HIGHLIGHTS• A biomimetic nanoprobe was built with cancer cell membrane-coated and Gd 3+ -doped upconversion nanoparticles.• The nanoprobe could be applied to in vivo UCL/MRI/PET multimodality precise imaging and successfully differentiated MDA-MB-231 tumor models through in vivo tri-modality imaging, which may be used for breast cancer molecular classification.ABSTRACT Triple-negative breast cancer (TNBC) is a subtype of breast cancer in which the estrogen receptor and progesterone receptor are not expressed, and human epidermal growth factor receptor 2 is not amplified or overexpressed either, which make the clinical diagnosis and treatment very challenging. Molecular imaging can provide an effective way to diagnose TNBC. Upconversion nanoparticles (UCNPs), are a promising new generation of molecular imaging probes. However, UCNPs still need to be improved for tumor-targeting ability and biocompatibility.This study describes a novel probe based on cancer cell membrane-coated upconversion nanoparticles (CCm-UCNPs), owing to the low immunogenicity and homologous-targeting ability of cancer cell membranes, and modified multifunctional UCNPs. This probe exhibits excellent performance in breast cancer molecular classification and TNBC diagnosis through UCL/MRI/PET tri-modality imaging in vivo. By using this probe, MDA-MB-231 was successfully differentiated between MCF-7 tumor models in vivo. Based on the tumor imaging and molecular classification results, the probe is also expected to be modified for drug delivery in the future, contributing to the treatment of TNBC. The combination of nanoparticles with biomimetic cell membranes has the potential for multiple clinical applications.
Upconversion nanoparticles (UCNPs) have been widely employed for tumor imaging using magnetic resonance imaging (MRI) and upconversion luminescence (UCL) imaging.
Bmi1 gene overexpression is found in various human tumors and has been shown as a potential target for gene treatment. However, siRNA-based treatments targeting Bmi1 gene have been restricted to limited delivery, low bioavailability and hence relatively reduced efficacy. To overcome these barriers, we developed a folate receptor targeted co-delivery system folate-doxorubicin/Bmi1 siRNA liposome (FA-DOX/siRNA-L). The FA-DOX/siRNA-L was prepared through electrostatic interaction between folate doxorubicin liposome (FA-DOX-L) and Bmi1 siRNA. In vitro and in vivo studies showed that FA-DOX/siRNA-L inhibited tumor growth by combinatory role of Bmi1 siRNA and doxorubicin (DOX). Co-delivery of Bmi1 siRNA and DOX by FA-DOX/siRNA-L showed significantly higher efficacy than sole delivery of either DOX or Bmi1 siRNA. Real-time PCR and western blot analysis showed that FA-DOX/siRNA-L silenced the expression of Bmi1 gene. In addition, higher accumulation of the siRNA and DOX in tumor cells indicated that folate ligand displayed tumor targeting effect. These results suggest that Bmi1 is an effective therapeutic target for siRNA based cancer treatment that can be further improved by co-delivery of DOX through targeted liposomes.
We sought to evaluate the performance of 68 Ga-DOTA-FAPI-04 ( 68 Ga-FAPI) PET/MR for the diagnosis of primary tumor and metastatic lesions in patients with gastric carcinomas and to compare the results with those of 18 F-FDG PET/CT. Methods: Twenty patients with histologically proven gastric carcinomas were recruited, and each patient underwent both 18 F-FDG PET/CT and 68 Ga-FAPI PET/MR. A visual scoring system was established to compare the detectability of primary tumors and metastases in different organs/regions (the peritoneum, abdominal lymph nodes, supradiaphragmatic lymph nodes, liver, ovary, bone, and other tissues). The original maximum standardized uptake value (SUVmax) and normalized SUVmax (calculated by dividing a lesion's original SUVmax with the mean SUV of the descending aorta) of selected lesions on both 18 F-FDG PET/CT and 68 Ga-FAPI PET/MR were measured.Original/normalized SUVmax-FAPI and SUVmax-FDG were compared for patient-based (including a single lesion with the highest activity uptake in each organ/region) and lesion-based (including all lesions [≤ 5] or the 5 lesions with highest activity [> 5]) analyses, respectively.
Results:The 20 recruited patients (median age: 56.0 y; range: 29-70 y) included 9 men and 11 women, 14 patients for initial staging and 6 for recurrence detection. 68 Ga-FAPI PET was superior to 18 F-FDG PET for primary tumor detection (100.00% [14/14] vs 71.43% [10/14], p = 0.034), and the former had higher tracer uptake levels (p < 0.05). 68 Ga-FAPI PET was superior to 18 F-FDG PET in both patient-based and lesion-based evaluation except for the metastatic lesions in supradiaphragmatic lymph nodes and ovaries. Additionally, multiple sequences of MR images were beneficial for the interpretation of hepatic metastases in 3 patients, uterine and rectal metastases in 1 patient, ovarian lesions in 7 patients, and osseous metastases in 2 patients.
Conclusion:68 Ga-FAPI PET/MR outperformed 18 F-FDG PET/CT in visualizing the primary and most metastatic lesions of gastric cancer, and might be a promising method with the potential of replacing 18 F-FDG PET/CT.
Preparation of small molecule based dual-modality probes remains a challenging task due to the complicated synthetic procedure. In this study, a novel concise and generic strategy for preparing dual-modality optical/PET imaging probes via photo-click chemistry was developed, in which the diazole photo-click linker functioned not only as a bridge between the targeting-ligand and the PET imaging moiety, but also as the fluorophore for optical imaging. A dual-modality AE105 peptidic probe was successfully generated via this strategy and subsequently applied in the fluorescent staining of U87MG cells and the 68Ga based PET imaging of mice bearing U87MG xenograft. In addition, dual-modality monoclonal antibody cetuximab has also been generated via this strategy and labeled with 64Cu for PET imaging studies, broadening the application of this strategy to include the preparation of macromolecule based imaging probes.
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