Barbara Mognetti

The application of nanosponges to cancer drug delivery

Introduction: The design of new nanocarriers as a strategy for the delivery of anti-cancer drugs offers a potential platform to overcome some limitations of current clinical treatments and to achieve targeted release into tumour tissues. Cyclodextrin-based nanosponges are a novel nanosized delivery system composed of hyper-cross-linked cyclodextrins connected in a three-dimensional network. They form porous nanoparticles with sizes lower than 500 nm, spherical shape and negative surface charge. They show a good capacity for incorporating small molecules, macromolecules, ions and gases within their structure. Area covered: This review will describe some applications of cyclodextrin-based nanosponges as carriers for anticancer drugs. Recent smart nanosponges, able to be responsive to an external stimulus, will be also discussed. In vitro and in vivo experimental results, obtained with currently used molecules, such as paclitaxel, doxorubicin, 5-fluorourcil and tamoxifen, will be shown. Expert opinion: Cyclodextrin-based nanosponges can be considered a challenging technology for the development of innovative formulations, suitable for various administration routes for anti-cancer drugs.

Bone marrow mesenchymal stem cells increase motility of prostate cancer cells via production of stromal cell-derived factor-1α

Prostate cancer frequently metastasizes to the bone, and the interaction between cancer cells and bone microenvironment has proven to be crucial in the establishment of new metastases. Bone marrow mesenchymal stem cells (BM‐MSCs) secrete various cytokines that can regulate the behaviour of neighbouring cell. However, little is known about the role of BM‐MSCs in influencing the migration and the invasion of prostate cancer cells. We hypothesize that the stromal cell‐derived factor‐1α released by BM‐MSCs may play a pivotal role in these processes. To study the interaction between factors secreted by BM‐MSCs and prostate cancer cells we established an in vitro model of transwell co‐culture of BM‐MSCs and prostate cancer cells DU145. Using this model, we have shown that BM‐MSCs produce soluble factors which increase the motility of prostate cancer cells DU145. Neutralization of stromal cell‐derived factor‐1α (SDF1α) via a blocking antibody significantly limits the chemoattractive effect of bone marrow MSCs. Moreover, soluble factors produced by BM‐MSCs greatly activate prosurvival kinases, namely AKT and ERK 1/2. We provide further evidence that SDF1α is involved in the interaction between prostate cancer cells and BM‐MSCs. Such interaction may play an important role in the migration and the invasion of prostate cancer cells within bone.

Impact of cell division on intracellular uptake and nuclear targeting with fluorescent SiC-based nanoparticles

Semiconductor nanoparticles (NPs) became important and wide-used tool for cell imaging because of their unique remarkable properties. Nevertheless, all previous investigations in this area were done on proliferating cells. For the first time, this work demonstrates strong influence of cell active proliferation/contact inhibition of proliferation on uptake of NPs. In addition, we show that cell division plays key-role in penetration of silicon carbide based NPs (SiC NPs) inside the cell nucleus. This may very likely concern other types of NPs able to reach the cell nuclei. In particular, observed effect of cell division gives perspectives for future selective cancer treatment with NPs.

A DNA Vaccine against ERBB2 Impairs Chemical Carcinogenesis in Random-Bred Hamsters

Vaccines against oncoantigens halt early neoplastic lesions in several cancer-prone, genetically engineered mouse models, whereas their ability to prevent chemical carcinogenesis has not been explored. This is a significant issue, as exposure to chemical mutagens is responsible for a substantial percentage of cancers worldwide. Here, we show that the archetypal oncoantigen ERBB2 is transiently overexpressed in Syrian hamsters during the early stages of 7,12-dimethylbenz[α]anthracene (DMBA)-induced oral carcinogenesis. Repeated DNA vaccinations against ERBB2 significantly reduce the number, size, and severity of oral lesions in a manner directly proportional to the anti-ERBB2 antibody response. These results support the prospects of vaccines as a fresh strategy in the management of individuals at risk for exposure to defined carcinogenic agents. Cancer Prev Res; 4(7); 994–1001. ©2011 AACR.

Anti-HER-2 DNA vaccine protects Syrian hamsters against squamous cell carcinomas.

