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HSV infections, both type 1 and type 2, are among the most widespread viral diseases affecting people of all ages. Their symptoms could be mild, with cold sores up to 10 days of infection, blindness and encephalitis caused by HSV-1 affecting immunocompetent and immunosuppressed individuals. The severe effects derive from co-evolution with the host, resulting in immune evasion mechanisms, including latency and growing resistance to acyclovir and derivatives. An efficient alternative to controlling the spreading of HSV mutations is the exploitation of new drugs, and the possibility of enhancing their delivery through the encapsulation of drugs into nanoparticles, such as liposomes. In this work, liposomes were loaded with a series of 2-aminomethyl- 3-hydroxy-1,4-naphthoquinones derivatives with n-butyl (compound 1), benzyl (compound 2) and nitrobenzene (compound 3) substituents in the primary amine of naphthoquinone. They were previously identified to have significant inhibitory activity against HSV-1. All of the aminomethylnaphthoquinones derivatives encapsulated in the phosphatidylcholine liposomes were able to control the early and late phases of HSV-1 replication, especially those substituted with the benzyl (compound 2) and nitrobenzene (compound 3), which yields selective index values that are almost nine times more efficient than acyclovir. The growing interest of the industry in topical administration against HSV supports our choice of liposome as a drug carrier of aminomethylnaphthoquinones derivatives for formulations of in vivo pre-clinical assays.

This work has focused on the synthesis of three nanosystems composed of superparamagnetic iron oxide nanoparticles (SPIONs) coated either with a carboxylate platinum(IV) complex (PD = cis,cis,trans-[Pt(NH3)2Cl2(HOOCCH2CH2COO)(OH)]) or with platinum(II) complex functionalized dextrans (DexPt1 = [Pt(Dex-NH2)Cl3] and DexPt2 = [Pt(Dex-NH2)(NH3)2(H2O)]). All nanosystems have shown superparamagnetic behavior. Powder X-ray diffraction (XRD) has confirmed that the SPIONs were iron oxide phase and transmission electron microscopy (TEM) has shown average size of 6 nm (M6). Characterization of the nanosystems by inductively coupled plasma atomic emission spectroscopy (ICP AES) has revealed the presence of platinum on their surface (M6@PD, 0.54 mmol g-1 of Fe and M6@CA@DexPt1-2, 0.32-1.20 mmol g-1 of Fe); infrared spectroscopy (IR) and thermogravimetric and differential thermal analyses (TG-DTA) have confirmed the presence of dextran. Furthermore, the colloidal properties of these nanosystems (M6@PD and M6@CA@DexPt1-2) have been evaluated in water and in PBS buffer. Although M6@PD has shown good colloidal dispersion in water in the pH range of 2.0-8.0, the system underwent rapid agglomeration in PBS buffer. The M6@CA@DexPt1-2 nanosystems have exhibited improved colloidal behavior both in water and in PBS, where hydrodynamic sizes were kept below 100 nm over a large pH range (2.0-12.0). Furthermore, the latter systems have displayed isoelectric points below pH 5.0 and low surface charges at pH 7.0 (ζ-potential = -10 mV) and therefore PBS did not affect their colloidal stability., The authors would like to thank the Brazilian agencies National Council for Scientific and Technological Development (CNPq: Jovens Pesquisadores em Nanotecnologia grant number 550572/2012-0 and G. B. da Silva was recipient of Science without borders fellowship grant number 279444/2013-9), Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) and Rio de Janeiro Research Foundation (FAPERJ) for financial support. M. D. Vargas and C. M. Ronconi are recipients of CNPq research fellowships. We also thank the Multiuser Laboratory of Material Characterization (http://www.uff.br/lamate/). R. Costo and M. P. Morales would like to thank NANOMAG project (EC FP-7 grant agreement number 604448) for funding. X-ray diffraction, FTIR spectroscopy and thermogravimetric and chemical analysis were carried out in the support laboratories of Instituto de Ciencia de Materiales de Madrid (ICMM/CSIC).

