Alpha-ketoglutarate decorated iron oxide-gold core-shell nanoparticles for active mitochondrial targeting and radiosensitization enhancement in hepatocellular carcinoma.

The ability of some tumours to impart radioresistance serves as a barrier in the cancer therapeutics. Mitochondrial metabolism significantly persuades this cancer cell survival, incursion and plays a crucial role in conferring radioresistance. It would be of great importance to target the active mitochondria to overcome this resistance and achieve tumoricidal efficacy. The current report investigates the improved radiosensitization effect (under Gamma irradiation) in hepatocellular carcinoma through active mitochondrial targeting of alpha-ketoglutarate decorated iron oxide-gold core-shell nanoparticles (GNP). The loading of a chemotherapeutic drug N-(4-hydroxyphenyl)retinamide in GNP allows adjuvant chemotherapy, which further sensitizes cancerous cells for radiotherapy. The GNP shows a drug loading efficiency of 8.5 wt% with a sustained drug release kinetics. The X-Ray diffraction (XRD) pattern and High-Resolution Transmission Electron microscopy (HRTEM) indicates the synthesis of core iron oxide nanoparticles with indications of a thin layer of gold shell on the surface with 1:7 ratios of Fe: Au. The GNP application significantly reduced per cent cell viability in Hepatocellular carcinoma cells through improved radiosensitization at 5 Gy gamma radiation dose. The molecular mechanism revealed a sharp increment in reactive oxygen species (ROS) generation and DNA fragmentation. The mitochondrial targeting probes confirm the presence of GNP in the mitochondria, which could be the possible reason for such improved cellular damage. In addition to the active mitochondrial targeting, the currently fabricated nanoparticles work as a potent Magnetic Resonance Imaging (MRI)/Computed Tomography (CT) contrast agent. This multifunctional therapeutic potential makes GNP as one of the most promising theragnostic molecules in cancer therapeutics.

Melatonin-loaded chitosan nanoparticles endows nitric oxide synthase 2 mediated anti-inflammatory activity in inflammatory bowel disease model.

Inflammatory Bowel Disease (IBD) is a complex inflammatory condition arising due to interactions of environmental and genetic factors that lead to dysregulated immune response and inflammation in intestine. Complementary and alternative medicine approaches have been utilized to treat IBD. However, chronic inflammatory diseases are not medically curable. Hence, potent anti-inflammatory therapeutic agents are urgently warranted. Melatonin has emerged as a potent anti-inflammatory and neuroprotective candidate. Although, it's therapeutic efficacy is compromised due to less solubility and rapid clearance. Hence, we have synthesized melatonin loaded chitosan nanoparticle (Mel-CSNPs) to improve drug release profile and evaluate its in-vitro and in-vivo therapeutic efficacy. Mel-CSNPs exhibited better anti-inflammatory response in an in-vitro and in-vivo IBD model. Significant anti-inflammatory activity of Mel-CSNPs is attributed to nitric oxide (NO) reduction, inhibited nuclear translocation of NF-kB p65 and reduced IL-1ß and IL-6 expression. In-vivo biodistribution study has shown a good distribution profile. Effective in-vivo therapeutic efficiency of Mel-CSNPs has been confirmed with reduced disease activity index parameters and inhibited neutrophilic infiltration. Histological evaluation has further proved the protective effect of Mel-CSNPs by preventing crypt damage and immune cells infiltration against Dextran Sodium Sulphate induced insults. Immuno-histochemical analysis has confirmed anti-inflammatory action of Mel-CSNPs with reduction of inflammatory markers, Nitric Oxide Synthase-2 (NOS2) and Nitro-tyrosine. Indeed, this study divulges anti-inflammatory activity of Mel-CSNPs by improving the therapeutic potential of melatonin.

Genistein nanoformulation promotes selective apoptosis in oral squamous cell carcinoma through repression of 3PK-EZH2 signalling pathway.

BACKGROUND: Overexpression of polycomb protein contributes to epigenetic repression in oral squamous cell carcinoma (OSCC) ensuing in poor prognosis and aggressive phenotype. Several plant-based compounds could help prevent epigenome alteration and cancer progression, but their low bioavailability limits their therapeutic activity. HYPOTHESIS: In this study, we have synthesized genistein nanoformulation (GLNPs) and evaluated its epigenetic regulation mechanism for selective apoptosis induction in OSCC. METHODS: Lactalbumin was used to prepare nanoformulation of Genistein. The mechanism of epigenetic regulation and selective apoptosis by Genistein loaded nanoparticles was studied in OSCC cell line JHU011 and fibroblast cell line L929 using immunofluorescence, Western blotting and ChIP-qPCR assay. RESULTS: We have found that GLNPs treatment selectively induced apoptosis in OSCC compared to the normal fibroblast cells. This selective effect in OSCC is achieved through enhanced reactive oxygen species (ROS) generation followed by Bax mitochondrial translocation and caspase 3 activation. Further, GLNPs induced withdrawal of epigenetic transcription repression through concurrent downregulation of the polycomb group proteins (PcG) Bmi 1 and EZH2 along with their successive targets, UbH2AK119 and H3K27me3, which have immense therapeutic implications in the treatment of OSCC. Last, we have established that GLNPs regulate EZH2expression through proteasomal mediated degradation and 3PK inhibition; 3PK protein was found physically linked with EZH2 protein and its promoter region (-1107 to -1002). This event indicates that 3PK might play some crucial role in EZH2 expression and epigenetic control of OSCC. Moreover, the formulation showed improved biodistribution, aqueous dispersibility and enhanced biocompatibility In-vivo. CONCLUSIONS: These results provide evidence that GLNPs may withdraw epigenetic transcriptional repression and selectively induce apoptosis in human oral squamous cell carcinoma.