Intracellular targeting of sodium mercaptoundecahydrododecaborate (BSH) to solid tumors by transferrin-PEG liposomes, for boron neutron-capture therapy (BNCT)
Intracellular targeting of sodium mercaptoundecahydrododecaborate (BSH) to solid tumors by transferrin-PEG liposomes, for boron neutron-capture therapy (BNCT)
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DOI：
10.1016/j.jconrel.2004.04.018
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发表时间：
2004-08-11
影响因子：
10.8
通讯作者：
Yanagie, H
中科院分区：
文献类型：
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作者：
Maruyama, K;Ishida, O;Yanagie, H
用硼中子俘获疗法(BNCT)成功地治疗癌症需要选择性地将相对高浓度的B-10化合物输送到恶性肿瘤组织。本研究重点研究了一种新型的肿瘤靶向给药系统，该系统使用小分子(直径小于200 nm)的单层硫代十二烷基硼酸脂(BSH)包裹转铁蛋白(Tf)-聚乙二醇脂质体(TF-PEG脂质体)。当以35 mg B-10/kg剂量注射TF-PEG脂质体时，我们观察到荷瘤小鼠循环中滞留时间延长，网状内皮系统(RES)摄取低，导致B-10在实体瘤组织中的积聚增加(例如，35.5微克/克)。转移因子-聚乙二醇脂质体在肿瘤内维持较高的B-10水平，注射后至少72小时内其浓度均在30微克/克以上。B-10在肿瘤组织中的高滞留率表明，外渗的TF-PEG脂质体分别通过TF受体和受体介导的内吞作用与细胞结合和摄取。而血浆B-10水平下降，72h后肿瘤/血浆比值为6.0。因此，选择注射转移因子-聚乙二醇脂质体72h作为BNCT治疗的时间点。以5或20 mg B~(-10)/kg的剂量将BSH包裹在TF-PEG脂质体中，以2×10~(12)中子/cm~(2)照射37min，与聚乙二醇脂质体、裸脂质体和游离BSH相比，可抑制肿瘤生长，提高长期存活率。因此，静脉注射TF-PEG脂质体可以增加B-10原子的肿瘤滞留，这些B-10原子是通过受体介导的脂质体结合后的内吞作用而引入的，在热中子照射下引起体内肿瘤生长抑制。这些结果表明，BSH包裹的TF-PEG脂质体可能作为一种新的细胞内靶向载体用于肿瘤的BNCT治疗。(C)2004爱思唯尔B.V.保留所有权利。
The successful treatment of cancer by boron neutron-capture therapy (BNCT) requires the selective delivery of relatively high concentration of B-10 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 B-10/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 B-10 into the solid tumor tissue (e.g., 35.5 mug/g). TF-PEG liposomes maintained a high B-10 level in the tumor, with concentrations over 30 mug/g for at least 72 h after injection. This high retention of B-10 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 B-10 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 B-10/kg and irradiation with 2 x 10(12) neutronS/cm(2) 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 B-10 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. (C) 2004 Elsevier B.V. All rights reserved.