Young-Hwa Kim

Radiotherapy is widely used as an effective non-surgical strategy to control malignant tumors. However, recurrence is one of common causes of treatment failure even after the effective radiotherapy. In this study, we focused on the effects of radiation-induced exosomal miR-21 on the tumor microenvironment to investigate the causes of recurrence. Analysis of the TCGA database revealed that breast cancer patients with high levels of miR-21 have significantly reduced overall survival when treated with radiotherapy compared to those who did not receive radiotherapy, indicating a high hazard ratio for miR-21 in patients undergoing this treatment. Additionally, exosomal miR-21 is found to be highly expressed in the serum of breast adenocarcinoma patients. To explore how miR-21 induces poor prognosis in irradiated breast cancer, we irradiated 4T1 cell line with low or high doses of radiation, and examined the impact of secreted exosomal miR-21 on breast cancer cell and tumor microenvironment. After 10 Gy irradiation, 4T1 cells secreted 2.20 ± 0.10 times more exosomes and exhibited a 1.85 ± 0.01-fold increase in exosomal miR-21 levels. Treatment with exosomes from 10 Gy-irradiated cancer cells led to enhanced tumor cell proliferation, wound healing, and migration. The survival rate of 10 Gy-irradiated tumor cells incubated with 10 Gy-derived exosomes increased by 2.83-fold. Moreover, the growth of subcutaneous tumors treated with 10 Gy exosomes (n = 13) was significantly faster compared to tumors treated with 0 Gy exosomes (n = 10, P < 0.05). In summary, our study revealed high-dose irradiation-induced exosomes were found to enhance tumor proliferation and invasiveness via the transfer of exosomal miR-21. Based on these findings, we suggest that radiation-induced exosomal miR-21 may contribute to a poorer prognosis of breast cancer patients undergoing radiotherapy.

Immune checkpoint inhibitors (ICIs) are widely used in cancer immunotherapy, requiring effective methods for response monitoring. This study evaluated changes in ¹⁸F-2-fluoro-2-deoxy-D-glucose (FDG) and ¹⁸F-fluorothymidine (FLT) uptake by tumors following ICI treatment as potential imaging biomarkers in mice. Tumor uptakes of ¹⁸F-FDG and ¹⁸F-FLT were measured and compared between the ICI treatment and control groups. A combined imaging index of glucose–thymidine uptake ratio (GTR) was defined and compared between groups. In the ICI treatment group, tumor growth was effectively inhibited, and higher proportions of immune cells were observed. In the early phase, ¹⁸F-FDG uptake was higher in the treatment group, whereas ¹⁸F-FLT uptake was not different. There was no difference in ¹⁸F-FDG uptake between the two groups in the late phase. However, ¹⁸F-FLT uptake of the control group was markedly increased compared with the ICI treatment group. GTR was consistently higher in the ICI treatment group in the early and late phases. After ICI treatment, changes in tumor cell proliferation were observed with ¹⁸F-FLT, whereas ¹⁸F-FDG showed altered metabolism in both tumor and immune cells. A combination of ¹⁸F-FLT and ¹⁸F-FDG PET, such as GTR, is expected to serve as a potentially effective imaging biomarker for monitoring ICI treatment.

Dolastatin derivatives, represented by monomethylauristatin E (MMAE), have been translated in clinic with a form of antibody–drug conjugate; however, their potential in nanoparticle systems has not been well established due to the potential risk of immature release of extremely high cytotoxic dolastatin drugs during blood circulation. Herein, we rationally propose monomethylauristatin F (MMAF), a dolastatin-derived, loaded nanoparticle system composed of bombesin (BBN)-tethered ROS-responsive micelle system (BBN-PEG-PPADT) to achieve efficient anticancer therapy with targeted and efficient delivery of MMAF. The developed MMAF-loaded BBN-PEG-PPADT micelles (MMAF@BBN-PEG-PPADT) exhibited improved cellular uptake via interactions between BBN and gastrin-releasing peptide receptors on the cancer cells and the intracellular burst release of MMAF, owing to the ROS-responsive disruption, which allowed the efficient anticancer effects of MMAF in vitro. This study suggests the potential of nanoparticle systems in the delivery of dolastatin drugs.

There has been considerable interest in the clinical use of exosomes as delivery vehicles for treatments as well as for promising diagnostic biomarkers, but the physiological distribution of exosomes must be further elucidated to validate their efficacy and safety. Here, we aimed to develop novel methods to monitor exosome biodistribution in vivo using positron emission tomography (PET) and optical imaging. Exosomes were isolated from cultured mouse breast cancer cells and labeled for PET and optical imaging. In mice, radiolabeled and fluorescently labeled exosomes were injected both via lymphatic and hematogenous metastatic routes. PET and fluorescence images were obtained and quantified. Radioactivity and fluorescence intensity of ex vivo organs were measured. PET signals from exosomes in the lymphatic metastatic route were observed in the draining sentinel lymph nodes. Immunohistochemistry revealed greater exosome uptake in brachial and axillary versus inguinal lymph nodes. Following administration through the hematogenous metastasis pathway, accumulation of exosomes was clearly observed in the lungs, liver, and spleen. Exosomes from tumor cells were successfully labeled with ⁶⁴Cu (or ⁶⁸Ga) and fluorescence and were visualized via PET and optical imaging, suggesting that this simultaneous and rapid labeling method could provide valuable information for further exosome translational research and clinical applications.