Novel Toll-like Receptor 2 Ligands for Targeted Pancreatic Cancer Imaging and Immunotherapy
Novel Toll-like Receptor 2 Ligands for Targeted Pancreatic Cancer Imaging and Immunotherapy
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DOI：
10.1021/jm301002f
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发表时间：
2012-11-22
影响因子：
7.3
通讯作者：
Vagner, Josef
中科院分区：
文献类型：
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作者：
Amanda Shanks Huynh;Chung, Woo Jin;Vagner, Josef
Toll样受体2（TLR 2）是癌症免疫治疗期间免疫系统刺激的靶点，也是胰腺癌的细胞表面标志物：为了开发用于癌症成像和治疗的靶向药物，我们设计了。合成并表征了新的全合成高亲和力TLR 2激动剂。抗肿瘤剂10具有最高的激动剂活性（NF-κ B功能测定，EC 50 = 20 nM）和结合亲和力（竞争性结合测定，Ki = 25 nM）。作为免疫佐剂，化合物10刺激小鼠的免疫系统。通过抗原特异性CD 8 + T细胞的产生和持续存在，体内显示其在癌症免疫治疗中的潜在用途。在近红外染料与10缀合后，激动剂活性（EC 50 = 34 nM）和结合亲和力（Ki = 11 nM）在13中保留。在注射13后24小时，在表达TLR 2的胰腺肿瘤异种移植物中存在荧光信号，而过量的未标记配体阻断13与肿瘤结合，导致信号显著降低（P < 0.001），证明了体内选择性。
Toll-like receptor 2 (TLR2) is a target for immune system stimulation during cancer immunotherapy and a cell-surface marker for pancreatic cancer: To develop targeted agents for Cancer imaging and therapy, we designed,. synthesized, and characterized novel, fully synthetic high affinity TLR2 agonists. Analogue 10 had the highest agonist activity (NF-kappa B functional assay, EC50 = 20 nM) and binding affinity (competitive binding assay, K-i = 25 nM). As an immune adjuvant; compound 10 stimulated the immune system in. vivo by generation and persistence of antigen-specific CD8+ T cells indicating its potential use in cancer immunotherapy. After Conjugation of near-infrared dye to 10, agonist activity (EC50 = 34 nM) and binding affinity (K-i = 11 nM) Were retained in 13. Fluorescence Signal was present in TLR2 expressing pancreatic tumor xenografts 24 h after injection of 13, while an excess of unlabeled ligand blocked 13 from binding to the tumor, resulting in significantly decreased signal (P < 0.001) demonstrating in vivo selectivity.