Optimization Of Parameters For Tumor-targeting Of Radio-biologicals

放射生物制剂肿瘤靶向参数的优化

• 批准号: 7733644
• 负责人: Chang Hum Paik
• 金额: $ 5万
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733644
• 关键词: Affinity; Animals; Biodistribution; Blood; Blood Vessels; Blood flow; Chemicals; Combined Modality Therapy; Daily; Detection; Dose; Drug Controls; Endothelial Cells; Generations; Glycoproteins; Goals; Image; Immunotoxins; Implant; Indium-111; Injection of therapeutic agent; Integrin alphaV; Integrin alphaVbeta3; Kinetics; Label; Malignant Neoplasms; Measures; Methods; Molecular Target; Mus; Nuclear; Nude Mice; Nutrient; Organ; Oxygen; Paclitaxel; Pathway interactions; Pharmaceutical Preparations; Physiological Processes; Process; Protein Overexpression; RGD (sequence); Radio; Radioactivity; Radioisotopes; Radiolabeled; Reagent; Reporting; Research; Site; Solid Neoplasm; Surrogate Markers; Therapeutic; Therapeutic Effect; Therapeutic Index; Time; Tumor Angiogenesis; Tumor-Associated Vasculature; angiogenesis; antiangiogenesis therapy; cytotoxic; day; improved; killings; mesothelin; neoplastic cell; peptidomimetics; radiotracer; receptor; receptor binding; receptor expression; research study; response; size; tumor; tumor growth; uptake

The aims of the research in the past year was to quantify integrin alpha(V)beta(3) receptor expression on tumor-induced angiogenic blood vessels with In-111-labeled antagonists during a course of therapy, and to investigate a co-relationship between the level of the receptor expression and therapeutic response reflected in the changes in tumor size. Our preliminary studies demonstrated that In-111-labeled second generation peptidomimetic antagonist and In-111-labeled dimeric cyclic RGD peptide were good molecular targeting agents for alpha(V)beta(3) receptor. Among these In-111 labeled reagents, In-111 labeled dimeric cyclic RGD peptide was most suitable for quantifying the changes in the level of the receptor. Methods: Groups of nude mice (n = 5-10 per time point) implanted s.c. with A431/K5 tumor cells, expressing mesothelin and not alpha(V)beta(3), were treated with taxol alone i.p. at 50 mg/kg on day 0, mesothelin-specific immunotoxin SS1P alone i.v. at 0.2 mg/kg on days 0 and 2, or the two agents together; taxol (day 0), and SS1P (days 1 and 3). The tumor size was 100 cubic mm on day 0 and was measured daily. For the assessment of therapeutic response, the mice received i.v. In-111-labeled dimeric cyclic RGD peptide (2.0 micro-Ci/<0.1 micro-g) in 0.2 ml of PBS containing 1% BSA on days 1 and 4 for the taxol alone groups and on days 1 and 3 for the immunotoxin alone groups, and were euthanized at 1 or 2 hr post-injection for biodistribution. For the combination therapy groups, the mice were injected i.v. with the radiolabel on days 2 and 4, and were euthanized at 1 or 2 hr post-injection of the radiolabel. Results: The combination therapy was synergistic, using doses at which either agent alone causes stabilization of tumor growth as reported previously (Clin Cancer Res 2006;12:4695). The biodistribution of the radiolabel in blood and major organs was similar between the control and the drug treated animals. However, compared to the control, the tumor uptake (% ID/g) of the radiolabel decreased by 25% on day 1 but increased by 33% on day 4 for the taxol treated animals. Comparatively, the uptake increased by 11% on day 1 and by 39% on day 3 for the immunotoxin treated animals. The combined therapy decreased the uptake (% ID/g) by 8.5% on day 2 but increased the uptake by 25% on day 4. Since the taxol or immunotoxin treatment stopped the tumor growth and the tumor sizes remained unchanged for the duration of this experiment, the negative changes in tumor uptake (% ID/g) appear to indicate that taxol treatment down-regulated the receptor expression and thus, reduced the total level of the receptors on angiogenic vessels on day 1. However, the receptor level (%ID/g) increased on day 4, indicating that the receptor expression became up-regulated to induce angiogenesis for the re-growth of tumors. In contrast, immunotoxin treatment increased the receptor level for a 4 day period, indicating that immunotoxin treatment up-regulated the receptor expression. The changes in the tumor uptake by the combination therapy are the results of the combined effects of the drugs on the receptor expression. Conclusions: This study demonstrated that In-111 labeled dimeric cyclic RGD peptide is a good molecular targeting agent for alpha(V)beta(3) receptors and that the changes in the level of the alpha(V)beta(3) receptors (%ID/g tumor) expressed on neovasculature could be used as a sensitive surrogate marker for therapeutic response. The opposite direction of the changes in the receptor level suggests that the therapeutic effects of these two drugs were induced by different pathways of action. The direction and the magnitude of the changes in the receptor expression may be a sensitive predictive marker for therapeutic response of drugs.

