-
肿瘤微环境是肿瘤细胞赖以生存的复杂环境，主要由多种不同的细胞外基质和基质细胞组成，其中癌症相关成纤维细胞（cancer-associated fibroblasts，CAFs）是肿瘤微环境的核心要素[1]。正常成纤维细胞（normal fibroblasts，NFs）主要起组织稳态的作用[2]，而在肿瘤微环境中，癌症伴发炎症，促进了NFs向CAFs的转化，此外，CAFs还来源于局部成纤维细胞、循环成纤维细胞和经内皮细胞向间充质转化的血管内皮细胞、脂肪细胞、骨髓干细胞，起源谱广是肿瘤CAFs表型异质性和许多标志物异质性表达的主要原因[3]，但成纤维细胞激活蛋白（fibroblast activation protein，FAP）在多种肿瘤类型的活化CAFs细胞表面和部分肿瘤细胞中过表达，其在结构上是一种丝氨酸蛋白酶家族的Ⅱ型跨膜糖蛋白，具有二肽基肽酶Ⅳ的活性，常以二聚体形式存在，在具有强烈促结缔组织增生反应的上皮性癌中占肿瘤质量的90%[4]，而在正常组织的静息成纤维细胞中低表达[5]，是良好的肿瘤靶向显像和治疗的潜在靶点，因此FAP靶向药物的研发和临床研究成为近年来的热点。
-
FAP靶向药物结构组成上主要包括FAP靶向配体、偶联剂或螯合物和诊疗元件3部分。从显像原理上讲，FAP靶向药物通过特异性结合肿瘤微环境高丰度表达的FAP受体，并内化入胞[6-8]，导致FAP配体偶联的诊疗元件在靶器官内有效摄取、聚集，并获得较高的T/NT，达到靶向显像和治疗的目的。FAP靶向药物在肿瘤内的滞留时间延长，也利于其应用于临床。促进诊疗元件在肿瘤的靶向聚集是目前FAP靶向诊疗药物研究的热点：一方面是通过优化配体结构或偶联剂的选择，筛选药代动力学理想的FAP靶向配体，使肿瘤靶向摄取高、迅速、血本底清除快，获得较高的肿瘤/非肿瘤摄取，且不良反应少；另一方面是通过对FAP配体载体给药系统或剂型的选择，增加FAP靶向药物在血液中的循环时间和在肿瘤部位的滞留时间。
-
FAP靶向配体包括抗体、小分子抑制剂、多肽及其二聚体和多聚体，以及不同的载体或剂型，包括白蛋白、纳米递送系统等。
在早期报道中，FAP靶向免疫显像和治疗使用的是基于对FAP表达水平进行鉴定的免疫组化用F19抗体，通过放射性核素131I标记用于转移性结直肠癌患者的诊治[9]。抗体的优势在于其特异性高、亲和力强，但其相对分子量大、血液清除缓慢，作为显像剂，其呈现背景信号高，微小病变检测灵敏度略差，且荷载诊断和治疗元件少，对于相同摩尔数的有效载荷，抗体药物需要量大，且具有免疫源性，对偶联体的要求高，容易脱标（如131I等），进一步增加了其带来的不良反应。近年来，随着对纳米抗体、单域抗体或单链抗体小尺寸抗体的进一步研究，可能会带来FAP靶向抗体在肿瘤诊治中的新进展。
FAP小分子酶活性抑制剂（fibroblast activation protein inhibitor，FAPI）是目前科研和临床转化的热点，［（2R）-1-（（2S）-2-氨基-3-甲基丁酰基）吡咯烷-2-基］硼酸（talabosta，PT-100）是第1个被用来进行临床试验的FAPIs[10]，目前FAPIs是多以（4-喹啉酰基）-甘氨酰-2-氰基吡咯烷为基础框架的抑制剂及其衍生物，如FAPI-01、FAPI-02、FAPI-04、FAPI-46[11]和FAPI-74[12]等，其中FAPI-04和FAPI-46是目前临床转化报道较多的主要探针前体。FAPIs衍生物优势在于其结构容易修饰，药代动力学（如特异性结合、摄取内化率和速度、瘤内滞留时间）理想的衍生物容易获得。同FAPI-01及FAPI-02相比，作为FAPI-02变异体的FAPI-04，其在药代动力学上具有肿瘤摄取率高、摄取迅速和非靶组织中清除迅速的优势，更适合用于肿瘤的FAP靶向显像[7-8, 13]。FAPI-46、FAPI-21、FAPI-74等单体轻度增加了FAP靶向药物在肿瘤部位的摄取和滞留，倾向应用于靶向治疗，但相对于核素的半衰期和治疗作用发挥的时间来说，仍然太短，且其中FAPI-21在唾液腺、甲状腺和口腔黏膜部位的摄取较高[6]，也进一步限制了其在治疗中的应用。
177Lu-FAP-2286是目前文献报道的首个FAP靶向多肽，其在原发及转移肿瘤部位摄取高、保留时间长、不良反应少，因此在治疗不同侵袭性腺癌方面具有可行性[14]。同抗体相比，多肽的优势在于分子量小，无免疫原性，结构易于修饰，易于通过偶联剂、螯合物与显像元件或治疗元件稳定性结合，临床用药化学量少，不良反应可控可调，易于产业化和临床转化，具有较好的临床转化前景。
-
FAP靶向药物的显像诊断和治疗元件主要包括放射性核素和荧光，其中放射性核素包括诊断用放射性核素如放射性碘（123I、124I、125I、131I）、99Tcm、68Ga、18F、64Cu、89Zr等，治疗用放射性核素如125I、131I、188Re、90Y、64Cu、177Lu、211At、153Sm、188Re、67Cu和α核素如223Ra、225Ac等，其中放射性碘、99Tcm、68Ga、177Lu、18F在国内临床较易获得。而能够实现诊疗一体化的配对核素包括123I、124I 和131I，68Ga和177Lu，86Y和90Y，原因在于配对核素对FAP靶向配体的偶联方法类似，具有类似的药代动力学，通过显像核素标记FAP靶向配体进行显像，对FAP靶向治疗进行适应症患者的筛选、疗效预测、个体化剂量制定。荧光探针尤其是近红外一区和二区探针，可用于FAP靶向荧光显像及其导航的精准手术、光热治疗等[15]，其中部分近红外荧光探针[16]、组合前药探针[17]和基于铁蛋白的纳米荧光学探针[18]已经成功地在小鼠体内可视化了FAP表达的肿瘤组织。
-
