Synthesis of a nickel tetracarboranylphenylporphyrin for boron neutron-capture therapy: biodistribution and toxicity in tumor-bearing mice.
Nickel-2,3,7,8,12,13,17,18-octaacetic acid-5,10,15,20-tetra-[3-carboranyl-methoxyphenyl]-porphyrin octamethylester (NiTCP) was given in a Cremophor EL, a polyethoxylated castor oil, and propylene glycol emulsion to BALB/c mice bearing transplanted s.c. KHJJ mammary carcinomas. A total dose of 244 microg NiTCP/gram body weight (gbw) (54 microg B/gbw) was given in 6 i.p. injections over a 32 hr period. Observations of behavior and changes in body weight and chemical and hematological blood tests indicated little or no toxicity from NiTCP over a period of 6-90 hr after injections. Boron concentrations near tumor margins were 160-180 microg B/g at 41-90 hr after the last injection. Tumor:normal brain boron concentration ratios reached approx. 10:1 and tumor:blood ratios reached approx. 250:1 after 4 days. There was no evidence of thrombocytopenia or other potentially important toxicities. Our findings place NiTCP among the leading candidates for pre-clinical experiments aimed toward improvement upon the compounds being tested for boron neutron-capture therapy of glioblastoma multiforme.
Miura
M
M
Medical Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA.
Micca
P L
PL
Fisher
C D
CD
Heinrichs
J C
JC
Donaldson
J A
JA
Finkel
G C
GC
Slatkin
D N
DN
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001806:Blood Urea Nitrogen; D001895:Boron / Q000032:analysis / Q000097:blood; D016754:Boron Neutron Capture Therapy; D001923:Brain Chemistry; D005260:Female; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000737:chemistry / Q000532:radiotherapy*; D008665:Metalloporphyrins / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D014018:Tissue Distribution
D008665:Metalloporphyrins; C102101:nickel-2,3,7,8,12,13,17,18-octaacetic acid-5,10,15,20-tetra-(3-carboranylmethoxyphenyl)porphyrin octamethyl ester; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001895:Boron