Ginsenoside Rg1 as a promising adjuvant agent for enhancing the anti-cancer functions of granulocytes inhibited by noradrenaline.

Introduction: In recent years, numerous studies have confirmed that chronic stress is closely related to the development of cancer. Our previous research showed that high levels of stress hormones secreted in the body during chronic stress could inhibit the cancer-killing activity of granulocytes, which could further promote the development of cancer. Therefore, reversing the immunosuppressive effect of stress hormones on granulocytes is an urgent problem in clinical cancer treatment. Here, we selected noradrenaline (NA) as a representative stress hormone. Methods and results: After screening many traditional Chinese herbal medicine active ingredients, a promising compound, ginsenoside Rg1, attracted our attention. We verified the immunoprotective effect of ginsenoside Rg1 on granulocytes in vitro and ex vivo, and attempted to understand its potential immunoprotective mechanism. We confirmed the immunoprotective effect of ginsenoside Rg1 on granulocytes using cell and animal experiments. Cell counting kit-8 (CCK-8) and ex vivo experiments were performed to investigate the immunoprotective effects of ginsenoside Rg1 on the anti-cancer function of granulocytes inhibited by NA. Transcriptome sequencing analysis and qRT-PCR showed that NA elevated the mRNA expression of ARG2, MMP1, S100A4, and RAPSN in granulocytes, thereby reducing the anti-cancer function of granulocytes. In contrast, ginsenoside Rg1 downregulated the mRNA expression of ARG2, MMP1, S100A4, and RAPSN, and upregulated the mRNA expression of LAMC2, DSC2, KRT6A, and FOSB, thereby enhancing the anti-cancer function of granulocytes inhibited by NA. Transwell cell migration experiments were performed to verify that ginsenoside Rg1 significantly enhanced the migration capability of granulocytes inhibited by NA. Tumor-bearing model mice were used to verify the significant immunoprotective effects in vivo. Finally, CCK-8 and hematoxylin and eosin staining experiments indicated that ginsenoside Rg1 exhibited high biosafety in vitro and in vivo. Discussion: In future clinical treatments, ginsenoside Rg1 may be used as an adjuvant agent for cancer treatment to alleviate chronic stress-induced adverse events in cancer patients.

Dual-targeted and MRI-guided photothermal therapy via iron-based nanoparticles-incorporated neutrophils.

Nanoparticle-mediated photothermal therapy (PTT) has shown promising capability for tumor therapy through the high local temperature at the tumor site generated by a photothermal agent (PTA) under visible or near-infrared (NIR) irradiation. Improving the accumulation of PTA at the tumor site is crucial to achieving effective photothermal treatment. Here, we developed temperature-activatable engineered neutrophils (Ne) by combining indocyanine green (ICG)-loaded magnetic silica NIR-sensitive nanoparticles (NSNP), which provide the potential for dual-targeted photothermal therapy. The combined effect of neutrophil targeting and magnetic targeting increased the accumulation of PTA at the tumor site. According to magnetic resonance imaging (MRI), the retention of intravenous injected NSNP-incorporated neutrophils within the tumor site was markedly augmented as compared to free NSNP. Furthermore, when irradiated by NIR, NSNP could cause a high local temperature at the tumor site and the thermal stimulation of neutrophils. The heat can kill tumor cells directly, and also lead to the death of neutrophils, upon which active substances with tumor-killing efficacy will be released to kill residual tumor cells and thus reduce tumor recurrence. Thereby, our therapy achieved the elimination of malignancy in the mouse model of the pancreatic tumor without recurrence. Given that all materials used in this system have been approved for use in humans, the transition of this treatment method to clinical application is plausible.

Cell membrane camouflaged nanoparticles: a new biomimetic platform for cancer photothermal therapy.

Targeted drug delivery by nanoparticles (NPs) is an essential technique to achieve the ideal therapeutic effect for cancer. However, it requires large amounts of work to imitate the biomarkers on the surface of the cell membrane and cannot fully retain the bio-function and interactions among cells. Cell membranes have been studied to form biomimetic NPs to achieve functions like immune escape, targeted drug delivery, and immune modulation, which inherit the ability to interact with the in vivo environments. Currently, erythrocyte, leukocyte, mesenchymal stem cell, cancer cell and platelet have been applied in coating photothermal agents and anti-cancer drugs to achieve increased photothermal conversion efficiency and decreased side effects in cancer ablation. In this review, we discuss the recent development of cell membrane-coated NPs in the application of photothermal therapy and cancer targeting. The underlying biomarkers of cell membrane-coated nanoparticles (CMNPs) are discussed, and future research directions are suggested.

Biomarkerless targeting and photothermal cancer cell killing by surface-electrically-charged superparamagnetic Fe3O4 composite nanoparticles.

A major challenge in cancer therapy is localized targeting of cancer cells for maximum therapeutic effectiveness. However, due to cancer heterogeneities, the biomarkers are either not readily available or specific for effective targeting of cancer cells. The key, therefore, is to develop a new targeting strategy that does not rely on biomarkers. A general hallmark of cancer cells is the much increased level of glycolysis. The loss of highly mobile lactate from the cytoplasm inevitably removes labile inorganic cations to form lactate salts and acids as part of the lactate cycle, creating a net of negative surface charges. This net of negative charges on cancer cell surfaces biophysically distinguishes themselves from normal cells. In this study, cancer cells are targeted by using positively-charged, fluorescent, superparamagnetic Fe3O4-composite nanoparticles. The positively-charged Fe3O4 composite nanoparticles bind predominantly to cancer cells due to their negatively-charged surfaces. Upon electrical-charge-mediated Fe3O4 nanoparticle binding onto cancer cells, irradiation by using an 808 nm laser is subsequently applied to induce photothermal hyperthermia that kills the cancer cells directly. The negatively-charged composite nanoparticles are found, however, not to target and bind the cancer cells due to the electrostatic repulsive force between them. This unique strategy paves a new path for effective targeting and direct cancer cell killing without relying on any biomarkers and anticancer drugs.