Tuo Yali,Zhang Zijun,Tian Cheng,Hu Qinyu,Xie Rui,Yang Jian,Zhou Hong,Lu Lili,Xiang Ming
Methionine enkephalin (MENK), an endogenous opioid peptide, has a role in nervous system, immune system, and anticancer therapy. Inflammation, metabolism and cancer are closely intertwined with each other. This study is to identify the correlation of the antitumor effects of MENK with systemic inflammation, liver metabolism, and immune cells as myeloid-derived suppressor cells (MDSCs). We established a subcutaneous CT26 colon carcinoma model and a cyclophosphamide-induced immunosuppressive model subjected to MENK. AML12 and MDSCs were used as in vitro models. The results showed that MENK treatment degraded tumor growth and inhibited proinflammatory cytokines both in tumor tissues and serum. The MENK-treated tumor mice showed normalized liver function with glycolipid metabolic homeostasis. No inhibitory effect on CT26 tumor cell in vitro, but only reduced lipid synthesis in AML12 were presented by MENK. Meanwhile, MENK invigorated immune response in both two animal models by markedly suppressing MDSCs and enhancing T cells response. In vitro MENK-treated MDSCs showed reduced glycolysis and less ROS production, which was mediated by PI3K/AKT/mTOR pathway. Opioid receptor antagonist naltrexone reversed most of the regulation. These results illustrate that MENK preventing development of colon carcinoma might be correlated with the suppression of inflammation, improving metabolism in liver as well as in MDSCs partly through opioid receptor, which brings new elements supporting the adjuvant therapy for tumor by MENK.
Tumors are usually hypoxic, which limits the efficacy of current tumor therapies, especially radiotherapy in which oxygen is essential to promote radiation-induced cell damage. Herein, by taking advantage of the ability of perfluorocarbon (PFC) to promote red blood cell penetration, we developed a simple but effective two-stage oxygen delivery strategy to modulate the hypoxic tumor microenvironment using PFC nanoparticles. Methods: We first examined the two-stage oxygen delivery ability of PFC nanoparticles on relieving tumor hypoxia through platelet inhibition. To evaluate the effect of PFC nanoparticles on radiation sensitization, CT26 tumor and SUM49PT tumor model were used. Results: In this study, PFC was encapsulated into albumin and intravenously injected into tumor-bearing mice without hyperoxic breathing. After accumulation in the tumor, PFC nanoparticles rapidly released the oxygen that was physically dissolved in PFC as the first-stage of oxygen delivery. Then, PFC subsequently promoted red blood cell infiltration, which further released O 2 as the second-stage of oxygen delivery. Conclusion: The hypoxic tumor microenvironment was rapidly relieved via two-stage oxygen delivery, effectively increasing radiotherapy efficacy. The safety of all substances used in this study has been clinically demonstrated, ensuring that this simple strategy could be rapidly and easily translated into clinical applications to solve the clinical problems associated with tumor hypoxia.
The stimulator of interferon genes (STING) is a pivotal protein in the production of STING-dependent type I interferon, which has the potential to enhance tumor rejection. The visualization of STING in the tumor microenvironment is valuable for STING-related treatments, but few STING imaging probes have been reported to date. In this study, we developed a novel 18F-labeled agent ([18F]F-CRI1) with an acridone core structure for the positron emission tomography (PET) imaging of STING in CT26 tumors. The probe was successfully prepared with a nanomolar STING binding affinity of Kd = 40.62 nM. [18F]F-CRI1 accumulated quickly in the tumor sites and its uptake reached a maximum of 3.02 ± 0.42% ID/g after 1 h i.v. injection. The specificity of [18F]F-CRI1 was confirmed both in in vitro cell uptake and in vivo PET imaging by blocking studies. Our findings suggest that [18F]F-CRI1 may be a potential agent for visualizing STING in the tumor microenvironment.
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