title: Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model.
abstract: 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 degrees 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.
authors: Division of Health Sciences and Technology, MIT/Harvard University, USA.
authors: Grace Y
authors: GY
authors: Kim
authors: Betty M
authors: BM
authors: Tyler
authors: Malinda M
authors: MM
authors: Tupper
authors: Jeffrey M
authors: JM
authors: Karp
authors: Robert S
authors: RS
authors: Langer
authors: Henry
authors: H
authors: Brem
authors: Michael J
authors: MJ
authors: Cima
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001672:Biocompatible Materials; D002330:Carmustine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical; D003652:Decanoic Acids / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D004343:Drug Implants; D004355:Drug Stability; D005260:Female; D018316:Gliosarcoma / Q000473:pathology / Q000517:prevention & control*; D006207:Half-Life; D019344:Lactic Acid / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods*; D011091:Polyesters / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D011916:Rats, Inbred F344; D015203:Reproducibility of Results; D012995:Solubility; D013997:Time Factors
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001672:Biocompatible Materials; D003652:Decanoic Acids; D004337:Drug Carriers; D004343:Drug Implants; D011091:Polyesters; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); C055401:decanedioic acid-4,4'-(1,3-propanediylbis(oxy))bis(benzoic acid) copolymer; D002330:Carmustine