靶向成纤维细胞活化蛋白放射性探针研究进展

陆智彭; 许庆龙; 陈盼盼; 秦亚娟; 唐立钧; 厉廷有

doi:10.11665/j.issn.1000-5048.20220603

靶向成纤维细胞活化蛋白放射性探针研究进展

1.
南京医科大学药学院，南京 211166
2.
中国药科大学药物科学研究院，南京 210009
3.
南京医科大学核医药临床转化中心，南京 210029
4.
江苏省人民医院，南京 210029

基金项目: 南京医科大学内涵建设重点资助项目；中国博士后科学基金资助项目（No.2022M711419）；南京医科大学科技发展基金资助项目（No.NMUB20210013）

计量
- 文章访问数: 0322
- HTML全文浏览量: 0
- PDF下载量: 0655
出版历程
- 收稿日期: 2022-10-24
- 修回日期: 2022-11-11
- 刊出日期: 2022-12-24

Research progress of radioprobes targeting fibroblast activating protein

1.
School of Pharmacy, Nanjing Medical University, Nanjing 211166
2.
Institute of Pharmaceutical Sciences, China Pharmaceutical university, Nanjing 210009
3.
Clinical Transformation Center of Nuclear Medicine, Nanjing Medical University, Nanjing 210029
4.
Jiangsu Province Hospital, Nanjing 210029, China

Funds: This study was supported by the Key Project of Connotation Construction of Nanjing Medical University;China Postdoctoral Science Foundation (No.2022M711419);and the Science and Technology Development Foundation of Nanjing Medical University (No.NMUB20210013)

摘要

摘要: 成纤维细胞活化蛋白（FAP）是癌症相关成纤维细胞和活化成纤维细胞的重要生物标志物，在许多肿瘤和纤维化组织的活化成纤维细胞上高表达，而在正常组织和非恶性肿瘤中基本不表达。因此，FAP已经成为肿瘤等疾病的诊断和治疗的优良靶标。基于FAP抑制剂（FAPI）的PET显像和内放射疗法已成为包括癌症、纤维化等多种疾病在内的新型诊疗手段，以介绍FAP介导疾病发生发展的机制及其作为靶标的诊疗意义为开端，对¹²⁵I、⁶⁸Ga、⁶⁴Cu等多种放射性核素标记靶向FAP探针的结构演进、显像、体内生物分布及其药代动力学性质进行了系统总结，归纳了改善探针的药代动力学性质和靶标亲和力的相关策略，包括采用方酰胺连接子、使用白蛋白结合剂加以修饰、开发双靶向探针，对未来靶向FAP新型放射性探针的开发和经典探针的临床应用提出了一些参考建议。
- 成纤维细胞活化蛋白 /
- 靶向 /
- 放射性探针 /
- 诊疗应用 /
- 进展
Abstract: Fibroblast activating protein (FAP) is an important biomarker of cancer associated fibroblasts and activated fibroblasts, which is highly expressed in activated fibroblasts of many tumor and fibrotic tissues, but not in normal tissues and non malignant lesions. Therefore, FAP has become an excellent target for diagnosis and treatment of tumors and other diseases. PET imaging and internal radiotherapy based on FAP inhibitor (FAPI) have been used in the diagnosis and treatment of many diseases, such as cancer and fibrosis. We first introduce the mechanism of disease occurrence and progression mediated by FAP and its clinical significance as a therapeutic target.Then,we systematically summarize the FAP probes labeled with ¹²⁵I, ⁶⁸Ga, ⁶⁴Cu and other radionuclides, including their structural evolution, imaging, biodistribution and pharmacokinetic properties.After that, the reported strategies to improve the pharmacokinetic properties and target affinity of probes are summarized, including the use of squaramide linkers,modification with albumin binding agent,the development of dual-targeting probes.Finally, some suggestions for the future development of novel radioactive probes targeting FAP and the clinical application of classical probes are proposed.
- fibroblast activating protein /
- targeting /
- radioactive probe /
- application of diagnosis and treatment /
- progress

HTML全文

参考文献(40)

