Intracellular targeting of sodium mercaptoundecahydrododecaborate (BSH) to solid tumors by transferrin-PEG liposomes, for boron neutron-capture therapy (BNCT).
The successful treatment of cancer by boron neutron-capture therapy (BNCT) requires the selective delivery of relatively high concentration of 10B compounds to malignant tumor tissue. This study focuses on a new tumor-targeting drug delivery system for BNCT that uses small (less than 200 nm in diameter), unilamellar mercaptoundecahydrododecaborate (BSH)-encapsulating, transferrin (TF)-conjugated polyethyleneglycol liposomes (TF-PEG liposomes). When TF-PEG liposomes were injected at a dose of 35 mg 10B/kg, we observed a prolonged residence time in the circulation and low uptake by the reticuloendothelial system (RES) in Colon 26 tumor-bearing mice, resulting in enhanced accumulation of 10B into the solid tumor tissue (e.g., 35.5 microg/g). TF-PEG liposomes maintained a high 10B level in the tumor, with concentrations over 30 microg/g for at least 72 h after injection. This high retention of 10B in tumor tissue indicates that binding and concomitant cellular uptake of the extravasated TF-PEG liposomes occurs by TF receptor and receptor-mediated endocytosis, respectively. On the other hand, the plasma level of 10B decreased, resulting in a tumor/plasma ratio of 6.0 at 72 h after injection. Therefore, 72 h after injection of TF-PEG liposomes was selected as the time point of BNCT treatment. Administration of BSH encapsulated in TF-PEG liposomes at a dose of 5 or 20 mg 10B/kg and irradiation with 2 x 10(12) neutrons/cm2 for 37 min produced tumor growth suppression and improved long-term survival compared with PEG liposomes, bare liposomes and free BSH. Thus, intravenous injection of TF-PEG liposomes can increase the tumor retention of 10B atoms, which were introduced by receptor-mediated endocytosis of liposomes after binding, causing tumor growth suppression in vivo upon thermal neutron irradiation. These results suggest that BSH-encapsulating TF-PEG liposomes may be useful as a new intracellular targeting carrier in BNCT therapy for cancer.
Maruyama
Kazuo
K
Department of Pharmaceutics, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan. maruyama@pharm.teikyo-u.ac.jp
Ishida
Osamu
O
Kasaoka
Satoshi
S
Takizawa
Tomoko
T
Utoguchi
Naoki
N
Shinohara
Atsuko
A
Chiba
Momoko
M
Kobayashi
Hisao
H
Eriguchi
Masazumi
M
Yanagie
Hironobu
H
D000818:Animals; D019540:Area Under Curve; D001894:Borohydrides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001895:Boron / Q000032:analysis; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis; D007554:Isotopes / Q000032:analysis; D008081:Liposomes; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy*; D009502:Neutrons; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015996:Survival Rate; D014018:Tissue Distribution; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism
D001894:Borohydrides; D007554:Isotopes; D008081:Liposomes; D013438:Sulfhydryl Compounds; D014168:Transferrin; C014651:mercaptoundecahydrododecaborate; D011092:Polyethylene Glycols; D001895:Boron