EMERGING GAMUT OF CARDIOVASCULAR NANOMEDICINE: FUTURE IS BRIGHT

The aim of cardiovascular nanomedicine- CVN is to reduce off-target toxicity issues with therapeutic selectivity to the heart .The lipophilic barrier of the cellular membranes should be circumvented to deliver cargo inside the cell. Lipidbased NPs, which show low side effects and greater ability to passively accumulate at tissues with higher vascular permeability (enhanced permeation rate), have been largely used since the earlier times of cardiovascular nanomedicine-CVN. Polymeric NPs, silica NPs, carbon nanotubes, polymeric micelles, quantum dots, nanobers and nanocrystals represent other examples of nano-formulations for controlled drug delivery. NP-loaded drugs are expected to be protected from systemic degradation, show reduced toxicity and immunogenicity, possess ameliorated pharmacokinetics and increased half-life and exhibit increased bioavailability and precise bio distribution. Nanodrug formulations are expected to enhance selective delivery to the site of interest and benet from a lower clearance from the body. Nanotechnology represents a convergent discipline in which the margins separating research areas, such as chemistry, biology, physics, mathematics and engineering become blurred with the much needed emergence of integrated science as a new discipline.

Differential effects of selenium (Se) on normal and malignant cells treated with chemotherapy (CT) and radiation (RT).

e13583 Background: Preclinical work has demonstrated that Se compounds potentiate anticancer effects of CT and RT while reducing normal tissue toxicities. The molecular basis for the therapeutic selectivity has yet to be fully elucidated but includes modulation of intracellular glutathione (GSH) concentrations, endoplasmic reticulum (ER) stress responses, DNA repair, induction of apoptosis and cellular resistance to CT and RT. Our aim was to evaluate the dose-response relationship of the Se compound methylseleninic acid (MSA) on molecular pathways involved in the response of normal and malignant cells to CT and RT. Methods: Peripheral blood mononuclear cells (PBMC) obtained from healthy blood donors and malignant THP-1 human monocytic leukaemia cells were exposed in vitro to MSA 2.5, 5 or 15 µM in varying combinations with MSA, RT, cisplatin (Pt), doxorubicin (Dox) and cytosine arabinoside (Ara-C). GSH concentration was measured by ELISA, DNA damage and repair by COMET assay, cell viability by MTT assay and ER stress response protein expression by western blotting. Results: MSA was selectively toxic to THP-1 cells and induced a protective increase in GSH in PBMC but a decrease in high concentrations within THP-1 cells. DNA damage induced by Ara-C or Dox in the COMET assay was significantly reduced by MSA in PBMC but increased in THP-1 cells. Cell death after 2 Gy RT was increased by all doses of MSA in THP-1 cells but only by the highest dose in PBMC. The cytotoxicity of Dox and Ara-C at sublethal doses was significantly enhanced by MSA in THP-1 cells and to a lesser extent in PBMC, but MSA increased cell death from Pt only in THP-1 cells. MSA induced a protective ER stress response in PBMC exposed to Ara-C but an apoptotic response in THP-1 cells. Conclusions: MSA at clinically-relevant concentrations had a differential effect on cell survival and death responses to RT and CT with relative protection of PBMC and enhanced death of THP-1 cells. Several mechanisms mediated this therapeutic selectivity and the dose-dependence of the Se effect varied between malignant and normal cells. These assays could potentially be used in clinical trials to evaluate pharmacodynamic markers of Se effects in conjunction with CT and/or RT.

Enhancement of Imatinib-Induced Apoptosis through Catalase Activity Modulation in Imatinib-Resistant Chronic Myelogenous Leukemia Blastic Phase Cells.

Therapeutic selectivity and drug resistance are two major issues in cancer chemotherapy. Strategies to improve therapeutic selectivity largely rely on our understanding of the biological difference between cancer and normal cells, and on the availability of therapeutic agents that target biological events critical for cancer cells but not essential for normal cells. Imatinib is a selective inhibitor of the BCR-ABL tyrosine kinase activity in chronic myelogenous leukemia (CML). Resistance to imatinib is a major problem in CML patients especially in blast phase (BP). Recently, it was also described that reactive oxygen species (ROS) is another mechanism through which imatinib induces apoptosis. To evaluate the possible role of catalase (a well known ROS enzyme scavenger) in imatinib resistant cells, we studied through apoptosis/necrosis analysis, K562 cells in presence or absence of 3-amino-1,2,4-triazole (AT), an inhibitor of catalase activity. Cell apoptosis index was tested in cells labeled with Annexin V-FITC/PI and analysed by flow cytometry. In order to examine the efficacy of imatinib apoptosis induction we evaluated firstly the apoptosis index in K562 cells after 24 hours of incubation with imatinib at the less cytotoxic concentrations of 0.5, 1.0 and 5.0 μM. Induced imatinib early apoptosis, was significantly higher, (25%, p < 0.05) than control in all concentrations tested. After that, we conducted the same assay in K562 cells previously treated with aminotriazole (AT-K562) and, to address the question of whether the resistance to imatinib could also be counteracted by glutathione modulation, another ROS scavenger, K562 cells previously treated with buthionine S,R-sulphoximine (BSO) a specific inhibitor of g-glutamylcysteine synthetase the rate limiting enzyme in glutathione synthesis, were also analysed. Untreated K562 cells and those previously treated with AT or BSO were incubated with imatinib (0.5, 1.0 and 5.0 μM) and hydrogen peroxide (H2O2) 1.0 μM, a well known apoptosis inductor inhibited by catalase. Only AT-K562 cells had their apoptosis significantly enhanced when compared with non treated cells (p < 0.05). Indeed, we showed that inhibition of catalase activity in K562 cells overcame imatinib resistance in 35% of these cells in the final concentration of 0.5 μM which is equivalent to the half mean plasma concentration used in clinical practice. The present findings suggest that combination of catalase inhibitors with imatinib in lower dosage represent an emerging therapeutic concept for preventing or overcoming resistance formation in CML. Therefore, further studies with drugs clinically available that inhibit catalase activity should be explored.