诊断和治疗性元件对FAP靶向配体的标记常有两种手段，除放射性123I、124I、125I、131I等直接标记外，主要通过引入双功能螯合剂、偶联剂来实现配体与诊治元件的偶联，常用的包括1,4,7,10-四氮杂环十二烷1,4,7,10-四乙酸（1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid，DOTA）、1，4，7-三氮杂环壬烷-N,N′,N″-三乙酸（1,4,7-triazacyclononane-N,N',N''-triacetic acid，NOTA）、1,4,7-三氮杂环壬烷-1-戊二酸-4,7-二乙酸（NODAGA）、二亚乙基三胺五乙酸（Diethylenetriaminepentaacetic acid，DTPA）、去铁胺（DFO）、联肼尼克酰胺（HYNIC）、巯基乙酰三甘氨酸（MAG3）等。新的杂合络合剂如6-戊酸-6-氨基-1，4-二氮杂四乙酸 （AAZTA5）或6-戊酸-6-氨基-1，4-二氮平-三乙酸酯（DATA5M）的方酸（SA）修饰的高亲和力抑制剂，其制备简单，稳定性好，更适合温度敏感的目标分子的标记[19-20]。
FAP靶向抗体的核素标记早期多通过Iodogen或氯胺T法进行放射性碘标记进行SPECT显像，简单快捷，而通过去铁胺、DOTA、NOTA、DTPA等偶联剂进行正电子核素标记和PET显像，可以获得药代动力学定量数据，其中去铁胺更受青睐，主要原因在于偶联的89Zr半衰期合适，产物稳定性更好。
FAPIs和FAP靶向多肽的标记，目前报道最多和最理想的是DOTA，包括68Ga、177Lu、225Ac等，其标记方法简单、产率高且稳定性良好。此外，18F易于产业化生产和供应，18F标记的糖基化FAP抑制剂（18F-FGlc-FAPI）[21]和18F-Alf-FAPI-74更受关注，尤其是18F-Alf-FAPI-74表现出良好的肿瘤摄取和滞留能力[12]。99Tcm、186Re、188Re主要通过联肼尼克酰胺偶联，99Tcm作为目前SPECT显像最常用核素，其标记的FAPI示踪剂如99Tcm-FAPI-34具有良好的亲和力、结合性能和肿瘤摄取能力，且获得的图像质量佳[22]。
-
FAP单体衍生物可在肿瘤内迅速富集，但其滞留时间短、清除快，同源二聚体的结构如[68Ga]Ga-DOTAGA.（SA.FAPi）2增加了核素在肿瘤部位的蓄积和滞留，但血液清除缓慢，非靶器官的辐射剂量增加[23]，而[177Lu]Lu-DOTAGA.（SA.FAPi）2同源二聚体显示出快速内化、更高的亲和力、更长的肿瘤滞留时间等优势，且非靶器官清除快[24]，为提高治疗疗效、减少不良反应提供可能。
-
白蛋白可作为药物输送的多功能载体，其已成为增加放射性标记探针在肿瘤中的摄取和保留的一种策略。FAP靶向特异性结合与白蛋白被动扩散效应的结合，能够明显改善肿瘤摄取和保留作用[25]。4-对氯苯基丁酸及伊文思蓝（evans blue，EB）均可介导FAPI与白蛋白结合，增加FAPI在肿瘤中的快速摄取、高亲和力结合、长时间循环和瘤内滞留[26]，且177Lu-EB-FAPI-B1比B2、B3和B4具有更高的肿瘤摄取率和更低的正常组织信号，这体现了EB修饰的FAPI与白蛋白的结合和释放动态变化，影响后续治疗周期和剂量的平衡[27]。
-
CAF是纳米粒子深入渗透肿瘤的重要屏障，基于可切割的两亲性多肽（cleavable amphiphilic peptide，CAP）制备的刺激响应型纳米载体可以打破基质屏障，促进局部药物积累，极大地提高了肿瘤靶向和药物输送效率[28]。双重响应型（FAP-α响应型和热敏型）脂质-白蛋白纳米粒（HSA-BMS@CAP-ILTSL），可在FAP-α和温和的光热刺激下快速释放HSA-BMS（10 nm），实现了肿瘤内纳米颗粒大小的调整策略，增加了对肿瘤细胞的摄取，延长了循环时间，增加了肿瘤蓄积[29]。
-
根据肿瘤FAP表达水平和对FAP靶向显像剂的摄取率，Kratochwil等[13]初步将不同的实体肿瘤分为高摄取组（SUVmax>12，如肉瘤、乳腺癌、食管癌、肺癌和胃癌）、中摄取组（SUVmax为6~12，如肝细胞癌、结直肠癌、头颈癌、卵巢癌、胰腺癌和前列腺癌）和低摄取组（SUVmax<6，如嗜铬细胞瘤、肾细胞癌、DTC和腺样囊性癌），为肿瘤的显像诊断、精准分期、疗效评估及未来的FAP靶向治疗提供了新思路，并被辅助用于胶质母细胞瘤、头颈部肿瘤和下消化道肿瘤[30-32]患者的靶区勾画和放疗计划的制定。
-
低度恶性肉瘤对18F- FDG的摄取较低，而肉瘤间质和肿瘤细胞均呈FAP高丰度表达，对放射性核素标记的FAPI摄取高[33]。乳腺癌原发病灶、转移病灶对68Ga-FAPI的摄取（肿瘤/非肿瘤摄取比值）明显高于18F-FDG，更利于微小病灶的探测，提高诊断和临床分期的准确性，且结合月经周期可有效排除子宫内膜和乳腺的生理性摄取干扰[34]。在食管癌患者中，同18F-FDG 相比，68Ga-FAPI PET/CT成像显示出更好的摄取和肿瘤靶区勾画的边界[35]。对肺癌的分期及病理类型诊断，FAP靶向显像剂比18F-FDG显示出更好的价值，如对肺腺癌的初级分期，对脑、淋巴结、骨和胸膜等肺癌转移灶的精准分期等[36]；不同病理类型的转移灶之间的摄取不同，可能对区分不同病理类型的肺癌具有重要意义[37]。FAP在胃癌中高表达，可能与胃癌分级高、腹膜浸润、预后差有关[38]，FAP显像比18F-FDG有更高的肿瘤摄取率和灵敏度，尤其是在识别胃印戒细胞癌的原发性和转移性病变方面更具优势[39]。
-
同18F-FDG相比，68Ga-FAPI-04等FAP靶向显像剂在正常脑组织、肝脏、腹腔中的分布极少且清除迅速，且FAP靶向显像显示肝脏、骨骼、腹膜、网膜和肠系膜等部位转移灶的SUVmax高于18F-FDG PET/CT[40]，因此FAP靶向显像更利于头颈部肿瘤（鼻咽癌）、肝细胞癌、结直肠癌、卵巢癌、胰腺癌和前列腺癌等中摄取组肿瘤原发灶和转移灶的检测，尤其是在原发和转移性肝脏恶性肿瘤的鉴别诊断方面，68Ga-FAPI-04的诊断灵敏度与增强CT和MRI相当[41]。FAP存在于97%的卵巢癌中，与不良的临床预后、化疗耐药性等相关[42]，且在健康卵巢中不表达，为卵巢癌的治疗提供了一个潜在的靶点。有关胰腺癌的研究结果显示，双时相FAP靶向显像可能有助于鉴别高FAP表达的胰腺炎和恶性肿瘤[43-44]。在前列腺特异性膜抗原低表达前列腺癌的诊断中，FAP靶向PET成像可以得到更准确的结果，但FAP表达的异质性，阻碍了其在诊断早期前列腺癌中的应用[45]。
