Development of tumor targeting bioprobes (111In-chimeric L6 monoclonal antibody nanoparticles) for alternating magnetic field cancer therapy
Development of tumor targeting bioprobes (111In-chimeric L6 monoclonal antibody nanoparticles) for alternating magnetic field cancer therapy
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DOI：
10.1158/1078-0432.ccr-1004-0022
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发表时间：
2005-10-01
影响因子：
11.5
通讯作者：
Ivkov, R
中科院分区：
文献类型：
--
作者：
DeNardo, SJ;DeNardo, GL;Ivkov, R
目的：研究In-111嵌合L6(ChL6)单抗(MAb)连接的氧化铁纳米粒子(BioProbe)在荷人乳腺癌HBT 3477裸鼠体内的药代动力学、肿瘤摄取及交变磁场(AMF)诱导加热的治疗作用。方法：用1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide盐酸盐将In-111-7，10-四氮杂环十二烷-N，N‘，N’‘，N’，N‘-四乙酸四乙二醇偶联于20 nm的葡聚糖包被的聚乙二醇单抗颗粒上，每纳米粒1~2个单抗。经磁净化和无菌过滤后，静脉注射In-111-ChL6生物探针剂量(20 ng/2.2 mg ChL6/BioProbe)，进行药代动力学、组织病理学和AMF/生物探针治疗。在荷HBT 3477的裸鼠体内注射50 mU g ChL6；注射后72小时给予153 kHzAMF，幅度分别为1,300，1,000或700 Oe。结果：In-111-ChL6生物探针与HBT 3477细胞的体外结合率是In-111-ChL6的50%~70%。在48小时内，In-111-ChL6生物探针对肿瘤、肺、肾脏和骨髓的摄取与先前In-111-ChL6研究中观察到的没有什么不同。AMF/生物探针治疗显示出显著的治疗效果，与未治疗相比，治疗后肿瘤体积增加五倍的平均时间长达8倍(P=0.0013)。毒性只出现在1300 Oe AMF队列中，12人中有4人立即死亡和皮肤红斑。电子显微镜显示，AMF/BioProbe治疗24小时后，切除肿瘤和肿瘤坏死的HBT 3477细胞表面有BioProbe。结论：本研究表明，静脉注射单抗偶联的BioProbe后，可以逃逸到血管外间隙并与癌细胞膜抗原结合，从而使BioProbe可以与AMF外用联合应用于热消融癌症治疗。
Objectives: In-111-chimeric L6 (ChL6) monoclonal antibody (mAb) - linked iron oxide nanoparticle (bioprobes) pharmacokinetics, tumor uptake, and the therapeutic effect of inductively heating these bioprobes by externally applied alternating magnetic field (AMF) were studied in athymic mice bearing human breast cancer HBT 3477 xenografts. Tumor cell radioimmunotargeting of the bioprobes and therapeutic and toxic responses were determined.Methods: Using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl, In-111-7,10-tetraazacycloclodecane-N, N',N'',N'''-tetraacetic acid-ChL6 was conjugated to the carboxylated polyethylene glycol on dextran-coated iron oxide 20 nm particles, one to two mAbs per nanoparticle. After magnetic purification and sterile filtration, pharmacokinetics, histopathology, and AMF/bioprobe therapy were done using In-111-ChL6 bioprobe doses (20 ng/2.2 mg ChL6/ bioprobe), i.v. with 50 mu g ChL6 in athymic mice bearing HBT 3477; a 153 kHz AMF was given 72 hours postinjection for therapy with amplitudes of 1,300, 1,000, or 700 Oe. Weights, blood counts, and tumor size were monitored and compared with control mice receiving nothing, or AMF or bioprobes alone.Results: In-111-ChL6 bioprobe binding in vitro to HBT 3477 cells was 50% to 70% of that of In-111-ChL6. At 48 hours, tumor, lung, kidney, and marrow uptakes of the In-111-ChL6 bioprobes were not different from that observed in prior studies of In-111-ChL6. Significant therapeutic responses from AMF/bioprobe therapy were shown with up to eight times longer mean time to quintuple tumor volume with therapy compared with no treatment (P = 0.0013). Toxicity was only seen in the 1,300 Oe AMF cohort, with 4 of 12 immediate deaths and skin erythema. Electron micrographs showed bioprobes on the surfaces of the HBT 3477 cells of excised tumors and tumor necrosis 24 hours after AMF/bioprobe therapy.Conclusion: This study shows that mAb-conjugated nanoparticles (bioprobes), when given i.v., escape into the extravascular space and bind to cancer cell membrane antigen, so that bioprobes can be used in concert with externally applied AMF to deliver thermoablative cancer therapy.