胃癌单克隆抗体的硼化及其硼中子俘获治疗效应

Boronation of Monoclonal Antibody MGb2 for Targeted Boron Neutron Capture Therapy of Human Castric Cancer

胃癌单克隆抗体MGb2与硼化物Cs_2^(10)B_(12)H_(11)SH通过马来酰亚胺苯甲酸-N-羟基琥珀酰亚胺酯反应交联,每个单抗分子连接220个^(10)B原子。硼化抗体与人胃癌细胞SGC-7901孵育2h,可结合2.6×10~9 ^(10)B/细胞,是正常人胚肺细胞SL7的5.2倍,达到BNCT所需浓度。用^(125)Ⅰ标记MGb2-^(10)B,腹腔注射荷人胃癌裸鼠(SWISS DF nu/nu,370 KBq/只),第5天肿瘤摄取为10.14％1D/g,显著高于正常鼠IgG-^(10)B(1.19％ID/g),(P<0.01)。SPECT放射免疫显像可见^(125)Ⅰ-MGb2-^(10)B在肿瘤部位明显的放射性浓集,而胸腹腔放射性少。MGB2-^(10)B处理的胃癌细胞经49-2型核反应堆热中子照射(3.12×10^(11)n/cm^2,γ-射线0.84Gy),存活率30％,显著低于未照射组和非特异硼化物组(P<0.001),显示出导向硼中子俘获治疗效应。

Boron neutron capture therapy (BNCT) is based on the nuclear reaction [10B+1n→(11He+7Li+2.8 MeV] yielding Li-7 and alpha particles with high energy when boron-10 is irradiated with thermal neutrons. The particles have a path length of 10 μm and are capable of destroying 10B attached cells. The essential factor for successful BNCT is a sufficient amount 10B concentrated in tumor tissues so that antitum-our antibodies may serve as boron-carriers for targeted delivery of 10B. In the present study, the boron compound Cs210B11SH was conjugated to MGb2, a monoclonal antibody against human gastric cancer. Up to 220 10B atoms were incorporated into one MGb2 molecule without significantly impairing immunoreactivity. When boronated antibody MGb2-10B was incubated with human gastric cancer cell SGC-7901 for 2h, 2.6x 109 10B atoms were bound on each cell, which was 5.2-fold more than that of human normal embryonic lung cell SL7. SPECT radioimmunoimaging and biodistribution studies were performed with 125I-MGb2-10B in SWISS DF nude mice bearing SGC-7901 s. c. xenografts. Good tumor localization was observed on day 5 when tumor accumulation was 10.41%ID/g and T/NT ratio was 2.56 for blood, 8.33 for liver, 7.44 for kidney and 9.55 for stomach, respectively. Irradiated with thermal neutrons (0.0025eV, 3.12×1011n/cm2) from 49-2 reactor, MGb2-10B pre-treated tumor cells survived by 30%, significantly lower than that of non-irradiated cells and non-pretreated cells with or without irradiation (p<0.001). The results demonstrate that boronated MGb2 may have the potentiality in BNCT of human gastric cancer.