-
虽然在嗜铬细胞瘤、DTC、肾细胞癌和腺样囊性癌中，68Ga-FAPI的SUVmax较低，但FAPI显像在这些肿瘤中仍具有重要作用。如[177Lu]Lu -DOTAGA.（SA.FAPi） 2（新型成纤维细胞激活蛋白抑制剂）似乎为放射性碘难治性DTC患者开辟了一条新的治疗途径[46]。对于肾细胞癌，FAP在预测其分级和分期上可发挥一定作用[47]。在腺样囊性癌中，FAPI显像与CT和MRI相比，提高了放射治疗靶区勾画的准确性[48]，因此FAPI在腺样囊性癌中也具有一定的应用价值。
-
FAP靶向显像为靶向核素治疗提供了分子影像数据支持和患者筛选，目前基于FAPIs的90Y-FAPI-04和基于多肽的177Lu-2286等药物已被用于临床转化的研究，结果显示，其可在肿瘤中高浓聚，也能缓解患者的临床症状。FAPIs、多肽等肿瘤滞留时间仍不够理想，这是FAP靶向治疗需要克服的困难，FAP靶向纳米抗体、新剂型的研发有望解决这一难题。α核素作为射程短、生物学效应极强的核素，近年来备受关注，FAP靶向药物在正常组织中的分布少且清除迅速的特性，为α核素标记FAP靶向药物走向临床提供了可能[49-50]。荧光标记的FAP靶向药物如铁蛋白轻链-S-S0456，以高亲和力和高特异性在实体瘤中聚集，可精准导航手术[51]。随着光热荧光剂的转化，FAP靶向肿瘤的光热治疗也具有一定的潜力。
-
FAP作为一种良好的肿瘤靶点，随着靶向配体、偶联剂和显像治疗元件的不断研发和涌现，其在肿瘤靶向显像用于肿瘤分子水平的诊断、临床分期、小病灶的早期探测、靶向治疗患者筛选、放疗计划制定、精准手术导航中的角色越来越明显。尤其是随着纳米抗体、抗体片段、优良结构的小分子抑制剂和多肽、结合稳定的偶联剂、响应性纳米转运系统的构建，在保证肿瘤靶向聚集和非肿瘤组织迅速清除的基础上，有效延长其在肿瘤内的滞留时间来提高其生物学作用，将有力推动其临床转化，新的治疗性核素如α核素和光热材料、近红外二区探针也为FAP靶向治疗提供了新的思路和方向。除在肿瘤的应用中显示出明显的优势外，其在部分FAP高表达的炎性疾病中，有望提高对疾病或疾病病程的认识，也为部分炎性疾病的治疗提供新的靶点。
利益冲突 所有作者声明无利益冲突
作者贡献声明 吴丹丹负责综述的撰写与修订、数据的获取与分析；邵国强负责命题的提出、设计及最终版本的修订；孔霞和张莉负责文献资料的获取、提供与分析
成纤维细胞激活蛋白靶向药物及其用于疾病显像和治疗的研究进展
Research progress of fibroblast activation protein targeting drugs and their application in disease imaging and therapy
-
摘要: 成纤维细胞激活蛋白（FAP）在90%以上的上皮性肿瘤的癌症相关成纤维细胞（CAFs）中高丰度表达，具有特异性和广谱性，是肿瘤微环境靶向显像和治疗的研究热点。FAP靶向抗体、小分子抑制剂和多肽作为配体，通过偶联核素以及荧光探针用于肿瘤靶向显像、治疗、精准手术导航，并通过二聚体化以及新剂型构建（如白蛋白、纳米递送系统等）优化FAP靶向药物的生物分布，进而增加其在肿瘤内的滞留时间和增强生物学作用，推动其用于肿瘤靶向内放射性治疗和光热治疗。除了肿瘤，FAP也可为炎性疾病的显像和治疗提供有价值的靶点。笔者就近年来FAP在肿瘤和非肿瘤性疾病中的显像和治疗的研究进展进行综述。Abstract: Fibroblast activation protein (FAP) is highly expressed in cancer-associated fibroblasts (CAFs) of more than 90% epithelial tumors with specificity and broad spectrum. FAP ligands, such as targeted antibodies, small molecule inhibitors and peptides, are used in tumor targeted imaging, therapy and precise surgical navigation by coupling radionuclides and fluorescent probes. Moreover, through dimerization, construction of new dosage forms such as albumin, nano-delivery system and other means to optimize the biological distribution of FAP targeted drug to increase its retention and biological effects in tumor and promote its use in tumor targeted internal radiation therapy and photothermal therapy. In addition to neoplastic diseases, FAP can also provide valuable targets for imaging and therapy of inflammatory disease. This article reviews the research progress of imaging and therapy of FAP in tumor and non-tumor diseases in recent years.
