Interstitial taxol delivered from a biodegradable polymer implant against experimental malignant glioma.
Taxol is a novel antitumor agent with demonstrated efficacy against ovarian, breast, and non-small cell lung cancers in Phase II clinical trials, but which has been shown not to cross the blood-brain barrier. To adapt taxol as a therapy for brain tumors, we have incorporated it into a biodegradable polyanhydride matrix for intracranial implantation and evaluated this formulation in a rat model of malignant glioma. Fischer 344 rats bearing intracranial 9L glioma tumors were treated with 10 mg poly[bis(p-carboxyphenoxy)propane-sebacic acid] (20:80) copolymer discs, containing 20-40% taxol by weight, 5 days after tumor implantation. The taxol-loaded polymers doubled (38 days, 40% taxol loading, P < 0.02) to tripled (61.5 days, 20% taxol loading, P < 0.001) the median survival of rats bearing tumor relative to control rats (19.5 days). Drug loadings of 20-40% taxol by weight released intact taxol for up to 1000 h in vitro. In rats followed up to 30 days postimplant, the polymer maintained a taxol concentration of 75-125 ng taxol/mg brain tissue (100-150 microM taxol) within a 1-3-mm radius of the disc. At points more distant from the disc (up to 8 mm away, the size limit of the rat brain), the polymer maintained a taxol concentration of greater than 4 ng taxol/mg brain tissue (5 microM). We conclude that taxol shows promise as a therapy for malignant glioma when delivered interstitially from a biodegradable polymer.
Walter
K A
KA
Department of Neurological Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Cahan
M A
MA
Gur
A
A
Tyler
B
B
Hilton
J
J
Colvin
O M
OM
Burger
P C
PC
Domb
A
A
Brem
H
H
D000818:Animals; D001704:Biopolymers; D001921:Brain / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D003652:Decanoic Acids; D004343:Drug Implants; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011091:Polyesters; D051381:Rats; D011916:Rats, Inbred F344; D016019:Survival Analysis; D014018:Tissue Distribution
D001704:Biopolymers; D003652:Decanoic Acids; D004343:Drug Implants; D011091:Polyesters; C055401:decanedioic acid-4,4'-(1,3-propanediylbis(oxy))bis(benzoic acid) copolymer; D017239:Paclitaxel