MOF-derived novel porous Fe3O4@C nanocomposites as smart nanomedical platforms for combined cancer therapy: magnetic-triggered synergistic hyperthermia and chemotherapy.

Multifunctional nanomedical platforms have broad prospects in imaging-guided combination therapy in cancer precision medicine. In this work, metal-organic framework (MOF)-derived novel porous Fe3O4@C nanocomposites were developed as an intelligent cancer nanomedical platform for combined cancer therapy with MRI-guided magnetic-triggered hyperthermia and chemotherapy functions. The magnetic behavior, porous character and good surface modification endowed this smart nanoplatform with favorable biocompatibility, high-efficiency MRI imaging, magnetic-triggered on-demand DOX release function, and synergistic therapy of magnetic hyperthermia and chemotherapy, which proposed an all-in-one platform for cancer therapy. Additionally, in vivo animal experiments verified the significant suppression of malignant tumor growth with negligible side effects, which were attributed to the consecutive 13 day synergistic therapy of magnetic hyperthermia and chemotherapy in one. To be specific, Fe3O4@C-PVP@DOX significantly decreases the volume (2.5 to 0.44 of tumor volume ratio) and weight (0.49 g to 0.10 g) of tumors after magnetic-triggered hyperthermia and chemotherapy treatments. Moreover, no big difference of body weight and associated damage was observed among all major organs. Therefore, owing to its high-efficiency combined therapy of magnetic-triggered hyperthermia and chemotherapy, this smart nanoplatform holds great potential application in the precise treatments of clinical cancer.

Ultrasound hyperthermia enhances chemo-sensitivity in oral squamous cell carcinoma by TRIF-mediated pathway.

BACKGROUND: Hyperthermia is currently used as an alternative to surgery or in combination with chemotherapy and/or radiation therapy in the treatment of oral squamous cell carcinoma. However, little has been known about the change in chemo-sensitivity after hyperthermia and the mechanism underlie it in oral squamous cell carcinoma. METHODS: The aim of this study was to explore the influence of chemo-sensitivity of CAL-27 and SCC-4 cells by histoculture drug response assay after the animal model treated by the ultrasound hyperthermia. Then, we conducted a microarray between xenograft after hyperthermia at 42°C for 45 minutes and that with no treatment. We further confirmed the expression of TRIF in hyperthermia by immunohistochemistry, RT-PCR and Western blot. RESULTS: The chemo-sensitivity to five kinds of drugs demonstrated ultrasound hyperthermia performed in 42°C for 45 minutes would reach the highest inhibition rate in CAL-27 and SCC-4 cells. The microarray dataset revealed that 847 mRNA were upregulated and 1031 were downregulated. GO and pathway analyses indicated that they play an important role in translational initiation, nucleoplasm, and poly (A) RNA binding in the hyperthermia process. We further confirmed the expression of TRIF was downregulated in hyperthermia along with inactivation of NF-κB pathway. CONCLUSIONS: The experiments confirms the rationality of synchronous combination of hyperthermia and chemotherapy and may provide a better treatment that the use of sensitivity testing in such cases may lead to individualized, more effective therapy.

Ultrasound hyperthermia induces apoptosis in head and neck squamous cell carcinoma: An in vitro study

BACKGROUND: Hyperthermia is considered an efficient complement in the treatment of head and neck squamous cell carcinoma (HNSCC). Hyperthermia induces cell apoptosis in a temperature- and time-dependent manner. However, the molecular mechanism of hyperthermia remains unclear. The aim of this study was to investigate the mechanism of apoptosis induced by ultrasound hyperthermia in HNSCC cell lines HN-30 and HN-13. MATERIAL AND METHODS: We examined the dynamic changes of early apoptosis and secondary necrosis in HN-30 and HN-13 cells treated by hyperthermia at 42°C for 10 min. We further examined mitochondrial membrane potential in vitro by ultrasound hyperthermia for different heating temperatures (38-44°C, 10 min) and heating times (42°C, 10-50 min). After heating by ultrasound at 42°C for 10 min, the apoptosis index achieved its highest level at 8 h after treatment, decreased rapidly and remained constant at a reduced level at 12 h. RESULTS: The level of secondary necrosis increased with the level of early apoptosis but remained at a higher level until 14 h. The level of secondary necrosis correlated with the level of early apoptosis (HN-13: r = 0.7523, P = 0.0030; HN-30: r = 0.6510, P = 0.016). The fractions of cells with low mitochondrial membrane potential (Δψ) in the heating-temperature grads group and heating-time grads group decreased significantly over time. Therefore, HN-30 and HN-13 cells developed apoptosis after ultrasound hyperthermia treatment with decreases in the mitochondrial transmembrane potential level. CONCLUSIONS: Ultrasound hyperthermia induces apoptosis in HN-30 and HN-13 cells, possibly via the mitochondrial caspase pathway

Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma.

The retinoic-acid-inducible gene (RIG)-like receptor (RLR) family proteins are major pathogen reorganization receptors (PRR) responsible for detection of viral RNA, which initiates antiviral response. Here, we evaluated the functional role of one RLR family member, RIG-I, in human head and neck squamous cell carcinoma (HNSCC). RIG-I is abundantly expressed both in poorly-differentiated primary cancer and lymph node metastasis, but not in normal adjacent tissues. Activation of RIG-I by transfection with low dose of 5'-triphosphate RNA (3p-RNA) induces low levels of interferon and proinflammatory cytokines and promotes NF-κB- and Akt-dependent cell proliferation, migration and invasion. In contrast, activation of RIG-I by a high dose of 3p-RNA induces robust mitochondria-derived apoptosis accompanied by decreased activation of Akt, which is independent of the interferon and TNFα receptor, but can be rescued by over-expression of constitutively active Akt. Furthermore, co-immunoprecipitation experiments indicate that the CARD domain of RIG-I is essential for inducing apoptosis by interacting with caspase-9. Together, our results reveal a dual role of RIG-I in HNSCC through regulating activation of Akt, in which RIG-I activation by low-dose viral dsRNA increases host cell survival, whereas higher level of RIG-I activation leads to apoptosis. These findings highlight the therapeutic potential of dsRNA mediated RIG-I activation in the treatment of HNSCC.