-
Key words:
- Fibroblasts /
- Radiotherapy /
- Radioisotopes /
- Targeting preparation /
- Fibroblast activation protein
-
[1] Park D, Sahai E, Rullan A. SnapShot: cancer-associated fibroblasts[J]. Cell, 2020, 181(2): 486−486.e1. DOI: 10.1016/j.cell.2020.03.013. [2] Lebleu VS, Neilson EG. Origin and functional heterogeneity of fibroblasts[J]. FASEB J, 2020, 34(3): 3519−3536. DOI: 10.1096/fj.201903188R. [3] Bu LK, Baba H, Yoshida N, et al. Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment[J]. Oncogene, 2019, 38(25): 4887−4901. DOI: 10.1038/s41388-019-0765-y. [4] Scanlan MJ, Raj BK, Calvo B, et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers[J]. Proc Natl Acad Sci USA, 1994, 91(12): 5657−5661. DOI: 10.1073/pnas.91.12.5657. [5] Hamson EJ, Keane FM, Tholen S, et al. Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy[J]. Proteomics Clin Appl, 2014, 8(5/6): 454−463. DOI: 10.1002/prca.201300095. [6] 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. DOI: 10.2967/jnumed.118.224469. [7] 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. DOI: 10.2967/jnumed.118.210435. [8] 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. DOI: 10.2967/jnumed.118.210443. [9] Welt S, Divgi CR, Scott AM, et al. Antibody targeting in metastatic colon cancer: a phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts[J]. J Clin Oncol, 1994, 12(6): 1193−1203. DOI: 10.1200/JCO.1994.12.6.1193. [10] Eager RM, Cunningham CC, Senzer N, et al. Phase II trial of talabostat and docetaxel in advanced non-small cell lung cancer[J]. Clin Oncol, 2009, 21(6): 464−472. DOI: 10.1016/j.clon.2009.04.007. [11] Meyer C, Dahlbom M, Lindner T, et al. Radiation dosimetry and biodistribution of 68Ga-FAPI-46 PET imaging in cancer patients[J]. J Nucl Med, 2020, 61(8): 1171−1177. DOI: 10.2967/jnumed.119.236786. [12] Giesel FL, Adeberg S, Syed M, et al. FAPI-74 PET/CT using either 18F-AlF or cold-Kit 68Ga labeling: biodistribution, radiation dosimetry, and tumor delineation in lung cancer patients[J]. J Nucl Med, 2021, 62(2): 201−207. DOI: 10.2967/jnumed.120.245084. [13] Kratochwil C, Flechsig P, Lindner T, et al. 68Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer[J]. J Nucl Med, 2019, 60(6): 801−805. DOI: 10.2967/jnumed.119.227967. [14] 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. DOI: 10.2967/jnumed.120.259192. [15] Watanabe S, Noma K, Ohara T, et