Nanoparticles for Targeting Intratumoral Hypoxia: Exploiting a Potential Weakness of Glioblastoma.

Extensive hypoxic regions are the daunting hallmark of glioblastoma, as they host aggressive stem-like cells, hinder drug delivery and shield cancer cells from the effects of radiotherapy. Nanotechnology could address most of these issues, as it employs nanoparticles (NPs) carrying drugs that selectively accumulate and achieve controlled drug release in tumor tissues. Methods overcoming the stiff interstitium and scarce vascularity within hypoxic zones include the incorporation of collagenases to degrade the collagen-rich tumor extracellular matrix, the use of multistage systems that progressively reduce NP size or of NP-loaded cells that display inherent hypoxia-targeting abilities. The unfavorable hypoxia-induced low pH could be converted into a therapeutical advantage by pH-responsive NPs or multilayer NPs, while overexpressed markers of hypoxic cells could be specifically targeted for an enhanced preferential drug delivery. Finally, promising new gene therapeutics could also be incorporated into nanovehicles, which could lead to silencing of hypoxia-specific genes that are overexpressed in cancer cells. In this review, we highlight NPs which have shown promising results in targeting cancer hypoxia and we discuss their applicability in glioblastoma, as well as possible limitations. Novel research directions in this field are also considered.

Repositioning metformin in cancer: genetics, drug targets, and new ways of delivery.

After sitting many years on the shelves of drug stores as a harmless antidiabetic drug, metformin comes back in the spotlight of the scientific community as a surprisingly effective antineoplastic drug. Metformin targets multiple pathways that play pivotal roles in cancer progression, impacting various cellular processes, such as proliferation, cell death, metabolism, and even the cancer stemness features. The biomolecular characteristics of tumors, such as appropriate expression of organic cation transporters or genetic alterations including p53, K-ras, LKB1, and PI3K may impact metformin's anticancer efficiency. This could indicate a need for tumor genetic profiling in order to identify patients most likely to benefit from metformin treatment. Considering that the majority of experimental models suggest that higher, supra-clinical doses of metformin should be used in order to obtain an antineoplastic effect, new ways of drug delivery could be developed, such as metformin-loaded nanoparticles or incorporation of metformin into microparticles used in transarterial chemoembolization, with the aim of obtaining higher intratumoral drug concentrations and a targeted therapy which will ultimately maximize metformin's efficacy.

The role of depression and neuroimmune axis in the prognosis of cancer patients.

New exciting research in psycho-oncology has shed light on the mechanisms by which biobehavioral signaling in cancer interplays with the neuroimmune axis, as well as on the progression and mortality of cancer patients. Cancer and cancer therapy can collectively result in inflammation and cytokine production, which have been associated with occurrence of depression. Conversely, depression supports a chronic activated hypothalamopituitary-adrenal axis (HPA) and further determines cortisol and adrenal disturbances, as well as immune dysfunction and increased cytokine production. Through these processes, depression is associated with a worse cancer outcome. New treatment strategies which counter the aberrant pathways between depression and cancer, such as drugs that target cytokines, pro-inflammatory signaling, neuroendocrine, metabolic pathways and sympathetic activation, might disrupt important vehicles for cancer progression. In this review, we emphasize the major pathways that link inflammation, depression and immunity, in order to highlight potential therapeutic strategies which may become of paramount importance to those depressed individuals with cancer that have a higher risk for developing a more aggressive disease.

Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells.

