Radiopharmacy and Molecular Imaging Center, School of Pharmacy, Fudan University, Shanghai 201203, China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China.
Radiopharmacy and Molecular Imaging Center, School of Pharmacy, Fudan University, Shanghai 201203, China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Nucl Med Biol. 2023 Mar-Apr;118-119:108330. doi: 10.1016/j.nucmedbio.2023.108330. Epub 2023 Feb 28.
Glucose-Regulated Protein 78 (GRP78) is an attractive anticancer target for its selective anchoring on the surface of tumor cells and cancer endothelial cells rather than normal cells. Cell-surface GRP78 overexpression of tumor indicates that GRP78 is a crucial target for relative tumor imaging and clinical treatment. Herein, we report the design and preclinical evaluation of a new D peptide ligand [F]AlF-NOTA-VAP recognizing GRP78 expressed on the cell surface of breast cancer.
Radiochemical synthesis of [F]AlF-NOTA-VAP was achieved via a one-pot labeling process by heating NOTA-VAP in the presence of in situ prepared [F]AlF for 15 min at 110 °C and purified through HPLC.
The radiotracer showed high in vitro stability in rat serum at 37 °C over 3 h. Both biodistribution studies and in vivo micro-PET/CT imaging studies in BALB/c mice bearing 4 T1 tumor showed [F]AlF-NOTA-VAP had a rapid and high uptake in tumor, as well as a long residence time. The high hydrophilicity of the radiotracer enables its fast clearance from most normal tissues and thus improves the tumor-to-normal tissue ratios (4.40 at 60 min) which is better than [F]FDG (1.31 at 60 min). Pharmacokinetic studies showed the average in vivo mean residence time of the radiotracer was just 0.6432 h and indicated that this hydrophilic radiotracer was quickly eliminated from the body to reduce the distribution of non-target tissues.
These results suggest that [F]AlF-NOTA-VAP is a very promising PET probe for tumor-specific imaging of cell-surface GRP78-positive tumor.
葡萄糖调节蛋白 78（GRP78）因其选择性地锚定于肿瘤细胞和癌症内皮细胞表面，而不是正常细胞，成为一种有吸引力的抗癌靶点。肿瘤细胞表面 GRP78 的过表达表明，GRP78 是相对肿瘤成像和临床治疗的关键靶点。在此，我们报告了一种新的 D 肽配体 [F]AlF-NOTA-VAP 的设计和临床前评估，该配体可识别乳腺癌细胞表面表达的 GRP78。
通过在 110°C 下加热 NOTA-VAP 并同时存在原位制备的 [F]AlF，通过一锅标记过程实现 [F]AlF-NOTA-VAP 的放射性化学合成，并通过 HPLC 进行纯化。
放射性示踪剂在 37°C 的大鼠血清中具有超过 3 小时的高体外稳定性。在荷 4T1 肿瘤的 BALB/c 小鼠中进行的生物分布研究和体内 micro-PET/CT 成像研究表明，[F]AlF-NOTA-VAP 在肿瘤中具有快速和高摄取，并具有较长的滞留时间。该示踪剂的高亲水性使其能够快速从大多数正常组织中清除，从而提高肿瘤与正常组织的比值（60 分钟时为 4.40），优于 [F]FDG（60 分钟时为 1.31）。药代动力学研究表明，放射性示踪剂的平均体内平均停留时间仅为 0.6432 小时，这表明这种亲水性放射性示踪剂很快从体内消除，以减少非靶组织的分布。
这些结果表明，[F]AlF-NOTA-VAP 是一种非常有前途的用于肿瘤细胞表面 GRP78 阳性肿瘤的肿瘤特异性成像的 PET 探针。
