Search

The search for novel chemotherapeutic agents and approaches to cancer treatment is an active research field stimulated by the discovery of new biological targets and by the possibility of obtaining new drugs without serious and undesirable side effects. Several anticancer agents have been developed so far based on different mechanism of action; despite this, intercalator agents still remain an interesting class of molecules to focus on. In particular, in the literature there are several examples of Naphthalimmide and 1,4,5,8-Naphtalentetracaboxylic diimide derivatives as intercalating and anticancer agents. It is well-known that, at physiological pH, protonated polyamines interact strongly with the phosphate residues of DNA. Therefore, the inclusion of these basic functionalities, on an intercalating moiety, may improve the interaction with DNA structure. Recently, we reported on the design and synthesis of substituted Naphtalen(di)immides as anticancer agents (1). Among the several developed compounds, 1 and 2 were the most interesting derivatives showing the ability to bind DNA, trigger caspase activation, cause accumulation of p53 protein, down-regulate the survival kinase AKT, cause a decrease of ERK1/2 and, inhibit ERK’s phosphorylation. The aim of the present work is to further investigate the promising biological profile of 1 and 2, and the role of the 2-methoxy substituents on the benzyl moieties, For this purpose several analogues, with different substituents on the two aromatic rings, were synthesized evaluated for their antiproliferative activity. This research was supported by grants from MUR, the University of Bologna, and Polo Scientifico-Didattico di Rimini. We thank the National Cancer Institute for the anticancer assays. (1) Tumiatti, V., et al. J. Med. Chem. 2009, 52, 7873-7.

Chlorhexidine (CHX) is a bis-bis-guanide widely used to treat skin and mucosa infections, efficient against a wide range of microbial species. The aim of this work was to design and evaluate gels containing CHX associated to mucoadhesive and swelling agents, such as CMC, HPMC, HPC and Poloxamer, to control both the residence time in the oral cavity and the release rate of the drug. Three tests were carried out to evaluate the controlled release of CHX from the gels; also the interaction polymer-mucin by means of viscosimetric measurements was tested. The same tests were also applied to a commercial formulation, Corsodyl gel® for comparison.

Sodium ascorbate, at millimolar concentrations, induces apoptosis of neuroblastoma cell lines in vitro. The caspase cascade is activated following treatment with ascorbate, as assessed by fluorescence assay with the pan-caspase substrate z-VAD-fmk. Sodium ascorbate down-modulates CD71 (transferrin receptor) membrane expression, although overall (membrane and cytoplasmic) expression is not significantly affected. Since NB cells are strongly dependent on iron supply, it is likely that redistribution of CD71 within cellular compartments interferes with a correct iron metabolism, giving rise to apoptosis. The time- and dose-dependence, as well as the extent of the effects of sodium ascorbate on NB cells is likely to depend upon differences in its catabolism and the intensity of CD71 recycling and membrane re-expression among the different NB cell lines. Due to its lack of overt toxicity, high-dose sodium ascorbate can be considered as an additional drug in the traditional therapeutic schedules for NB.

Naphazoline (NPH) is a vasoconstrictor agent, and reduces inflammation and swelling of the conjunctiva. The effect of naphazoline arises from its direct binding to adrenergic receptor sites on unstriated muscle cells in the blood vessels. A modern tendency of ocular delivery is represented by systems capable of both lengthening pre-cornea1 contact time and slowing the release of drug from the vehicle. There is considerable logic in attempting the retention of the delivery systems in the front of the eye, because of the enormous loss of an instilled drug solution that typically occurs soon after administration. In this study we present a low viscous formulation with mucoadesive properties to control the residence time in pre-corneal area and the release and permeation rates of drug.

The anti-tumour activity of fatty acids has been extensively investigated upon a wide range of tumour cell lines. The fatty alcohols activity, on the contrary, has been scarcely studied. It has been reported that the alcohols are more active than the corresponding acids and that unsaturated fatty alcohols inhibits DNA synthesis and growth of Erlich ascites tumour cells more efficiently than their saturated analogs. The interest in oleyl alcohol arises from dietary effects of essential fatty acids and alcohols and their involvement in cardiovascular disorders and cancers. Moreover, oleyl alcohol (cis-9-octadecen-1-ol) was reported to be one of the most active among a series of saturated and unsaturated fatty alcohols and the presence of a single insaturation makes it more stable to oxidation than multiple unsaturations. Since activity is proportionally correlated to the fatty alcohol intracellular accumulation, which depends on the balance of their hydrophobic/ hydrophilic properties and, primarily, on their ability to be solubilized in aqueous media, in this work we evaluate the possibility to improve oleyl alcohol aqueous solubilization by complexation with non toxic amphiphilic polymers self-assembling in aqueous environment. The aim is to develop safe parenteral formulations holding oleyl alcohol solubilization levels suitable to elicit therapeutic responses. The amphiphilic polymers were prepared by partial substitution of polyvinyl alcohol with oleyl chains through a succinyl spacer, in the hypothesis, previously demonstrated in an almost similar situation concerning doxorubicin [1, 2], that structural similarities should improve mutual affinity between the solubilizer and the solubilizing agent.

Naphazoline (NPH) is a vasoconstrictor agent, and reduces inflammation and swelling of the conjunctiva. The effect of naphazoline arises from its direct binding to adrenergic receptor sites on unstriated muscle cells in the blood vessels. A modern tendency of ocular delivery is represented by systems capable of both lengthening pre-cornea1 contact time and slowing the release of drug from the vehicle. There is considerable logic in attempting the retention of the delivery systems in the front of the eye, because of the enormous loss of an instilled drug solution that typically occurs soon after administration. In this study we present a low viscous formulation with mucoadesive properties to control the residence time in pre-corneal area and the release and permeation rates of drug.