This paper illustrates the efficacy of DNA vaccination through electroporation in the prevention of oral transplantable carcinoma in Syrian hamsters. At 21 and 7 days before tumour challenge, 19 hamsters were vaccinated with plasmids coding for the extracellular and transmembrane domains of rat HER-2 receptor (EC-TM plasmids), whereas 19 control hamsters were injected intramuscularly with the empty plasmid. Immediately following plasmid injection, hamsters of both groups received two square-wave 25 ms, 375 V cm−1 electric pulses via two electrodes placed on the skin of the injection area. At day 0, all hamsters were challenged in the submucosa of the right cheek pouch with HER-2-positive HCPC I cells established in vitro from an 7,12-dimethylbenz[a]anthracene-induced oral carcinoma. This challenge gave rise to HER-2-positive buccal neoplastic lesions in 14 controls (73.37%), compared with only seven (36.8%, P<0.0027) vaccinated hamsters. In addition, the vaccinated hamsters displayed both a stronger proliferative and cytotoxic response than the controls and a significant anti-HER-2 antibody response. Most of the hamsters that rejected the challenge displayed the highest antibody titres. These findings suggest that DNA vaccination may have a future in the prevention of HER-2-positive human oral cancer.

Post‐ischaemic activation of kinases in the pre‐conditioning‐like cardioprotective effect of the platelet‐activating factor

Aim:  Platelet‐activating factor (PAF) triggers cardiac pre‐conditioning against ischemia/reperfusion injury. The actual protection of ischaemic pre‐conditioning occurs in the reperfusion phase. Therefore, we studied in this phase the kinases involved in PAF‐induced pre‐conditioning.

The lack of effect of sotalol in short QT syndrome patients carrying the T618I mutation in the KCNH2 gene

Carla Giustetto, MD, Chiara Scrocco, MD, Daniela Giachino, MD, PhD, Claudio Rapezzi, MD, Barbara Mognetti, PhD, Fiorenzo Gaita, MD From the Division of Cardiology, University of Torino, Department of Medical Sciences, Città della Salute e della Scienza Hospital, Torino, Italy, Medical Genetics, University of Torino, Department of Clinical and Biological Sciences, Torino, Italy, Medical Genetics San Luigi University Hospital, Orbassano, Italy, Institute of Cardiology, University of Bologna, and S. Orsola-Malpighi Hospital, Bologna, Italy, and Pharmacology Unit, University of Torino, Department of Clinical and Biological Sciences, Torino, Italy.

Bradykinin in asthma: modulation of airway inflammation and remodelling

Abstract Bradykinin, a pro‐inflammatory molecule, and its related peptides have been studied for their effects on acute reactions in upper and lower airways, where they can be synthesised and metabolized after exposure to different stimuli including allergens and viral infection. Bradykinin B1 and B2 receptors are constitutively expressed in the airways on several residential and/or immune cells. Their expression can also be induced by inflammatory mediators, usually associated with eosinophil and neutrophil recruitment, such as IL‐4, IL‐13, TNF‐&agr;, IL‐6 and IL‐8, via intracellular MAPK and NF‐&kgr;B signalling. In turn, the latters up‐regulate both bradykinin receptors. Bradykinin activates epithelial/endothelial and immune cells, neurons and mesenchymal cells (such as fibroblasts, myofibroblasts and smooth muscle cells), which are implicated in the development of airway chronic inflammation, responsiveness and remodelling (a major feature of severe asthma). This review highlights the role of bradykinin and its receptors in respect to chronic inflammatory response involving eosinophils/neutrophils and to vascular/matrix‐related airway remodelling in asthmatic airways. This scenario is especially important for understanding the mechanisms involved in the pathogenesis of eosinophilic and/or neutrophilic asthma and hence their therapeutic approach.

Regulation of breast cancer induced bone disease by cancer-specific IKKβ

NFκB is implicated in breast cancer bone metastasis and skeletal remodelling. However, the role of IKKβ, a key component of the canonical NFκB pathway, in the regulation of breast cancer osteolytic metastasis has not been investigated. Here, we describe the cancer-specific contribution of IKKβ to bone metastasis, skeletal tumour growth and osteolysis associated with breast cancer. IKKβ is highly expressed in invasive breast tumours and its level of expression was higher in patients with bone metastasis. IKKβ overexpression in parental MDA-MD-231 breast cancer cells, promoted mammary tumour growth but failed to convey osteolytic potential to these cells in mice. In contrast, IKKβ overexpression in osteotropic sub-clones of MDA-MB-231 cells with differing osteolytic phenotypes increased incidence of bone metastasis, exacerbated osteolysis and enhanced skeletal tumour growth, whereas its knockdown was inhibitory. Functional and mechanistic studies revealed that IKKβ enhanced the ability of osteotropic MDA-MB-231 cells to migrate, increase osteoclastogenesis, and to inhibit osteoblast differentiation via a mechanism mediated, at least in part, by cytoplasmic sequestering of FoxO3a and VEGFA production. Thus, tumour-selective manipulation of IKKβ and its interaction with FoxO3a may represent a novel strategy to reduce the development of secondary breast cancer in the skeleton.