To successfully develop biomedical applications for magnetic nanoparticles, it is imperative that these nanoreagents maintain their magnetic properties in vivo and that their by-products are safely metabolized. When placed in biological milieu or internalized into cells, nanoparticle aggregation degree can increase which could affect magnetic properties and metabolization. To evaluate these aggregation effects, we synthesized citric acid-coated iron oxide nanoparticles whose magnetic susceptibility can be modified by aggregation in agar dilutions and dextran-layered counterparts that maintain their magnetic properties unchanged. Macrophage models were used for in vitro uptake and metabolization studies, as these cells control iron homeostasis in the organism. Electron microscopy and magnetic susceptibility studies revealed a cellular mechanism of nanoparticle degradation, in which a small fraction of the particles is rapidly degraded while the remaining ones maintain their size. Both nanoparticle types produced similar iron metabolic profiles but these profiles differed in each macrophage model. Thus, nanoparticles induced iron responses that depended on macrophage programming. In vivo studies showed that nanoparticles susceptible to changes in magnetic properties through aggregation effects had different behavior in lungs, liver and spleen. Liver ferritin levels increased in these animals showing that nanoparticles are degraded and their by-products incorporated into normal metabolic routes. These data show that nanoparticle iron metabolization depends on cell type and highlight the necessity to assess nanoparticle aggregation in complex biological systems to develop effective in vivo biomedical applications. Statement of Significance Magnetic iron oxide nanoparticles have great potential for biomedical applications. It is however imperative that these nanoreagents preserve their magnetic properties once inoculated, and that their degradation products can be eliminated. When placed in a biological milieu nanoparticles can aggregate and this can affect their magnetic properties and their degradation. In this work, we showed that iron oxide nanoparticles trigger the iron metabolism in macrophages, the main cell type involved in iron homeostasis in the organism. We also show that aggregation can affect nanoparticle magnetic properties when inoculated in animal models. This work confirms iron oxide nanoparticle biocompatibility and highlights the necessity to assess in vivo nanoparticle aggregation to successfully develop biomedical applications., José M. Rojas was supported by a JAEdoc grant co-financed by the CSIC and the European Social Fund. Laura Sanz-Ortega receives a predoctoral FPU grant (13/05037) from the Spanish Ministry of Economy and Competitiveness. Marina Talelli received a JdC post-doctoral grant (JCI-2012-13159) from the Spanish Ministry of Economy and Competitiveness. Gustavo B. da Silva was beneficiary of a sandwich-PhD grant of the Brazilian agency CNPq (Science without borders – Process: 279444/2013-9). Lucía Gutiérrez was the beneficiary of a post-doctoral grant from the AXA Research Fund and also acknowledges financial support from the Ramón y Cajal subprogram (RYC-2014-15512). This work was supported in part by grants from the Spanish Ministry of Economy and Competitiveness (SAF-2011-23639 and SAF-2014-54057-R to DFB and MAT2014-52069-R to Sabino Veintemillas-Verdaguer).

In order to understand the properties involved in the heating performance of magnetic nanoparticles during hyperthermia treatments, a systematic study of different &gamma, Fe2O3 and Fe3O4 nanoparticles has been done. High-frequency hysteresis loops at 50 kHz carried out on particles with sizes ranging from 6 to 350 nm show susceptibility &chi, increases from 9 to 40 for large particles and it is almost field independent for the smaller ones. This suggests that the applied field induces chain ordering in large particles but not in the smaller ones due to the competition between thermal and dipolar energy. The specific absorption rate (SAR) calculated from hysteresis losses at 60 mT and 50 kHz ranges from 30 to 360 W/gFe, depending on particle size, and the highest values correspond to particles ordered in chains. This enhanced heating efficiency is not a consequence of the intrinsic properties like saturation magnetization or anisotropy field but to the spatial arrangement of the particles.

Background Herpes simplex viruses (HSV) are leading causes of human infections which result in severe manifestations, especially in neonates, immunocompromised and/or transplanted individuals. Current HSV type-1 (HSV-1) resistance to standard antiviral agents is a therapeutic challenge, especially for treating immunocompromised patients. Methods Herein we describe the promising antiviral profile of three 2-aminomethyl-3-hydroxy-1,4-naphthoquinones against HSV-1 using Vero cells. Results The in silico theoretical analysis indicated that the lowest unoccupied molecular orbital (LUMO) and the conformational features of these molecules are important structural features for modulating their biological activity. Our in vitro results showed that these compounds have significant anti-HSV-1 activity comparable to acyclovir, the antiviral currently used clinically. Importantly two of them showed a lower cytotoxicity profile against Vero cells than acyclovir. The inhibitory mechanism analysis using a time-of-addition assay revealed that all compounds inhibit the late phase of lytic replication. Finally, the highest selectivity index of the first tested compound was almost twice as high as that of acyclovir. Conclusions Since resistance is still a problem for treating HSV infections, these compounds present a promising profile toward the development of new strategies for anti-HSV-1 therapy.

