA52857. R.S.S. was supported by a U.S. National Science Foundation fellowship. All microfabrication work was carried out at the Microsystems Technology Laboratory at MIT. The AMS work was performed under the auspices of the U.S. Department of Energy by University of California Lawrence Livermore National Laboratory under Contract W-7405-Eng-48 and in collaboration with the National Center for Research Resources GrantRR13461. The authors gratefully acknowledge Karen Dingley for many useful discussions and insights. Kurt Haack and Ester Ubeck are recognized for their work in preparing the AMS samples used in this work. ",

year = "2004",

month = nov,

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doi = "10.1016/j.jconrel.2004.08.018",

language = "English (US)",

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AU - Li, Yawen

AU - Shawgo, Rebecca S.

AU - Tyler, Betty

AU - Henderson, Paul T.

AU - Vogel, John S.

AU - Rosenberg, Aron

AU - Storm, Phillip B.

AU - Langer, Robert

AU - Brem, Henry

AU - Cima, Michael J.

N1 - Funding Information: This work was funded by the U.S. National Institute of Health grant no. 1 R24 AI47739-01 and U19-CA52857. R.S.S. was supported by a U.S. National Science Foundation fellowship. All microfabrication work was carried out at the Microsystems Technology Laboratory at MIT. The AMS work was performed under the auspices of the U.S. Department of Energy by University of California Lawrence Livermore National Laboratory under Contract W-7405-Eng-48 and in collaboration with the National Center for Research Resources GrantRR13461. The authors gratefully acknowledge Karen Dingley for many useful discussions and insights. Kurt Haack and Ester Ubeck are recognized for their work in preparing the AMS samples used in this work.

PY - 2004/11/24

Y1 - 2004/11/24

N2 - 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.

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KW - Accelerator mass spectrometry (AMS)

KW - Carmustine (BCNU)

KW - Drug delivery

KW - In vivo release kinetics

KW - Microelectromechanical systems (MEMS)

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In vivo release from a drug delivery MEMS device

Abstract

Keywords

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