[1]	. Cancers （Basel），2021，13（19）：4946.
[2]	Yuan SJ，Liu YJ，Zhang N. Recent advances on cancer-assosiated fibroblasts treatment strategies and delivery systems［J］. Acta Pharm Sin（药学学报），2022，57：638-643.
[3]	Yang MM，Han XP，Qin C，et al. Strategies for targeting and remodeling tumor microenvironment ［J］. Acta Pharm Sin（药学学报），2022，57（1）：98-108.
[4]	Loktev A，Lindner T，Mier W，et al. A tumor-imaging method targeting cancer-associated fibroblasts［J］. J Nucl Med，2018，59（9）：1423-1429.
[5]	Giesel FL，Kratochwil C，Lindner T，et al. ⁶⁸Ga-FAPI PET/CT：biodistribution and preliminary dosimetry estimate of 2 DOTA-containing FAP-targeting agents in patients with various cancers［J］. J Nucl Med，2019，60（3）：386-392.
[6]	R?hrich M，Loktev A，Wefers AK，et al. IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein-specific PET/CT［J］. Eur J Nucl Med Mol Imaging，2019，46（12）：2569-2580.
[7]	Lindner T，Loktev A，Altmann A，et al. Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein［J］. J Nucl Med，2018，59（9）：1415-1422.
[8]	Ding F，Huang C，Liang CY，et al. ⁶⁸Ga-FAPI-04 vs. ¹⁸F-FDG in a longitudinal preclinical PET imaging of metastatic breast cancer［J］. Eur J Nucl Med Mol Imaging，2021，49（1）：290-300.
[9]	Kesch C，Yirga L，Dendl K，et al. High fibroblast-activation-protein expression in castration-resistant prostate cancer supports the use of FAPI-molecular theranostics［J］. Eur J Nucl Med Mol Imaging，2021，49（1）：385-389.
[10]	K?mek H，Gündo?an C，Etem H，et al. A case with ⁶⁸Ga-FAPI positive and ¹⁸F-FDG negative breast cancer［J］. Mol Imaging Radionucl Ther，2021，30（3）：201-204.
[11]	Watabe T，Liu YW，Kaneda-Nakashima K，et al. Theranostics targeting fibroblast activation protein in the tumor stroma：⁶⁴Cu- and ²²⁵Ac-labeled FAPI-04 in pancreatic cancer xenograft mouse models［J］. J Nucl Med，2020，61（4）：563-569.
[12]	Wang LJ，Zhang Y，Wu HB. Intense diffuse uptake of ⁶⁸Ga-FAPI-04 in the breasts found by PET/CT in a patient with advanced nasopharyngeal carcinoma［J］. Clin Nucl Med，2021，46（5）：e293-e295.
[13]	Fu LL，Hu KZ，Tang GH，et al. ［⁶⁸Ga］Ga-FAPI-04 PET/CT imaging in signet-ring cell carcinoma of sigmoid colon［J］. Eur J Nucl Med Mol Imaging，2021，48（5）：1690-1691.
[14]	Dorst DN，Rijpkema M，Buitinga M，et al. Targeting of fibroblast activation protein in rheumatoid arthritis patients：imaging and ex vivo photodynamic therapy［J］. Rheumatology （Oxford），2022，61（7）：2999-3009.
[15]	Zhou Y，Yang X，Liu HP，et al. Value of ［⁶⁸Ga］Ga-FAPI-04 imaging in the diagnosis of renal fibrosis［J］. Eur J Nucl Med Mol Imaging，2021，48（11）：3493-3501.
[16]	Varasteh Z，Mohanta S，Robu S，et al. Molecular imaging of fibroblast activity after myocardial infarction using a ⁶⁸Ga-labeled fibroblast activation protein inhibitor，FAPI-04［J］. J Nucl Med，2019，60（12）：1743-1749.
[17]	Hu KZ，Wang LJ，Wu HB，et al. ［¹⁸F］FAPI-42 PET imaging in cancer patients：optimal acquisition time，biodistribution，and comparison with ［⁶⁸Ga］Ga-FAPI-04［J］. Eur J Nucl Med Mol Imaging，2022，49（8）：2833-2843.
[18]	Ma H，Li FZ，Shen GH，et al. Synthesis and preliminary evaluation of ¹³¹I-labeled FAPI tracers for cancer theranostics［J］. Mol Pharm，2021，18（11）：4179-4187.
[19]	Ma H，Li FZ，Shen GH，et al. In vitro and in vivo evaluation of ²¹¹At-labeled fibroblast activation protein inhibitor for glioma treatment［J］. Bioorg Med Chem，2022，55：116600.
[20]	Loktev A，Lindner T，Burger EM，et al. Development of fibroblast activation protein-targeted radiotracers with improved tumor retention［J］. J Nucl Med，2019，60（10）：1421-1429.
[21]	Zhao L，Chen JH，Pang YZ，et al. Fibroblast activation protein-based theranostics in cancer research：a state-of-the-art review［J］. Theranostics，2022，12（4）：1557-1569.
[22]	Kratochwil C，Giesel FL，Rathke H，et al. ［¹⁵³Sm］ Samarium-labeled FAPI-46 radioligand therapy in a patient with lung metastases of a sarcoma［J］. Eur J Nucl Med Mol Imaging，2021，48（9）：3011-3013.
