Pharmacokinetics of core-polymerized, boron-conjugated micelles designed for boron neutron capture therapy for cancer.
Core-polymerized and boron-conjugated micelles (PM micelles) were prepared by free radical copolymerization of a PEG-b-PLA block copolymer bearing an acetal group and a methacryloyl group (acetal-PEG-b-PLA-MA), with 1-(4-vinylbenzyl)-closo-carborane (VB-carborane), and the utility of these micelles as a tumor-targeted boron delivery system was investigated for boron neutron capture therapy (BNCT). Non-polymerized micelles (NPM micelles) that incorporated VB-carborane physically showed significant leakage of VB-carborane (ca. 50%) after 12 h incubation with 10% fetal bovine serum (FBS) at 37 °C. On the other hand, no leakage from the PM micelles was observed even after 48 h of incubation. To clarify the pharmacokinetics of the micelles, (125)I (radioisotope)-labeled PM and NPM micelles were administered to colon-26 tumor-bearing BALB/c mice. The (125)I-labeled PM micelles showed prolonged blood circulation (area under the concentration curve (AUC): 943.4) than the (125)I-labeled NPM micelles (AUC: 495.1), whereas tumor accumulation was similar for both types of micelles (AUC(PM micelle): 249.6, AUC(NPM micelle): 201.1). In contrast, the tumor accumulation of boron species in the PM micelles (AUC: 268.6) was 7-fold higher than the NPM micelles (AUC: 37.1), determined by ICP-AES. Thermal neutron irradiation yielded tumor growth suppression in the tumor-bearing mice treated with the PM micelles without reduction in body weight. On the basis of these data, the PM micelles represent a promising approach to the creation of boron carrier for BNCT.
Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8573, Japan.
Shogo
S
Sumitani
Motoi
M
Oishi
Tatsuya
T
Yaguchi
Hiroki
H
Murotani
Yukichi
Y
Horiguchi
Minoru
M
Suzuki
Koji
K
Ono
Hironobu
H
Yanagie
Yukio
Y
Nagasaki
D000818:Animals; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D001895:Boron / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016754:Boron Neutron Capture Therapy; D007773:Lactates / Q000737:chemistry; D051379:Mice; D008823:Micelles; D009369:Neoplasms / Q000097:blood / Q000473:pathology / Q000532:radiotherapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D058105:Polymerization / Q000187:drug effects*; D013054:Spectrophotometry, Atomic; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
D007773:Lactates; D008823:Micelles; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D001895:Boron