TY - JOUR
T1 - Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model
AU - Kim, Grace Y.
AU - Tyler, Betty M.
AU - Tupper, Malinda M.
AU - Karp, Jeffrey M.
AU - Langer, Robert S.
AU - Brem, Henry
AU - Cima, Michael J.
N1 - Funding Information:
Financial disclosure: Michael Cima and Robert Langer are shareholders in MicroCHIPS, Inc., Bedford, Massachusetts. Henry Brem and the Johns Hopkins University are entitled to a share of royalty by MGI Pharma, Inc. on potential sales of some products that are in development. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Brem's laboratory is, and has been, supported by funding from Guilford Pharmaceuticals, Inc., MacroMed, Inc., and MGI Pharma, along with grants from the National Cancer Institute (NCI) and the National Institutes of Health (NIH).
Funding Information:
This work was funded by the U.S. National Institute of Health grant No. 1 R24 AI47739, the National Science Foundation Graduate Research Fellowship (GK). All in vivo experiments were carried out at the Johns Hopkins Animal Care Facility.
PY - 2007/11/6
Y1 - 2007/11/6
N2 - Sustained local delivery of single agents and controlled delivery of multiple chemotherapeutic agents are sought for the treatment of brain cancer. A resorbable, multi-reservoir polymer microchip drug delivery system has been tested against a tumor model. The microchip reservoirs were loaded with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU was more stable at 37 °C within the microchip compared to a uniformly impregnated polymeric wafer (70% intact drug vs. 38%, at 48 h). The half-life of the intact free drug in the microchip was 11 days, which is a marked enhancement compared to its half-life in normal saline and 10% ethanol (7 and 10 min, respectively) [P. Tepe, S.J. Hassenbusch, R. Benoit, J.H. Anderson, BCNU stability as a function of ethanol concentration and temperature, J. Neurooncol. 10 (1991) 121-127; P. Kari, W.R. McConnell, J.M. Finkel, D.L. Hill, Distribution of Bratton-Marshall-positive material in mice following intravenous injections of nitrosoureas, Cancer Chemother. Pharmacol. 4 (1980) 243-248]. A syngeneic Fischer 344 9L gliosarcoma rat model was used to study the tumoricidal efficacy of BCNU delivery from the microchip or homogeneous polymer wafer. A dose-dependent decrease in tumor size was found for 0.17, 0.67, and 1.24 mg BCNU-microchips. Tumors treated with 1.24 mg BCNU-microchips showed significant tumor reduction (p = 0.001) compared to empty control microchips at two weeks. The treatment showed similar efficacy to a polymer wafer with the same dosage. The microchip reservoir array may enable delivery of multiple drugs with independent release kinetics and formulations.
AB - Sustained local delivery of single agents and controlled delivery of multiple chemotherapeutic agents are sought for the treatment of brain cancer. A resorbable, multi-reservoir polymer microchip drug delivery system has been tested against a tumor model. The microchip reservoirs were loaded with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU was more stable at 37 °C within the microchip compared to a uniformly impregnated polymeric wafer (70% intact drug vs. 38%, at 48 h). The half-life of the intact free drug in the microchip was 11 days, which is a marked enhancement compared to its half-life in normal saline and 10% ethanol (7 and 10 min, respectively) [P. Tepe, S.J. Hassenbusch, R. Benoit, J.H. Anderson, BCNU stability as a function of ethanol concentration and temperature, J. Neurooncol. 10 (1991) 121-127; P. Kari, W.R. McConnell, J.M. Finkel, D.L. Hill, Distribution of Bratton-Marshall-positive material in mice following intravenous injections of nitrosoureas, Cancer Chemother. Pharmacol. 4 (1980) 243-248]. A syngeneic Fischer 344 9L gliosarcoma rat model was used to study the tumoricidal efficacy of BCNU delivery from the microchip or homogeneous polymer wafer. A dose-dependent decrease in tumor size was found for 0.17, 0.67, and 1.24 mg BCNU-microchips. Tumors treated with 1.24 mg BCNU-microchips showed significant tumor reduction (p = 0.001) compared to empty control microchips at two weeks. The treatment showed similar efficacy to a polymer wafer with the same dosage. The microchip reservoir array may enable delivery of multiple drugs with independent release kinetics and formulations.
KW - 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU)
KW - Biodegradable polymer
KW - Drug delivery
KW - Microchip
KW - Tumor
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U2 - 10.1016/j.jconrel.2007.08.003
DO - 10.1016/j.jconrel.2007.08.003
M3 - Article
C2 - 17884232
AN - SCOPUS:35248832087
VL - 123
SP - 172
EP - 178
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
IS - 2
ER -