Poly-vinylalcohol (PVA), conjugated with oleoyl (PVA-OL) or linoleoyl (PVA-LINOL) chain forms polymer micelles able to solubilize retinoic acid (ATRA). The functional properties of the solubilized systems were evaluated by dynamic light scattering (DLS) and correlated to the physico-chemical characteristics of ATRA and polymer solution. The mean diameter of the aggregates and the counts per second are indicative of the total micelle volume (TMV), used to predict the complexing ability of the amphiphilic micelles towards the hydrophobic drug. TMV was found higher for PVA-LINOL than for PVA-OL and increased at increasing polymer concentration. Increase of temperature increased TMV of both polymers. The effect of filtration on the nature of the final systems was also discussed. Changes, after filtration, was attributed to fragmentation occurring, when aggregates of size, larger than the filter pores, are forced to pass through these pores: aging of the systems in some cases again drives up the formation of larger aggregates. Thermodynamic entities for retinoic acid solubilization into polymer micelles were calculated, assuming that the process is a partition between the bulk solution and the hydrophobic core of micelles.

The dark brown mixture resulting from the autooxidation of catechinic acid (CA) (AOCA) has been reported to possess antiviral activity against Herpes Simplex Virus 1 and 2 (HSV-1 and HSV-2). Unfortunately, the constituents of AOCA were not separated or identified and the compound(s) responsible for AOCA’s antiviral activity remained unknown until recently. Colorless 4-hydroxy benzoic acid (4-HBA) has been reported as the main constituent (75%) of AOCA, and as being responsible for its antiviral activity. The findings seem not to be reliable because of the existence in the literature of very different findings, the high concentration that was attributed to the supposed 4-HBA in the dark mixture, and the insufficient or inaccurately interpreted analytical experiments reported in the study identifying 4-HBA in AOCA. Of particular concern is the lack of AOCA chromatograms highlighting a peak attributable to 4-HBA, using commercial 4-HBA as a standard, and investigations concerning the antiviral activity of marketed 4-HBA. Therefore, in this study, to verify the exactness of the recent reports, we prepared CA from catechin and AOCA from CA, and the absence of 4-HBA in the mixture was first established by thin-layer chromatography (TLC), and then was confirmed by UHPLC–MS/MS, UV–Vis, and ATR–FTIR analyses. For further confirmation, the ATR–FTIR spectral data were processed by principal components analysis (PCA), which unequivocally established strong structural differences between 4-HBA and AOCA. Finally, while the antiviral effects of AOCA against HSV-2 were confirmed, a commercial sample of 4-HBA was completely inactive.

Objectives The major limitation to successful chemotherapy of neuroblastoma (NB) is the toxicity and the poor bioavailability of traditional drugs. Methods We synthesised an amphiphilic dextrin derivative (DX-OL) able to host fenretinide (4-HPR) by complexation. In this study, we have investigated the effects of 4-HPR-loaded amphipilic dextrin (DX-OL/4-HPR) in comparison with 4-HPR alone both in vitro on human NB cells and in vivo in pseudometastatic NB models. The haemolysis assay was used as a measure of the potential damage caused by the pharmaceutical formulation in vivo. Pharmacokinetic experiments were performed to assess drug plasma levels in mice treated with free or complexed 4-HPR. Key findings DX-OL/4-HPR exerted a more potent cytotoxic activity on NB cells. Complexed 4-HPR significantly increased the proportion of sub-G1 cells with respect to free 4-HPR. Dextrin derivatives showed no haemolytic activity, indicating their suitability for parenteral administration. DX-OL/4-HPR increased the lifespan and the long-term survival of treated mice over controls. The analysis of drug plasma levels indicates that the complexed drug has a higher AUC due to a reduced clearance from the blood. Conclusions Our data suggest that DX-OL/4-HPR is an injectable formulation that is able to improve drug aqueous solubility and bioavailability.

This study relates to the preparation of a series of amphiphilic dextrins and their evaluation as complexing agents for anti-tumor hydrophobic drugs such as fenretinide, paclitaxel, etoposide, and camptothecin. The amphiphilic dextrins were obtained by conjugation of low molecular weight dextrin (average molecular weight 1670, average polymerization degree 9.33 glucose monomer) with hydrocarbon chains at substitution degree of about 0.1 mole hydrocarbon chain per mole of glucose monomer, as confirmed by 1H-NMR spectra. The conjugates were highly soluble in water and dissolved with formation of nano-aggregates endowed with hydrophobic inner cores able to host hydrophobic drugs by complexation. Complexation raised hydrophobic drugs aqueous solubility; the best results were obtained with fenretinide. Solid complexes with fenretinide were prepared by using three different approaches: the kneading method, the co-solubilisation method, and the co-precipitation method. Kneading method provided the complexes endowed with the best functional properties. Thermogravimetric analysis on solid samples suggested a notable thermal stability up to 300 degrees C for both the conjugated dextrins and the solid complexes. In differential scanning calorimetry profiles no significant differences were observed among amphiphilic dextrins and complexed drug, indicating that the guest molecule exists in an amorphous state in the solid matrices. Particle size analysis confirmed the dimensional suitability of the complexes for parenteral administration. Moreover, sustained drug release, in vitro, has been observed from all the complexes analyzed. Regarding the biological effects, the cytotoxicity of complexed fenretinide towards HTLA-230 neuroblastoma cell line was always higher than the free drug, suggesting that complexation increased drug bioavailability. These findings, taken together, indicated that these biodegradable, self-assembling dextrin conjugates may be regarded as new potential complexing agents for hydrophobic drugs and, in particular, for fenretinide, to increase drug solubility, bioavailability, and thus therapeutic efficacy.