18 F-Labeling Chemistry in Aqueous Media.

18 F-Labeled molecular tracers and subsequent positron emission tomography are indispensable molecular imaging tools in medical diagnosis and research. The preparation of 18 F-labeled molecular tracers involves critical steps such as the 18 F-labeling reaction, work-up, and 18 F-product purification, which are governed by 18 F-labeling chemistry. Since direct incorporation of 18 F in aqueous media exhibits many advantages in practice, this Review summarizes the existing 18 F-labeling methods in aqueous media, which are sorted by atoms forming chemical covalent bonds with F. The Review is focused on the respective reaction mechanism, the water effect and the applications of these methods for the development of 18 F-radiopharmaceuticals. The research progress on aqueous nucleophilic labeling methods using [18 F]F- as the 18 F source has been mainly discussed.

TNFAIP3 promotes ALDH-positive breast cancer stem cells through FGFR1/MEK/ERK pathway.

Breast cancer stem cells (BCSCs) are a tiny population of self-renewing cells that may contribute to cancer initiation, progression, and resistance to therapy in patients. In our prior study, we found that tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is necessary for fibroblast growth factors receptor 1 (FGFR1) signaling-promoted tumor growth and progression in breast cancer (BC). This study aims to investigate the involvement of TNFAIP3 in regulating BCSCs. In this work, we showed that ALDH-positive BCSCs were increased by activating the FGFR1-MEK-ERK pathway, meanwhile utilizing FGFR1 inhibitor, MEK inhibitor, or ERK inhibitor reversed the phenomenon in BC cells. Moreover, ALDH-positive BCSCs were decreased in TNFAIP3-knockout or TNFAIP3-depressing cells. In vivo analysis displayed that TNFAIP3-silenced MDA-MB-231 xenografts developed smaller tumors and ALDH immunostaining levels were significantly lower in TNFAIP3-depressing or TNFAIP3-knockout tumor tissues. Besides, our results also revealed that TNFAIP3 influences the transcription stemness factors gene expression. Taken together, TNFAIP3 could be a potential regulator in FGFR1-MEK-ERK-promoted ALDH-positive BCSCs.

TNFAIP3 mediates FGFR1 activation-induced breast cancer angiogenesis by promoting VEGFA expression and secretion.

PURPOSE: To investigate the role and mechanism of TNF-inducible protein 3(TNFAIP3) in breast cancer angiogenesis induced by fibroblast growth factor receptor1 (FGFR1) activation. METHODS: The immunohistochemical assay was used to detect the expression of vascular endothelial cell marker CD31 and CD105 in mice DCIS.COM-iFGFR1 transplanted tumor (previously established by our group). The effects of TNFAIP3 knockout/knockdown breast cancer cell lines on angiogenesis, migration, and invasion of Human Umbilical Vein Endothelial Cells (HUVEC) were detected by the tubulogenesis and Trewells assay. RNA-seq analysis of TNFAIP3 downstreams differential genes after TNFAIP3 knockdown. The expression and secretion of VEGFA after FGFR1 activation in breast cancer cells were detected by qPCR, Western blot, and ELISA. RESULTS: Immunohistochemistry showed that TNFAIP3 knockout inhibited the expression of CD31 and CD105 in DCIS grafted tumors promoted by FGFR1 activation. Tubulogenesis and Trewells experiments showed that TNFAIP3 gene knockout/knockdown inhibited the angiogenesis, migration, and invasion of HUVEC cells promoted by FGFR1 activation. qPCR assay showed that VEGFA mRNA level in the TNFAIP3 knockdown cell line was significantly down-regulated (p < 0.05). qPCR, Western blot and ELISA results showed that TNFAIP3 gene knockout/knockdown could inhibit the expression and secretion of VEGFA in breast cancer cells induced by FGFR1 activation. CONCLUSION: TNFAIP3 promotes breast cancer angiogenesis induced by FGFR1 activation through the expression and secretion of VEGFA.

HC-1119, a deuterated Enzalutamide, inhibits Migration, Invasion and Metastasis of the AR-positive triple-negative breast Cancer cells.

Triple-negative breast cancers (TNBCs) are aggressive, and they develop metastasis at earlier stages, relapse more frequently, and exhibits poorer prognosis than other subtypes of breast cancer. Due to the lack of estrogen receptor for endocrine therapy and HER2 for targeted therapy, new targeted therapies for TNBCs are urgently needed. Enzalutamide is a second-generation androgen receptor (AR) inhibitor, and HC-1119 is a new synthetic deuterated enzalutamide. Owing to the isotope effect, HC-1119 has many advantages over enzalutamide, including slow metabolism, high plasma concentration and low brain exposure. However, the efficacy of HC-1119 in inhibition of AR function in triple-negative breast cancer (TNBC) has not been studied. In this study, we found high-level AR expression in both Hs578T and SUM159PT TNBC cell lines. Activation of AR by dihydrotestosterone (DHT) in both cell lines increased AR protein, induced AR-nuclear localization, enhanced cell migration and invasion in culture, and promoted liver metastasis in mice. Importantly, cotreatment with HC-1119 of these cells efficiently abolished all of these effects of DHT on both Hs578T and SUM159PT cells. These results indicate that HC-1119 is a very effective new second-generation AR antagonist that can inhibit the migration, invasion and metastasis of the AR-positive TNBC cells.

Direct 18F-Labeling of Biomolecules via Spontaneous Site-Specific Nucleophilic Substitution by F- on Phosphonate Prostheses.

We describe a high radiochemical yield late-stage direct 18F-labeling of bare biomolecules containing common active groups. Spontaneity and site-selectivity are attributed to the remarkably higher rates of nucleophilic substitution reactions on phosphonates than on other electrophiles by F- at various hydrogen bond forms. Rapid access to many medicinally significant 18F-labeled biomolecules is achieved at 21-68% radiochemical yields and 35.9-55.1 GBq µmol-1 molar activities both manually or automatically.