Silicon particles have garnered attention as promising biomedical probes for hyperpolarized 29Si magnetic resonance imaging and spectroscopy. However, due to the limited levels of hyperpolarization for nanosized silicon particles, microscale silicon particles have primarily been the focus of dynamic nuclear polarization (DNP) applications, including in vivo magnetic resonance imaging (MRI). To address these current challenges, we developed a facile synthetic method for partially 29Si-enriched porous silicon nanoparticles (NPs) (160 nm) and examined their usability in hyperpolarized 29Si MRI agents with enhanced signals in spectroscopy and imaging. Hyperpolarization characteristics, such as the build-up constant, the depolarization time (T 1), and the overall enhancement of the 29Si-enriched silicon NPs (10 and 15%), were thoroughly investigated and compared with those of a naturally abundant NP (4.7%). During optimal DNP conditions, the 15% enriched silicon NPs showed more than 16-fold higher enhancementsfar beyond the enrichment ratiothan the naturally abundant sample, further improving the signal-to-noise ratio in in vivo 29Si MRI. The 29Si-enriched porous silicon NPs used in this work are potentially capable to serve as drug-delivery vehicles in addition to hyperpolarized 29Si in vivo, further enabling their potential future applicability as a theragnostic platform.

Irradiation in conjunction with gene therapy is considered for efficient cancer treatment. Mesenchymal stem cells (MSCs), due to their irradiation-promotable tumor tropism, are ideal delivery vehicles for gene therapy. In this study, we investigated whether treatment with radiation and interleukin (IL)-12-expressing MSCs (MSCs/IL-12) exerts improved antitumor effects on murine metastatic hepatoma. HCa-I and Hepa 1-6 cells were utilized to generate heterotopic murine hepatoma models. Tumor-bearing mice were treated with irradiation or MSCs/IL-12 alone, or a combination. Monocyte chemoattractant protein-1 (MCP-1/CCL2) expression was assessed in irradiated hepatoma tissues to confirm a chemotactic effect. Combination treatment strategies were established and their therapeutic efficacies were evaluated by monitoring tumor growth, metastasis and survival rate. IL-12 expression was assessed and the apoptotic activity and immunological alterations in the tumor microenvironment were examined. MCP-1/CCL2 expression and localization of MSCs/IL-12 increased in the irradiated murine hepatoma cells. The antitumor effects, including suppression of pulmonary metastasis and survival rate improvements, were increased by the combination treatment with irradiation and MSCs/IL-12. IL-12 expression was increased in tumor cells, causing proliferation of cluster of differentiation 8 1 T-lymphocytes and natural killer cells. The apoptotic activity increased, indicating that the cytotoxicity of immune cells was involved in the antitumor effect of the combined treatment. Treatment with irradiation and MSCs/IL-12 showed effectiveness in treating murine metastatic hepatoma. IL-12-induced proliferation of immune cells played an important role in apoptosis of tumor cells. Our results suggest that treatment with irradiation and MSCs/IL-12 may be a useful strategy for enhancing antitumor activity in metastatic hepatoma.

Existing therapies such as irradiation or sorafenib have limited success in the treatment of hepatocellular carcinoma (HCC) due to tumor recurrence and metastasis. Therefore, combination with other therapeutics is often considered. Macrophage inflammatory protein-1 alpha (MIP-1α) is a member of a family of chemoattractant cytokines that can induce the migration of monocytes, which in turn can play a role in fighting tumors. This study investigated whether intravenous injection of MIP-1α in conjunction with irradiation or sorafenib could enhance the antitumor effects on murine hepatoma. An HCa-I tumor was grown on the right thigh of each C3H/HeN mouse. Mice were then treated with 10 Gy of irradiation, sorafenib, or a combination of MIP-1α with either irradiation or sorafenib, and antitumor and antimetastatic effects were then investigated. To understand the mechanisms, changes in the level of immunological markers were also evaluated. Combination treatment of MIP-1α with irradiation or sorafenib resulted in a significant enhancement of antitumor effects, prevention of lung metastasis and increase in host survival. This was achieved by significantly increasing the levels of the immunological markers: Cluster Differentiation (CD) 8, CD107A and CD11C. We conclude that a combination treatment of MIP-1α with irradiation or sorafenib would be a useful strategy for management of hepatoma.

Radiotherapy (RT) is a potent anti-tumor modality. However, unwanted effects including increased recurrence and metastasis that involve factors such as cytokines, which induce complex molecular mechanisms, have also been reported. In a previous study, we showed that interleukin (IL)-12 and radiotherapy combination treatment suppressed tumor growth and metastasis in a hepatoma mouse model. In this study, we investigated the mechanism underlying the IL-12 anti-tumor effect during radiotherapy. In tumor-bearing mice, irradiation decreased IL-12 expression in the tumors and spleens. However, a number of dendritic cells infiltrated into the tumors in which IL-12 expression did not decrease. To further study the underlying detailed mechanism for this decrease in IL-12, LPS-stimulated bone marrow–derived dendritic cells (BMDCs) were irradiated, and then IL-12– and IL-6–associated molecules were examined in irradiated tumors and BMDCs. Irradiation resulted in IL-12 suppression and IL-6 increase. IL-6 and signal transducer and activator of transcription 3 (STAT3) inhibitors restored the irradiation-induced IL-12 decrease via suppression of C-Rel activation. Taken together, our study suggests that irradiation-induced IL-6 can decrease IL-12 production through the inhibition of C-Rel phosphorylation by the IL-6/STAT3 signaling pathway.

We investigated the efficacy of combined radiotherapy (RT) and zoledronic acid in treating painful bone metastases from gastrointestinal cancers. Sixty patients were prospectively enrolled between November 2014 and July 2016. The most common primary cancer type was hepatocellular carcinoma (HCC, n = 25), followed by colorectal cancer (n = 6). Patients received external beam RT of 30–54 Gy in 10–17 fractions or 20 Gy in 5 fractions for symptomatic bone metastases. On the first day of RT, patients received 4 mg intravenous zoledronic acid, which was repeated monthly for a total of six cycles. The mean pain score before treatment was 6.7, and it decreased to 2.8 at 1 month and 2.1 at 3 months (P < 0.001).The overall pain response rates at 1 and 3 months were 95% and 96%, respectively. Among the 24 patients who underwent magnetic resonance imaging, 71% were responders, with a complete response in 1 patient and partial in 16 patients. Combined treatment significantly decreased levels of macrophage inflammatory protein-1α and matrix metalloproteinase (MMP)-2 and -3 compared with baseline (all P < 0.05). In HCC patients, IL-6 and MMP-9 levels were significantly lower 1 month after treatment (P < 0.05). The mean quality of life (QOL) score improved from 66 to 56 at 1 month (P < 0.001) and 55 at 3 months (P = 0.016). The median survival was 7 months. In conclusion, RT with zoledronic acid decreased bone pain and improved QOL in patients with painful bone metastases from gastrointestinal cancers. Radiographic findings and serum biomarker measurements were closely correlated with therapeutic responses.