Herein we describe the structure–activity relationship of a large library of Mannich bases (MBs) synthesized from 2-hydroxy-1,4-naphthoquinone. In general, the compounds have shown high to moderate activity against the HL-60 (promyelocytic leukaemia) cell line with IC50 = 1.1–19.2 μM. Our results suggest that the nature of the aryl moiety introduced in the structure of MBs by the aldehyde component is crucial to the cytotoxicity, and although the group originated from the primary amine has a lesser influence, aromatic ones were found to suppress the activity. Thus, MBs derived from salicylaldehydes or 2-pyridinecarboxaldehyde and aliphatic amines are the most active compounds. A satisfactory correlation of the EpIIc versus IC50 (μM) in dimethylsulfoxide was observed. The most cytotoxic MBs (Series a–c, derived from salicylaldehydes) showed the least negative EpIIc values. Noteworthy, however, Series d (derived from 2-pyridinecarboxaldehyde) did not follow this correlation. They exhibited both the lowest IC50 and the most negative EpIIc values, thus suggesting that other factors also influence the cytotoxicity of the MBs, such as lipophilicity, electronic distribution and hydrogen bonding.

[Background] A deeper knowledge on the effects of the degradation of magnetic nanoparticles on their magnetic properties is required to develop tools for the identification and quantification of magnetic nanoparticles in biological media by magnetic means., [Methods] Citric acid and phosphonoacetic acid-coated magnetic nanoparticles have been degraded in a medium that mimics lysosomal conditions. Magnetic measurements and transmission electron microscopy have been used to follow up the degradation process., [Results] Particle size is reduced significantly in 24 h at pH 4.5 and body temperature. These transformations affect the magnetic properties of the compounds. A reduction of the interparticle interactions is observed just 4 h after the beginning of the degradation process. A strong paramagnetic contribution coming from the degradation products appears with time., [Conclusions] A model for the in vivo degradation of magnetic nanoparticles has been followed to gain insight on the changes of the magnetic properties of iron oxides during their degradation. The degradation kinetics is affected by the particle coating, in our case being the phosphonoacetic acid-coated particles degraded faster than the citric acid-coated ones., LG is the beneficiary of a postdoctoral grant from the AXA Research Fund and GBdS, of a sandwich-PhD grant from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq – Brazil). This work was also supported by the 7th framework programme of the European Commission Directorate-General for Research and Innovation (Nanomag 604448). X-ray diffraction, FTIR spectroscopy, and thermogravimetric and chemical analysis were carried out in the support laboratories of Instituto de Ciencia de Materiales de Madrid (CSIC).

Bovine herpesvirus type 5 (BoHV-5) is an etiologic agent of meningoencephalitis in cattle. The aim of this study was to evaluate the antiviral potential of a series of synthetic Mannich bases derived from lawsone and to investigate at which stage of the BoHV-5 replicative cycle the compounds might be acting. The most potent and selective inhibitor exhibited CC50 and EC50 values of 1867 μM ± 8.3 and 3.8 μM ± 1.2, respectively (ACV: 989 μM ± 2 and 166 μM ± 2, respectively).

The first examples of platinum(II) complexes of 3-(aminomethyl)naphthoquinone Mannich bases have been synthesised and their crystal structures are described. Neutral and charged complexes have been obtained, fully characterised and their cytotoxic activities have also been investigated. 3-[(R(1)-amino)(pyridin-2-yl)methyl]-2-hydroxy-1,4-naphthoquinones (R(1) = n-Bu, HL1; Bn, HL2; furfuryl, HL3; n-heptyl, HL4 and n-decyl, HL5) coordinate to platinum(II) through the two nitrogen atoms. The neutral complexes cis-[Pt(HL)Cl(2)] 1a-5a are analogous to cisplatin with the bidentate ligand HL and two chlorine atoms occupying cis positions. In the charged complexes cis-[Pt(L(-))(NH(3))(2)]NO(3)1b-5b the deprotonated form of the ligand L(-) also coordinates via the nitrogen atoms, and the other two positions around the platinum(II) ion are completed with NH(3) ligands. The cytotoxic activities of all compounds have been tested for six different cancer cell lines: MDA-MB-435 (melanoma), HL-60 (promyelocytic leukaemia), HCT-8 (colon), SF-295 (brain), OVCAR-8 (ovary) and PC-3 (prostate). Proligands HL4 and HL5 have exhibited high activity against HL-60 (IC(50) = 1.9 and 3.8 μmol L(-1), respectively), HCT-8 (IC(50) = 1.6 and 1.7 μmol L(-1), respectively) and SF-295 (IC(50) = 1.1 and 1.7 μmol L(-1), respectively). The chlorido complexes 1a-5a have shown high to moderate cytotoxic activities, complex 4a (R(1) = n-heptyl) being more active than proligand HL4 against melanoma (IC(50) = 6.4 and40 μmol L(-1), respectively) and more active than cisplatin against all tested cell lines. Among the amine charged complexes only 4b and 5b have exhibited significant cytotoxic activity against the tested cell lines, although they were only moderately active against the PC-3 cell line (IC(50) = 29.9 and 15.6 μmol L(-1), respectively). In general the compounds with the longest carbon chains (R(1) = n-heptyl and n-decyl) have exhibited the highest activities.