Light-Controlled Simultaneous "On Demand" Release of Cytotoxic Combinations for Bimodal Killing of Cancer Cells.

In this contribution, we report a novel entirely photocontrolled nanoplatform comprising a binary mixture of pluronic copolymers capable of self-assembling into core-shell micelles and co-entrapping two photoactivatable components: a benzoporphyrin photosensitizer for photodynamic therapy (PDT) and coumarin-photocaged chemotherapeutic agent Chlorambucil (CAB). The resulting supramolecular micellar assembly is about 30 nm in diameter with a polydispersity index <0.1, stable for more than 72 h, and exhibits excellent preservation of the photochemical properties of the two photoresponsive components, even though they are confined within the same host nanocarrier. Appropriate regulation of the relative concentrations of these components makes them capable of absorbing visible light in comparable amounts, leading to effective simultaneous photogeneration of singlet oxygen and photo-triggered release of CAB. This "on demand" release of cytotoxic combinations results in amplified anticancer activity against MCF-7 human breast adenocarcinoma cells.

Tackling myelin deficits in neurodevelopmental disorders using drug delivery systems.

Interest in myelin and its roles in almost all brain functions has been greatly increasing in recent years, leading to countless new studies on myelination, as a dominant process in the development of cognitive functions. Here, we explore the unique role myelin plays in the central nervous system and specifically discuss the results of altered myelination in neurodevelopmental disorders. We present parallel developmental trajectories involving myelination that correlate with the onset of cognitive impairment in neurodevelopmental disorders and discuss the key challenges in the treatment of these chronic disorders. Recent developments in drug repurposing and nano/micro particle-based therapies are reviewed as a possible pathway to circumvent some of the main hurdles associated with early intervention, including patient's adherence and compliance, side effects, relapse, and faster route to possible treatment of these disorders. The strategy of drug encapsulation overcomes drug solubility and metabolism, with the possibility of drug targeting to a specific compartment, reducing side effects upon systemic administration.

rGO outperforms GO in generating oxidative stress and DNA strand breaks in zebrafish liver cells.

Graphene oxide (GO) and reduced graphene oxide (rGO) are both widely applicable and there is a massive production throughout the world which imply in inevitable contamination in the aquatic environment by their wastes. Nevertheless, information about their interaction at the cellular level in fish is still scarce. We investigated the metabolic activity, reactive oxygen species (ROS) production, responses of antioxidant defenses, and total antioxidant capacity (TAC) as well as oxidative stress and DNA integrity in zebrafish liver cells (ZFL) exposed to (0.001, 0.01, 0.1 and 1 µg mL-1) of GO and rGO after two exposure period (24 and 72 h). Higher ROS production and no significant changes in the antioxidant defenses resulted in lipid peroxidation in cells exposed to rGO. Cells exposed to GO increased the activity of antioxidant defenses sustaining the TAC and avoiding lipid peroxidation. Comet assay showed that both, GO and rGO, caused DNA strand breaks after 24 h of exposure; however, only rGO caused DNA damage after 72 h of exposure. The exposure to rGO was significantly more harmful to ZFL cells than GO, even at very low concentrations. The cells showed a high capacity to neutralize ROS induced by GO preventing genotoxic effects and metabolic activity, thus sustaining cell viability. The time of exposure had different impacts for both nanomaterials, GO caused more changes in 24 h showing recovery after 72 h, while cells exposed to rGO were jeopardized at both exposure times. These results indicate that the reduction of GO by removal of the oxygen functional groups (rGO) increased toxicity leading to adverse effects in the cells, even at very low concentrations.

Concentration- and time-dependence toxicity of graphene oxide (GO) and reduced graphene oxide (rGO) nanosheets upon zebrafish liver cell line.

Graphene oxide (GO) and reduced graphene oxide (rGO) are carbon-based nanomaterials that have a wide range of applicability. Therefore, it is expected that their residual traces reach the aquatic environment, accumulate, and interact with its different compartments and the biota living in them. The concentration- and time-dependency response to GO and rGO in aquatic organisms are still poorly known. In the present study, the effects of GO and rGO on zebrafish hepatocytes were investigated using in vitro assays performed with established liver cell lines from zebrafish (ZFL). GO and rGO nanosheets were applied on ZFL cells at a concentration range of 1-100 µg mL-1 for 24 and 72 h. The internalization of GO and rGO nanosheets, reactive oxygen species (ROS) production, cell viability, and cell death were evaluated. The internalization of GO increased as the concentrations of GO increased. The rGO nanosheets were smaller than GO nanosheets, and their hydrophobic characteristic favors their interaction with the cell membrane. However, the rGO nanosheets were not observed in the uptake assay. Exposure for 72 h was found to cause harmful effects in ZFL cells, causing higher ROS production in cells exposed to rGO and stopping cell replication. Nevertheless, GO did not stop cell replication, but exposed cells had higher levels of apoptosis and necrosis. After 72 h, both GO and rGO were toxic, but with different mechanisms of toxicity.

Mesoporous Silica Nanoparticles Functionalized with Amino Groups for Biomedical Applications.

