Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model

• Published in: Journal of controlled release Vol. 123; no. 2; pp. 172 - 178
• Main Authors: Kim, Grace Y., Tyler, Betty M., Tupper, Malinda M., Karp, Jeffrey M., Langer, Robert S., Brem, Henry, Cima, Michael J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 06.11.2007; Elsevier
• Subjects: 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU); Animals; Antineoplastic agents; Antineoplastic Agents, Alkylating - chemistry; Antineoplastic Agents, Alkylating - pharmacokinetics; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Alkylating - therapeutic use; Biocompatible Materials; Biodegradable polymer; Biological and medical sciences; Carmustine - chemistry; Carmustine - pharmacokinetics; Carmustine - pharmacology; Carmustine - therapeutic use; Chemistry, Pharmaceutical; Chemotherapy; Decanoic Acids - chemistry; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug delivery; Drug Implants; Drug Stability; Female; General pharmacology; Gliosarcoma - pathology; Gliosarcoma - prevention & control; Half-Life; Lactic Acid - chemistry; Medical sciences; Microchip; Nanotechnology - methods; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyesters - chemistry; Polyglycolic Acid - chemistry; Polymers - chemistry; Rats; Rats, Inbred F344; Reproducibility of Results; Solubility; Time Factors; Tumor; Tumor; Drug delivery; Microchip; Biodegradable polymer; 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU); Antineoplastic agent; Rat; Biodegradability; Nitrosoureas; Drug carrier; Local administration; Microparticle; Drug combination; Pharmaceutical technology; Controlled release form; Carmustine; Rodentia; Microcapsule; Polymer; Malignant tumor; Alkylating agent; Vertebrata; Mammalia; Nitrogen mustard; Animal; Dosage form; Cancer
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2007.08.003

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.