al. Photoimmunotherapy for cancer-associated fibroblasts targeting fibroblast activation protein in human esophageal squamous cell carcinoma[J]. Cancer Biol Ther, 2019, 20(9): 1234−1248. DOI: 10.1080/15384047.2019.1617566. [16] Xing J, Gong Q Y, Zou R F, et al. A novel fibroblast activation protein-targeted near-infrared fluorescent off-on probe for cancer cell detection, in vitro and in vivo imaging[J]. J Mater Chem B, 2018, 6(10): 1449−1451. DOI: 10.1039/c7tb03303f. [17] Ke MR, Chen SF, Peng XH, et al. A tumor-targeted activatable phthalocyanine-tetrapeptide-doxorubicin conjugate for synergistic chemo-photodynamic therapy[J]. Eur J Med Chem, 2017, 127: 200−209. DOI: 10.1016/j.ejmech.2016.12.056. [18] Ji TJ, Zhao Y, Wang J, et al. Tumor fibroblast specific activation of a hybrid ferritin nanocage-based optical probe for tumor microenvironment imaging[J]. Small, 2013, 9(14): 2427−2431. DOI: 10.1002/smll.201300600. [19] Moon ES, Elvas F, Vliegen G, et al. Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators[J/OL]. EJNMMI Radiopharm Chem, 2020, 5(1): 19[2022-04-24]. https://ejnmmipharmchem.springeropen.com/articles/10.1186/s41181-020-00102-z. DOI: 10.1186/s41181-020-00102-z. [20] Moon ES, Van Rymenant Y, Battan S, et al. In vitro evaluation of the squaramide-conjugated fibroblast activation protein inhibitor-based agents AAZTA5. SA. FAPi and DOTA. SA. FAPi[J/OL]. Molecules, 2021, 26(12): 3482[2022-04-24]. https://www.mdpi.com/1420-3049/26/12/3482. DOI: 10.3390/molecules26123482. [21] Toms J, Kogler J, Maschauer S, et al. Targeting fibroblast activation protein: radiosynthesis and preclinical evaluation of an 18F-labeled FAP inhibitor[J]. J Nucl Med, 2020, 61(12): 1806−1813. DOI: 10.2967/jnumed.120.242958. [22] Lindner T, Altmann A, Krämer 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. DOI: 10.2967/jnumed.119.239731. [23] 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/OL]. Am J Nucl Med Mol Imaging, 2021, 11(6): 476−491[2022-04-24]. https://pubmed.ncbi.nlm.nih.gov/35003886. [24] Ballal S, Yadav MP, Moon ES, et al. First-in-human results on the biodistribution, pharmacokinetics, and dosimetry of [177Lu]Lu-DOTA. SA. FAPi and [177Lu]Lu-DOTAGA. (SA. FAPi)2[J/OL]. Pharmaceuticals (Basel), 2021, 14(12): 1212[2022-04-24]. https://www.mdpi.com/1424-8247/14/12/1212. DOI: 10.3390/ph14121212. [25] Kelly JM, Jeitner TM, Ponnala S, et al. A trifunctional theranostic ligand targeting fibroblast activation protein-α (FAPα)[J]. Mol Imaging Biol, 2021, 23(5): 