PURPOSE: Glioblastoma stem cells (GSCs), responsible for the dismal disease prognosis after conventional treatments, are driven by overactive signaling pathways, such as PI3K/ AKT/mTOR and RAS/RAF/MAPK. The objective of our study was to target in vitro-GSCs by combining metformin (Met) as a mTOR inhibitor, with sorafenib (Soraf) as a RAF inhibitor. METHODS: GSCs cultured under basal conditions were treated with Met, temozolomide (TMZ), Soraf, Met+TMZ and Met+Soraf; as untreated arm served as control. At 4 hrs of drug exposure, we measured the level of reactive oxygen species (ROS) by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, apoptosis by prodium iodide (PI)-V Annexin staining and efflux pump activity by using the fluorescent dye rhodamine 123. At 24 hrs, we measured cell proliferation by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and malondialdehyde (MDA) levels. MTT results were compared with corresponding measurements on cultures of non-stem glioblastoma cells and osteoblasts. RESULTS: Met+Soraf exerted the highest antiproliferative effects in GSCs and non-stem glioblastoma cells (p<0.001). Both Met and Soraf monotherapy exhibited a selective cytotoxic effect on GSCs (p<0.001), while no effect was detected on non-stem glioblastoma cells (p>0.05). Soraf, but not Met, impacted the proliferation of normal cells. Soraf displayed synergism with Met in producing high levels of ROS, decreasing efflux pump activity and generating the highest apoptotic rates when compared to either drug alone (p<0.001). CONCLUSION: GSCs were highly sensitive to the combination of Met and Soraf which reduced cell proliferation, increased oxidative stress, inhibited efflux pump activity and ultimately killed GSCs. We strongly believe that these results warrant further in vivo exploration.

The role of the pathology department in the preanalytical phase of molecular analyses.

After introducing the new molecules for the treatment of patients with tumoral pathology, the therapeutical decision will be taken depending on the molecular profile performed upon the harvested tissues. This major modification makes the molecular and morphological analysis an essential part in the clinical management of patients and the pathologist plays an important role in this process. The quality and reproducibility of the results are imperative today and they depend on both the reliability of the molecular techniques and the quality of the tissue we use in the process. Also, the genomics and proteomics techniques, used increasingly often, require high-quality tissues, and pathology laboratories play a very significant role in the management of all phases of this process. In this paper the parameters which must be followed in order to obtain optimal results within the techniques which analyze nucleic acids and proteins were reviewed.

Nanopharmacology in translational hematology and oncology.

Nanoparticles have displayed considerable promise for safely delivering therapeutic agents with miscellaneous therapeutic properties. Current progress in nanotechnology has put forward, in the last few years, several therapeutic strategies that could be integrated into clinical use by using constructs for molecular diagnosis, disease detection, cytostatic drug delivery, and nanoscale immunotherapy. In the hope of bringing the concept of nanopharmacology toward a viable and feasible clinical reality in a cancer center, the present report attempts to present the grounds for the use of cell-free nanoscale structures for molecular therapy in experimental hematology and oncology.

Metformin associated with photodynamic therapy--a novel oncological direction.

The aim of our study was to assess the effect of the combined treatment of Metformin (Metf) and 5, 10, 15, 20-tetra-sulfophenyl-porphyrin (TSPP)-mediated photodynamic therapy (PDT) on an in vivo tumour model. Wistar male rats were divided in 6 groups: group 1, treated with TSPP; groups 2 and 4 treated with TSPP and Metf, respectively, and irradiated 24h thereafter; group 3 was treated with Metf and the last two groups received the combined treatment, Metf administered prior (group 5) or after (group 6) irradiation. 72 h from the start of the treatment, tumour tissue was sampled for the investigation of oxidative and nitrosative stress. The apoptotic rate, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expressions and matrix metalloproteinases activities were also quantified. Malondialdehyde and glutathione levels were significantly elevated in the groups treated with combined therapy (p<0.05). Metf associated with TSPP-PDT reduced iNOS and COX-2 expressions and enhanced nitrotyrosine levels in both therapeutic regimens. Peroxynitrate formation and its cytotoxic effect on tumour cells were related to an elevated index of apoptosis and necrosis. Moreover, MMP-2 activity reached a minimum in the groups which received combined therapy. Our results confirmed that the association of Metf with PDT might prove a new and promising oncological approach.