通过整合素αVβ3靶向拟肽IAC推进癌症治疗:从工作台到病床。

IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Cancer Biotherapy and Radiopharmaceuticals Pub Date : 2024-11-01 Epub Date: 2024-07-08 DOI:10.1089/cbr.2023.0140
Somit Pandey, Gurvinder Kaur, Nivedita Rana, Sejal Chopra, Imran Rather, Rajender Kumar, Ishita Laroiya, Vijayta D Chadha, Stanley Satz, Micheal G Stabin, Bhagwant Rai Mittal, Jaya Shukla
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引用次数: 0

摘要

导言:α-5β-3(αVβ3)整合素的表达在各种发生血管生成的恶性肿瘤中上调。作为诊断探针的整合素拮抗剂的开发使αVβ3整合素成为靶向肿瘤血管生成的合适候选物。本研究的目的是优化共轭整合素拮抗剂氨基甲酸酯(IAC)的放射性标记,并评估其作为靶向肿瘤血管生成的治疗放射性药物的潜力。研究方法用[68Ga]Ga、[177Lu]Lu和[225Ac]Ac对DOTAGA[2,2',2" -{10-(2,6-二氧代四氢-2H-吡喃-3-基)-1,4,7,10-四氮杂环十二烷-1,4,7-三基}三乙酸]-IAC进行放射性标记。对 DOTAGA-IAC 与 αVβ3 受体和癌细胞株的结合亲和力(Kd)进行了量化。生物分布研究在健康的 Wistar 大鼠中进行。对[177Lu]Lu-DOTAGA-IAC分布数据进行了剂量测定分析。对五名经组织病理学确诊的乳腺癌患者进行了[68Ga]Ga-DOTAGA-IAC和[18F]FDG正电子发射断层扫描(PET/CT)成像试验研究。比较了这些患者的[68Ga]Ga-DOTAGA-IAC和[18F]FDG正电子发射断层扫描结果。结果:制备的放射性药物具有很高的放射化学纯度(>99.9%)。αVβ3受体蛋白的Kd和Bmax分别为15.02 nM和417 fmol:C6胶质瘤细胞的Kd和Bmax分别为115.7 nM和295.3 fmol。对大鼠的生物分布研究表明,[177Lu]通过肾脏排泄,部分通过肝胆途径排泄。研究发现,[177Lu]Lu-DOTAGA-IAC 的有效剂量为 0.17 mSv/MBq。对患者进行的动态研究显示,最佳成像时间为给药后 30-35 分钟。与[18F]FDG(SUVmax为13.8 ± 6.53)相比,[68Ga]Ga-DOTAGA-IAC能检测到所有五名患者的原发病灶,平均标准摄取值(SUVmax)为3.94 ± 0.58。结论该研究表明,DOTAGA-IAC 与 αVβ3 整合素的结合力很强,有望成为评估原发性和转移性癌症的 PET 探针。试点研究的结果表明,[68Ga]Ga-DOTAGA-IAC PET/CT 在乳腺癌诊断中具有潜力。虽然认识到 DOTAGA-IAC 对表达 αVβ3 整合素的肿瘤具有治疗潜力,但还需要进一步的临床研究来全面评估疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Advancing Cancer Theranostics Through Integrin αVβ3-Targeted Peptidomimetic IAC: From Bench to Bedside.

Introduction: The expression of alpha-five beta-three (αVβ3) integrins is upregulated in various malignancies undergoing angiogenesis. The development of integrin antagonists as diagnostic probes makes the αVβ3 integrin a suitable candidate for targeting tumor angiogenesis. The goal of this study was to optimize the radiolabeling and evaluate the potential of conjugated integrin antagonist carbamate (IAC), a peptidomimetic, as a theranostic radiopharmaceutical for targeting tumor angiogenesis. Methodology: Radiolabeling of DOTAGA [2,2',2"-{10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl} triacetic-acid]-IAC with [68Ga]Ga, [177Lu]Lu, and [225Ac]Ac was optimized. The binding affinity (Kd) of DOTAGA-IAC for the αVβ3 receptor and cancer cell lines was quantified. The biodistribution studies were conducted in healthy Wistar rats. Dosimetry analysis was performed on [177Lu]Lu-DOTAGA-IAC distribution data. A pilot study of [68Ga]Ga-DOTAGA-IAC and [18F]FDG Positron Emission Tomography (PET/CT) imaging was performed in five patients with histopathologically confirmed breast cancer. PET/CT findings were compared between [68Ga]Ga-DOTAGA-IAC and [18F]FDG in these patients. Results: Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). Kd and Bmax measurements were 15.02 nM and 417 fmol for αVβ3 receptor protein: 115.7 nM and 295.3 fmol for C6 glioma cells. Biodistribution studies in rats suggested the excretion via kidneys and partially through the hepatobiliary route. The effective dose of [177Lu]Lu-DOTAGA-IAC was found to be 0.17 mSv/MBq. The dynamic study in patients revealed the optimal imaging time to be 30-35 mins postadministration. Out of the cohort, [68Ga]Ga-DOTAGA-IAC detected the primary lesions in all five patients with a mean standard uptake value (SUVmax) of 3.94 ± 0.58 compared with [18F]FDG (SUVmax 13.8 ± 6.53). Conclusion: The study demonstrates that DOTAGA-IAC exhibits strong binding to αVβ3 integrin, positioning it as a promising PET agent for assessing primary and metastatic cancers. The outcomes from the pilot study suggest the potential of [68Ga]Ga-DOTAGA-IAC PET/CT in breast carcinoma diagnosis. While recognizing the theranostic potential of DOTAGA-IAC for αVβ3 integrin-expressing tumors, further clinical investigations are warranted to comprehensively assess therapeutic efficacy.

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来源期刊
CiteScore
7.80
自引率
2.90%
发文量
87
审稿时长
3 months
期刊介绍: Cancer Biotherapy and Radiopharmaceuticals is the established peer-reviewed journal, with over 25 years of cutting-edge content on innovative therapeutic investigations to ultimately improve cancer management. It is the only journal with the specific focus of cancer biotherapy and is inclusive of monoclonal antibodies, cytokine therapy, cancer gene therapy, cell-based therapies, and other forms of immunotherapies. The Journal includes extensive reporting on advancements in radioimmunotherapy, and the use of radiopharmaceuticals and radiolabeled peptides for the development of new cancer treatments.
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