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Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs.FAP-targeted molecular imaging agents, including FAP inhibitor (FAPI)-04 and FAPI-46, have shown promising results in tumor diagnosis. However, these molecules have relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a 68 Ga-labeled FAPI dimer (denoted as 68 Ga-DOTA-2P(FAPI)2) to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs.Methods: 68 Ga-DOTA-2P(FAPI)2 was synthesized based on the quinoline-based FAPI variants (FAPI-46), and its binding properties were assayed in CAFs.Preclinical pharmacokinetics was determined in FAP-positive patient-derived xenografts (PDXs) using small-animal PET and biodistribution experiments. The effective dosimetry of 68 Ga-DOTA-2P(FAPI)2 was evaluated in three healthy volunteers, and PET/ CT imaging of 68 Ga-FAPI-46 and 68 Ga-DOTA-2P(FAPI)2 was performed in three cancer patients. Results: 68 Ga-DOTA-2P(FAPI)2 was stable in phosphate-buffered saline and fetal bovine serum for 4 h. The FAPI dimer showed high affinity and specificity for FAP in-vitro and in-vivo. The tumor uptake of 68 Ga-DOTA-2P(FAPI)2 was approximately two-fold stronger than that of 4 68 Ga-FAPI-46 in PDXs, while the healthy organs showed low tracer uptake and fast body clearance. The effective dose of 68 Ga-DOTA-2P(FAPI)2 was 1.19E-02 mSv/MBq, calculated using OLINDA. Finally, PET/CT scans in three cancer patients revealed higher intratumoral uptake of 68 Ga-DOTA-2P(FAPI)2 than that of 68 Ga-FAPI-46 in all tumor lesions (maximum standardized uptake value: 8.1-39.0 vs. 1.7-24.0, respectively; P < 0.001). Conclusion: 68 Ga-DOTA-2P(FAPI)2 has increased tumor uptake and retention properties compared to 68 Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP.

The Hippo signaling pathway is a critical regulator of organ size control during development, and its deregulation is associated with cancers. Acting downstream of this pathway, Yes-associated protein (YAP) was implicated in tumorigenesis. The present study aimed to explore the expression patterns and clinical significance of YAP in human colorectal cancer (CRC). In addition, we investigated the relationship between YAP expression and Wnt/β-catenin pathway activation in CRC. A total of 139 cases of CRC tissues were investigated by immunohistochemistry for the expression of YAP, cyclin D1, and β-catenin. The association between YAP expression and clinicopathologic features was analyzed. Our results showed that YAP was overexpressed in 52.5 % (73/139) cases of CRC and predominantly presented in the nucleus. There was an excellent correlation between YAP expression and pTNM stage (p = 0.0024). YAP expression in CRC was significantly correlated with nodal status (p = 0.0034), tumor status (p = 0.0382), and cyclin D1 overexpression (p < 0.0001). Importantly, YAP expression was associated with short overall survival (p < 0.001). Furthermore, patients with YAP-positive and nuclear β-catenin-positive profiles had worse overall survival. Univariate and multivariate analyses revealed that YAP expression was an independent prognostic indicator of CRC (p = 0.0207). Our results indicated that YAP overexpression contributed to the tumorigenesis and played a pivotal role in the progression in CRC, and the interaction of YAP and Wnt/β-catenin pathways needs further exploration.