686−696. DOI: 10.1007/s11307-021-01593-1. [26] 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. DOI: 10.2967/jnumed.121.262533. [27] Wen XJ, Xu PF, Shi MQ, et al. Evans blue-modified radiolabeled fibroblast activation protein inhibitor as long-acting cancer therapeutics[J/OL]. Theranostics, 2022, 12(1): 422−433[2022-04-24]. https://www.thno.org/v12p0422.htm. DOI: 10.7150/thno.68182. [28] Ji TJ, Zhao Y, Ding YP, et al. Transformable peptide nanocarriers for expeditious drug release and effective cancer therapy via cancer-associated fibroblast activation[J]. Angew Chem Int Ed, 2016, 55(3): 1050−1055. DOI: 10.1002/anie.201506262. [29] Yu QW, Tang X, Zhao W, et al. Mild hyperthermia promotes immune checkpoint blockade-based immunotherapy against metastatic pancreatic cancer using size-adjustable nanoparticles[J]. Acta Biomater, 2021, 133: 244−256. DOI: 10.1016/j.actbio.2021.05.002. [30] Windisch P, Röhrich M, Regnery S, et al. Fibroblast activation protein (FAP) specific PET for advanced target volume delineation in glioblastoma[J]. Radiother Oncol, 2020, 150: 159−163. DOI: 10.1016/j.radonc.2020.06.040. [31] Syed M, Flechsig P, Liermann J, et al. Fibroblast activation protein inhibitor (FAPI) PET for diagnostics and advanced targeted radiotherapy in head and neck cancers[J]. Eur J Nucl Med Mol Imaging, 2020, 47(12): 2836−2845. DOI: 10.1007/s00259-020-04859-y. [32] Koerber SA, Staudinger F, Kratochwil C, et al. The role of 68Ga-FAPI PET/CT for patients with malignancies of the lower gastrointestinal tract: first clinical experience[J]. J Nucl Med, 2020, 61(9): 1331−1336. DOI: 10.2967/jnumed.119.237016. [33] Kessler L, Ferdinandus J, Hirmas N, et al. 68Ga-FAPI as a diagnostic tool in sarcoma: data from the 68Ga-FAPI PET prospective observational trial[J]. J Nucl Med, 2022, 63(1): 89−95. DOI: 10.2967/jnumed.121.262096. [34] Dendl K, Koerber SA, Finck R, et al. 68Ga-FAPI-PET/CT in patients with various gynecological malignancies[J]. Eur J Nucl Med Mol Imaging, 2021, 48(12): 4089−4100. DOI: 10.1007/s00259-021-05378-0. [35] Zhao L, Chen SY, Chen SJ, et al. 68Ga-fibroblast activation protein inhibitor PET/CT on gross tumour volume delineation for radiotherapy planning of oesophageal cancer[J]. Radiother Oncol, 2021, 158: 55−61. DOI: 10.1016/j.radonc.2021.02.015. [36] Wang LJ, Tang GH, Hu KZ, et al. Comparison of 68Ga-FAPI and 18F-FDG PET/CT in the evaluation of advanced lung cancer[J]. Radiology, 2022, 303(1): 191−199. DOI: 10.1148/radiol.211424. [37] Wei YC, Cheng K, Fu