[23]	Liu YW，Watabe T，Kaneda-Nakashima K，et al. Fibroblast activation protein targeted therapy using ［¹⁷⁷Lu］FAPI-46 compared with ［²²⁵Ac］FAPI-46 in a pancreatic cancer model［J］. Eur J Nucl Med Mol Imaging，2022，49（3）：871-880.
[24]	Trujillo-Benítez D，Luna-Gutiérrez M，Ferro-Flores G，et al. Design，synthesis and preclinical assessment of ^99mTc-iFAP for in vivo fibroblast activation protein （FAP） imaging［J］. Molecules，2022，27（1）：264.
[25]	Lindner T，Altmann A，Kr?mer S，et al. Design and development of ^99mTc-labeled FAPI tracers for SPECT imaging and 188Re therapy［J］. J Nucl Med，2020，61（10）：1507-1513.
[26]	Ruan Q，Feng JH，Jiang YH，et al. Preparation and bioevaluation of 99mTc-labeled FAP inhibitors as tumor radiotracers to target the fibroblast activation protein［J］. Mol Pharm，2022，19（1）：160-171.
[27]	Lin JJ，Chuang CP，Lin JY，et al. Rational design，pharmacomodulation，and synthesis of ［⁶⁸Ga］Ga-Alb-FAPtp-01，a selective tumor-associated fibroblast activation protein tracer for PET imaging of glioma［J］. ACS Sens，2021，6（9）：3424-3435.
[28]	Baum RP，Schuchardt C，Singh A，et al. Feasibility，biodistribution，and preliminary dosimetry in peptide-targeted radionuclide therapy of diverse adenocarcinomas using ¹⁷⁷Lu-FAP-2286：first-in-humans results［J］. J Nucl Med，2022，63（3）：415-423.
[29]	Grus T，Lahnif H，Klasen B，et al. Squaric acid-based radiopharmaceuticals for tumor imaging and therapy［J］. Bioconjug Chem，2021，32（7）：1223-1231.
[30]	Ballal S，Yadav MP，Moon ES，et al. Biodistribution，pharmacokinetics，dosimetry of ［⁶⁸Ga］Ga-DOTA.SA.FAPi，and the head-to-head comparison with ［¹⁸F］F-FDG PET/CT in patients with various cancers［J］. Eur J Nucl Med Mol Imaging，2021，48（6）：1915-1931.
[31]	Ballal S，Yadav MP，Kramer V，et al. A theranostic approach of ［⁶⁸Ga］Ga-DOTA.SA.FAPi PET/CT-guided ［¹⁷⁷Lu］Lu-DOTA.SA.FAPi radionuclide therapy in an end-stage breast cancer patient：new frontier in targeted radionuclide therapy［J］. Eur J Nucl Med Mol Imaging，2021，48（3）：942-944.
[32]	Moon ES，Elvas F，Vliegen G，et al. Targeting fibroblast activation protein （FAP）：next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA^5m chelators［J］. EJNMMI Radiopharm Chem，2020，5（1）：19.
[33]	Wen XJ，Xu PF，Shi MQ，et al. Evans blue-modified radiolabeled fibroblast activation protein inhibitor as long-acting cancer therapeutics［J］. Theranostics，2022，12（1）：422-433.
[34]	Xu MX，Zhang P，Ding J，et al. Albumin binder-conjugated fibroblast activation protein inhibitor radiopharmaceuticals for cancer therapy［J］. J Nucl Med，2022，63（6）：952-958.
[35]	Zhang P，Xu MX，Ding J，et al. Fatty acid-conjugated radiopharmaceuticals for fibroblast activation protein-targeted radiotherapy［J］. Eur J Nucl Med Mol Imaging，2022，49（6）：1985-1996.
[36]	Moon ES，Ballal S，Yadav MP，et al. Fibroblast activation protein （FAP） targeting homodimeric FAP inhibitor radiotheranostics：a step to improve tumor uptake and retention time［J］. Am J Nucl Med Mol Imaging，2021，11（6）：476-491.
[37]	Ballal S，Yadav MP，Moon ES，et al. Novel fibroblast activation protein inhibitor-based targeted theranostics for radioiodine-refractory differentiated thyroid cancer patients：a pilot study［J］. Thyroid，2022，32（1）：65-77.
[38]	Li HS，Ye SM，Li L，et al. ¹⁸F- or ¹⁷⁷Lu-labeled bivalent ligand of fibroblast activation protein with high tumor uptake and retention［J］. Eur J Nucl Med Mol Imaging，2022，49（8）：2705-2715.
[39]	Zhao L，Niu B，Fang JY，et al. Synthesis，preclinical evaluation，and a pilot clinical PET imaging study of ⁶⁸Ga-labeled FAPI dimer［J］. J Nucl Med，2022，63（6）：862-868.
[40]	Hu KZ，Li L，Huang Y，et al. Radiosynthesis and preclinical evaluation of bispecific PSMA/FAP heterodimers for tumor imaging［J］. Pharmaceuticals （Basel），2022，15（3）：383.

施引文献

资源附件(0)

计量

文章访问数:
HTML全文浏览量: 0
PDF下载量:
被引次数: 0

靶向成纤维细胞活化蛋白放射性探针研究进展

计量

出版历程

Research progress of radioprobes targeting fibroblast activating protein

计量

出版历程

目录