去年研究的目的是量化治疗过程中In-111标记拮抗剂在肿瘤诱导的血管生成血管上的整合素α(V)β(3)受体表达，并研究受体表达水平与肿瘤大小变化所反映的治疗反应之间的相互关系。 我们的初步研究表明，In-111标记的第二代拟肽拮抗剂和In-111标记的二聚环RGD肽是α（V）β（3）受体的良好分子靶向剂。在这些In-111标记的试剂中，In-111标记的二聚环RGD肽最适合定量受体水平的变化。方法：皮下植入裸鼠组（每个时间点 n = 5-10）。表达间皮素而非 α(V)β(3) 的 A431/K5 肿瘤细胞仅用紫杉醇腹膜内处理。第 0 天 50 mg/kg，单独静脉注射间皮素特异性免疫毒素 SS1P。第 0 天和第 2 天按 0.2 mg/kg 给药，或两种药物同时给药；紫杉醇（第 0 天）和 SS1P（第 1 天和第 3 天）。第0天肿瘤大小为100立方毫米并且每天测量。为了评估治疗反应，小鼠接受静脉注射。对于单独的紫杉醇组，在第 1 天和第 4 天，对于单独的免疫毒素组，在第 1 天和第 3 天，将 In-111 标记的二聚环 RGD 肽（2.0 micro-Ci/<0.1 micro-g）溶解在 0.2 ml 含 1% BSA 的 PBS 中，并在注射后 1 或 2 小时处以安乐死以进行生物分布。对于联合治疗组，对小鼠进行静脉注射。在第2天和第4天用放射性标记进行注射，并在注射放射性标记后1或2小时处以安乐死。结果：如先前报道的那样，联合治疗具有协同作用，使用任一药物单独使用的剂量即可稳定肿瘤生长（Clin Cancer Res 2006；12：4695）。对照动物和药物治疗动物之间血液和主要器官中放射性标记的生物分布相似。然而，与对照相比，紫杉醇治疗的动物的放射性标记的肿瘤摄取（％ID/g）在第1天减少了25％，但在第4天增加了33％。相比之下，接受免疫毒素治疗的动物的摄取量在第 1 天增加了 11%，在第 3 天增加了 39%。联合治疗在第 2 天将摄取量 (% ID/g) 降低了 8.5%，但在第 4 天将摄取量增加了 25%。由于紫杉醇或免疫毒素治疗阻止了肿瘤生长，并且在实验期间肿瘤大小保持不变，因此肿瘤摄取的负变化 (% ID/g) 似乎表明紫杉醇治疗下调了受体表达，从而降低了受体的总水平 在第1天的血管生成血管上。然而，受体水平(%ID/g)在第4天增加，表明受体表达上调以诱导血管生成以促进肿瘤的重新生长。相反，免疫毒素治疗在4天内增加了受体水平，表明免疫毒素治疗上调了受体表达。 联合治疗引起的肿瘤摄取的变化是药物对受体表达综合作用的结果。结论：本研究表明，In-111 标记的二聚环 RGD 肽是 α(V)β(3) 受体的良好分子靶向剂，并且新血管系统上表达的 α(V)β(3) 受体水平的变化（%ID/g 肿瘤）可用作治疗反应的敏感替代标志物。受体水平变化的相反方向表明这两种药物的治疗效果是由不同的作用途径引起的。受体表达变化的方向和幅度可能是药物治疗反应的敏感预测标记。

项目成果

Improved renal clearance and tumor targeting of 99mTc-labeled anti-Tac monoclonal antibody Fab by chemical modifications.

通过化学修饰改善 99mTc 标记的抗 Tac 单克隆抗体 Fab 的肾清除率和肿瘤靶向性。

• DOI: 10.1016/s0969-8051(01)00296-7
• 发表时间: 2002
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Kim,Meyoung-kon;Jeong,Hyeh-Jean;Kao,Chih-HaoK;Yao,Zhengsheng;Paik,DavidS;Pie,JaeEun;Kobayashi,Hisataka;Waldmann,ThomasA;Carrasquillo,JorgeA;Paik,ChangH
• 通讯作者: Paik,ChangH

Use of antibody as carrier of oligomers of peptidomimetic alphavbeta3 antagonist to target tumor-induced neovasculature.

使用抗体作为拟肽αvβ3拮抗剂寡聚物的载体来靶向肿瘤诱导的新血管系统。

• DOI: 10.1021/bc0603485
• 发表时间: 2007
• 期刊: Bioconjugate chemistry
• 影响因子: 4.7
• 作者: Shin,InSoo;Jang,Beom-Su;Danthi,SNarasimhan;Xie,Jianwu;Yu,Sarah;Le,Nhat;Maeng,Jin-Soo;Hwang,InSook;Li,KingCP;Carrasquillo,JorgeA;Paik,ChangH
• 通讯作者: Paik,ChangH

Activatable iRGD-based peptide monolith: Targeting, internalization, and fluorescence activation for precise tumor imaging.

• DOI: 10.1016/j.jconrel.2016.06.032
• 发表时间: 2016-09-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Cho HJ;Lee SJ;Park SJ;Paik CH;Lee SM;Kim S;Lee YS
• 通讯作者: Lee YS