The synthesis and characterization of amino-functionalized mesoporous silica nanoparticles are presented following two different synthetic methods: co-condensation and post-synthesis grafting of 3-aminopropyltriethoxysilane. The amino groups' distribution on the mesoporous silica nanoparticles was evaluated considering the aggregation state of a grafted photosensitizer (Verteporfin) by using spectroscopic techniques. The homogeneous distribution of amino groups within the silica network is a key factor to avoid aggregation during further organic functionalization and to optimize the performance of functionalized silica nanoparticles in biomedical applications. In addition, the formation of a protein corona on the external surface of both bare and amino-functionalized mesoporous silica was also investigated by adsorbing Bovine Serum Albumin (BSA) as a model protein. The adsorption of BSA was found to be favorable, reducing the aggregation phenomena for both bare and amino-modified nanoparticles. Nevertheless, the dispersant effect of BSA was much more evident in the case of amino-modified nanoparticles, which reached monodispersion after adsorption of the protein, thus suggesting that amino-modified nanoparticles can benefit from protein corona formation for preventing severe aggregation in biological media.

Discovery of a size-record breaking green-emissive fluorophore: small, smaller, HINA.

Astonishingly, 3-hydroxyisonicotinealdehyde (HINA) is despite its small size a green-emitting push-pull fluorophore in water (QY of 15%) and shows ratiometric emission response to biological relevant pH differences (pK a2 ∼ 7.1). Moreover, HINA is the first small-molecule fluorophore reported that possesses three distinctly emissive protonation states. This fluorophore can be used in combination with metal complexes for fluorescent-based cysteine detection in aqueous media, and is readily taken up by cells. The theoretical description of HINA's photophysics remains challenging, even when computing Franck-Condon profiles via coupled-cluster calculations, making HINA an interesting model for future method development.

Verteporfin based silica nanoparticle for in vitro selective inhibition of human highly invasive melanoma cell proliferation.

Photodinamic therapy (PDT) has gained an increasing interest as a new tool to treat skin cancers such as melanoma. This clinical approach take advantage from the combination of a photosensitizer and a specific light wavelength able to induce singlet oxygen production. Mesoporous silica nanoparticles (MSNs) have been widely investigated as drug nanocarriers as their structure and morphology could be customized to produce suitable nanoplatforms enabling high cargo capacity. In the present study MSNs were successfully conjugated with the second generation photosensitizer verteporfin and the resulting nanoplatform (Ver-MSNs) was tested in an in vitro PDT model as a potential tool for melanoma treatment. Ver-MSNs based PDT did not affect cell proliferation of neither a normal human keratinocyte cell line (HaCaT) or a low mestastatic melanoma cell line (A375P). On the other hand Ver-MSNs based PDT deeply affect the highly invasive SK-MEL-28 melanoma cell line behavior, as testified by the strong reduction in cell proliferation along with the dramatic change in cellular morphology, through a nanoparticle internalization dependent mechanism. In fact, experiments performed in the presence of endocytosis inhibitors (chlorpromazine and amiloride) resulted in an attenuation of Ver-MSNs based PDT induced cell death, along with a recover in cellular morphology. MSN doped with verteporfin could thus represent a promising and useful tool for PDT treatment of highly invasive melanoma.

Nanostructured Polymeric Micelles Carrying Xanthene Dyes for Photodynamic Evaluation.

It was evaluated the properties of the xanthene dyes Erythrosin B, Eosin Y and theirs Methyl, Butyl and Decyl ester derivatives as possible photosensitizers (PS) for photodynamic treatments. The more hydrophobic dyes self-aggregate in water/ethanol solutions above 70% water (vol/vol) in the mixture. In buffered water, these PS were encapsulated in Pluronic polymeric surfactants of P-123 and F-127 by two methodologies: direct addition and the thin-film solid dispersion methods. The thin-film solid method provided formulations with higher stabilities besides effective encapsulation of the PS as monomers. Size measurements demonstrated that Pluronic forms self-assembled micelles with uniform size, which present slightly negative surface potential and a spherical form detected by TEM microscopy. The ester length modulates xanthene localization in the micelle, which is deeper with the increase in the alkyl chain. Moreover, some PS are distributed into two populations: one on the corona micelle interface shell (PEO layer) and the other into the core (PPO region). Although all PS formulations show high singlet oxygen quantum yield, promising results were obtained for Erythrosin B esters with the hydrophobic P-123, which ensures their potential as drug for clinical photodynamic applications.

Adsorption of caffeic acid on titanium dioxide: a spectroscopic study.

Caffeic acid is an ortho-phenol found in vegetable tissues presenting important properties such as carcinogenesis inhibitor, anti-oxidant, anti-viral, anti-inflammatory and anti-rheumatic actions. It was observed that caffeic acid was not degraded in daylight during the adsorption on TiO(2) at pH 4.8. The adsorption fit very well to a Brunauer-Emmett-Teller isotherm equation with a monolayer coverage of 68.15 mg(CA)g(-1)(TiO2 and saturation coverage of 195.4 mg(CA)g(-1)(TiO2). A strong adsorption of caffeic acid was verified on TiO(2) for the dry solid obtained from the mixture. The Raman and IR spectroscopies revealed that the adsorption should occur through the interaction of the diphenol oxygens with contribution of CC double bond of the acrylic group, however, the carboxylic acid group did not have participation in the adsorption.