Z, et al. [18F]AlF-NOTA-FAPI-04 PET/CT uptake in metastatic lesions on PET/CT imaging might distinguish different pathological types of lung cancer[J]. Eur J Nucl Med Mol Imaging, 2022, 49(5): 1671−1681. DOI: 10.1007/s00259-021-05638-z. [38] Wen XY, He XP, Jiao F, et al. Fibroblast activation protein-α-positive fibroblasts promote gastric cancer progression and resistance to immune checkpoint blockade[J]. Oncol Res, 2017, 25(4): 629−640. DOI: 10.3727/096504016X14768383625385. [39] Fan CL, Guo W, Su GQ, et al. Widespread metastatic gastric signet-ring cell carcinoma shown by 68Ga-FAPI PET/CT[J]. Clin Nucl Med, 2021, 46(2): e78−e79. DOI: 10.1097/RLU.0000000000003245. [40] Lan LJ, Liu HX, Wang YW, et al. The potential utility of [68Ga]Ga-DOTA-FAPI-04 as a novel broad-spectrum oncological and non-oncological imaging agent-comparison with [18F]FDG[J]. Eur J Nucl Med Mol Imaging, 2022, 49(3): 963−979. DOI: 10.1007/s00259-021-05522-w. [41] Guo W, Pang YZ, Yao LL, et al. Imaging fibroblast activation protein in liver cancer: a single-center post hoc retrospective analysis to compare [68Ga]Ga-FAPI-04 PET/CT versus MRI and [18F]-FDG PET/CT[J]. Eur J Nucl Med Mol Imaging, 2021, 48(5): 1604−1617. DOI: 10.1007/s00259-020-05095-0. [42] Hussain A, Voisin V, Poon S, et al. Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21[J]. J Exp Med, 2020, 217(8): e20191094. DOI: 10.1084/jem.20191094. [43] Röhrich M, Naumann P, Giesel FL, et al. Impact of 68Ga-FAPI PET/CT imaging on the therapeutic management of primary and recurrent pancreatic ductal adenocarcinomas[J]. J Nucl Med, 2021, 62(6): 779−786. DOI: 10.2967/jnumed.120.253062. [44] Pang YZ, Zhao L, Shang QH, et al. Positron emission tomography and computed tomography with [68Ga]Ga-fibroblast activation protein inhibitors improves tumor detection and staging in patients with pancreatic cancer[J]. Eur J Nucl Med Mol Imaging, 2022, 49(4): 1322−1337. DOI: 10.1007/s00259-021-05576-w. [45] Kessel K, Seifert R, Weckesser M, et al. Prostate-specific membrane antigen and fibroblast activation protein distribution in prostate cancer: preliminary data on immunohistochemistry and PET imaging[J]. Ann Nucl Med, 2022, 36(3): 293−301. DOI: 10.1007/s12149-021-01702-8. [46] 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. DOI: 10.1089/thy.2021.0412. [47] Pang YZ, Wei JH, Shang QH, et al. 68Ga-fibroblast activation protein inhibitor, a promising radiopharmaceutical in PET/CT to detect the primary and metastatic lesions of chromophobe renal