Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model.
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.
Kim
Grace Y
GY
Division of Health Sciences and Technology, MIT/Harvard University, USA.
Tyler
Betty M
BM
Tupper
Malinda M
MM
Karp
Jeffrey M
JM
Langer
Robert S
RS
Brem
Henry
H
Cima
Michael J
MJ
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
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