Biological evaluation of a novel stable peptide PET molecular probe [18F]AlF-NOTA-DVAP targeting to tumor cell surface GRP78.

BACKGROUNDS: 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 [18F]AlF-NOTA-DVAP recognizing GRP78 expressed on the cell surface of breast cancer. METHODS: Radiochemical synthesis of [18F]AlF-NOTA-DVAP was achieved via a one-pot labeling process by heating NOTA-DVAP in the presence of in situ prepared [18F]AlF for 15 min at 110 °C and purified through HPLC. RESULTS: 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 [18F]AlF-NOTA-DVAP 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 [18F]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. CONCLUSIONS: These results suggest that [18F]AlF-NOTA-DVAP is a very promising PET probe for tumor-specific imaging of cell-surface GRP78-positive tumor.

Nuclear Imaging of CAR T Immunotherapy to Solid Tumors: In Terms of Biodistribution, Viability, and Cytotoxic Effect.

Immunotherapy has become a mainstay of cancer therapy. Since chimeric antigen receptor (CAR) T immunotherapy achieves unprecedented success in curing hematological malignancies, the possibility of it revolutionizing the paradigm of solid tumors has aroused increasing attention. However, the restricted accessibility to tumor parenchyma, the immunosuppressive tumor microenvironment, and antigen heterogeneity of solid tumors make it difficult to replicate its success. Therefore, dynamic evaluation of CAR T cells' tumor accessibility, intratumoral viability, and anti-tumor cytotoxicity is necessary to facilitate its translation to solid tumors. Besides, real-timely imaging above events in vivo can help evaluate therapeutic responses and optimize CAR T immunotherapy for solid tumors. Nuclear imaging, including positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging, is frequently applied for evaluating adoptive cell therapies owing to its excellent sensitivity, high tissue penetration, and great translation potential. In addition, quantitative analysis can be performed in dynamic and noninvasive patterns. This review focuses on recent advances in PET/SPECT technologies and imaging probes in monitoring CAR T cells' migration, viability, and cytotoxicity to solid tumors post-administration. Prospects of what should be done in the next stage to promote CAR T therapy's application in solid tumors are also discussed.

Enhanced antitumor immune responses via a new agent [131I]-labeled dual-target immunosuppressant.

Radionuclides theranostic are ideal "partners" for bispecific antibodies to explore the immune response of patients and synergistic treatment. A bispecific single-domain antibody-Fc fusion protein, KN046, exhibits a good treatment effect by binding to programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). An ionizing-radiation stimulus mediated by a low-dose of [131I] may be used for immunopotentiation. In this study, we established [131I]-labeled KN046 as a novel radioimmunotherapy agent to treat malignant melanoma and explored the mechanism. METHODS: After intravenous injection of [131I]-KN046, SPECT/CT imaging was applied to identify candidate targets for KN046 immunotherapy. [18F]-FDG and [68 Ga]-NOTA-GZP (granzyme B-specific PET imaging agent) micro-PET/CT imaging was used to assess the immune response in vivo after [131I]-KN046 treatment. The synergistic treatment effect of [131I]-KN046 was evaluated by exploring the [131I]-based radionuclide-induced release of tumor immunogenicity-related antigens as well as the histology and survival of tumor-bearing mice after treatment. RESULTS: The constructed [131I]-KN046 exhibited high affinity and specificity for PD-L1/CTLA-4 immune targets and had excellent in vivo intratumoral retention capability so as to achieve good antitumor efficacy. More importantly, the combination of low-dose [131I] and KN046-enhanced immunosensitivity increased the immunotherapy response rates significantly. Exposure of tumor cells to [131I]-KN046 led to upregulated expression of MHC-I and Fas surface molecules and significant increases in the degree of T-cell activation and counts of tumor-infiltrating immunocytes. CONCLUSION: Use of low-dose [131I] combined with a dual-target immunosuppressant could be exploited to identify the subset of treatment responders but also exhibited great potential for enhancing antitumor immune responses.

Direct Deoxyfluorination of Alcohols with KF as the Fluorine Source.

This report describes a method for the deoxyfluorination of alcohols with KF as the fluorine source via in situ generation of highly active CF3SO2F. Diverse functionalities, including halogen, nitro, ketone, ester, alkene, and alkyne, are well tolerated. Mild conditions, a short reaction time, and a wide substrate scope make this method an excellent choice for the construction of C-F bonds.