cell carcinoma[J]. Clin Nucl Med, 2021, 46(2): 177−179. DOI: 10.1097/RLU.0000000000003454. [48] Röhrich M, Syed M, Liew DP, et al. 68Ga-FAPI-PET/CT improves diagnostic staging and radiotherapy planning of adenoid cystic carcinomas-Imaging analysis and histological validation[J]. Radiother Oncol, 2021, 160: 192−201. DOI: 10.1016/j.radonc.2021.04.016. [49] Farzipour S, Shaghaghi Z, Abbasi S, et al. Recent achievements about targeted alpha therapy-based targeting vectors and chelating agents[J]. Anticancer Agents Med Chem, 2022, 22(8): 1496−1510. DOI: 10.2174/1871520621666210727120308. [50] 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. DOI: 10.1016/j.bmc.2021.116600. [51] Mukkamala R, Lindeman SD, Kragness KA, et al. Design and characterization of fibroblast activation protein targeted pan-cancer imaging agent for fluorescence-guided surgery of solid tumors[J]. J Mater Chem B, 2022, 10(12): 2038−2046. DOI: 10.1039/d1tb02651h. [52] Zheng JL, Lin KX, Zheng S, et al. 68Ga-FAPI and 18F-PET/CT images in intestinal tuberculosis[J]. Clin Nucl Med, 2022, 47(3): 239−240. DOI: 10.1097/RLU.0000000000003917. [53] Sun R, Huang ZW, Wei J, et al. 68Ga-FAPI and 18F-FDG PET/CT findings in a patient with pancreatic tuberculosis mimicking malignant tumor[J]. Clin Nucl Med, 2022, 47(5): 653−654. DOI: 10.1097/RLU.0000000000004099. [54] Alçın G, Tatar G, Şahin R, et al. Peritoneal tuberculosis mimicking peritoneal carcinomatosis on 68Ga-FAPI-04 and 18F-FDG PET/CT[J]. Clin Nucl Med, 2022, 47(8): e557−e558. DOI: 10.1097/RLU.0000000000004174. [55] Deng Y, Wu JH, Xu CQ, et al. Primary solitary tuberculosis in the hepatic round ligament detected by 68Ga-FAPI PET/CT[J]. Clin Nucl Med, 2022, 47(5): e414−e416. DOI: 10.1097/RLU.0000000000004122. [56] Tillmanns J, Hoffmann D, Habbaba Y, et al. Fibroblast activation protein alpha expression identifies activated fibroblasts after myocardial infarction[J]. J Mol Cell Cardiol, 2015, 87: 194−203. DOI: 10.1016/j.yjmcc.2015.08.016. [57] Schmidkonz C, Rauber S, Atzinger A, et al. Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging[J]. Ann Rheum Dis, 2020, 79(11): 1485−1491. DOI: 10.1136/annrheumdis-2020-217408. [58] Laverman P, van der Geest T, Terry SYA, et al. Immuno-PET and immuno-SPECT of rheumatoid arthritis with radiolabeled anti-fibroblast activation protein antibody correlates with severity of arthritis[J]. J Nucl Med, 2015, 56(5): 778−783. DOI: 10.2967/jnumed.114.152959. -
点击查看大图
计量
- 文章访问数: 6590
- HTML全文浏览量: 5017
- PDF下载量: 28
下载: