In vivo evaluation of the boronated porphyrin TABP-1 in U-87 MG intracerebral human glioblastoma xenografts.
Boron neutron capture therapy (BNCT) is an adjuvant therapy that has the potential to control local tumor growth. A selective delivery of sufficient amounts of boron to individual tumor cells, compared to surrounding normal tissues, is the key for successful BNCT. We have designed and synthesized a new highly water-soluble boronated porphyrin, TABP-1, as a possible BNCT agent. When we injected the maximum tolerated dose (MTD: 15 mg/kg) of TABP-1 systemically into the tail vein of athymic rats bearing intracerebral (i.c.) human glioblastoma U-87 MG xenografts, the compound accumulated preferentially in brain tumors compared to normal brain; however, the level of boron in the tumors was less than the 30 microg/g of tissue that is generally considered necessary for BNCT. We next investigated whether convection-enhanced delivery (CED) could improve the boron distribution. The compound was administered directly into i.c. tumors using an osmotic minipump attached to a brain-infusion cannula. TABP-1 doses from 0.25 to 1.0 mg infused locally over 24 h produced tumor boron concentrations greater than those obtained by systemic administration at the MTD. For example, CED administration of 0.5 mg of TABP-1 produced a tumor boron level of 65.4 microg/g of tumor, whereas the serum level was only 0.41 microg/g (tumor to serum ratio of approximately 160:1). CED also produced relatively high tumor to normal brain ratios of approximately 5:1 for ipsilateral brain and approximately 26:1 for contralateral brain tissues at the 0.5 mg dose. Thus, we may be able to achieve therapeutic BNCT efficacy with minimal systemic toxicity or radiation-induced damage to normal tissue by administering TABP-1 using CED.
Ozawa
Tomoko
T
Department of Neurological Surgery, University of California, San Francisco, California 94143, USA.
Santos
Raquel A
RA
Lamborn
Kathleen R
KR
Bauer
William F
WF
Koo
Myoung-Seo
MS
Kahl
Stephen B
SB
Deen
Dennis F
DF
D000818:Animals; D001896:Boron Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016754:Boron Neutron Capture Therapy / Q000379:methods; D001932:Brain Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D018481:Convection; D004333:Drug Administration Routes; D016503:Drug Delivery Systems / Q000379:methods; D005909:Glioblastoma / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D015394:Molecular Structure; D051381:Rats; D011917:Rats, Inbred Lew; D011923:Rats, Nude; D013997:Time Factors; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D001896:Boron Compounds; D008665:Metalloporphyrins; C503996:TABP-1 metalloporphyrin