Antibacterial activity of fluoxetine-loaded starch nanocapsules.

This work proposes the development of a starch-based drug carrier for fluoxetine (FLX) delivery and evaluate the improvement of the drug antibacterial activity. The starch nanocapsules were prepared via interfacial polyaddition reaction presenting a core-shell morphology, based on polyurethane linkage, with a particle size in the range 250-300 nm. Furthermore, FLX-loaded nanocapsules were evaluated regarding antibacterial potential against Staphylococcus aureus (ATCC® 6538P ™) and its clinical strains of methicillin-resistant. As expected, the FLX-loaded presented lower minimum inhibitory concentration (MIC) values, in the range of 190-95 µg mL-1, against all isolated microorganisms in comparison to FLX, 255 µg mL-1. According to results, the FLX-loaded starch nanocapsules have successfully improved drug antibacterial activity, generating promising perspectives on the field of the hydrophilic drug delivery systems.

Magnetic Porous Controlled Fe3O4-Chitosan Nanostructure: An Ecofriendly Adsorbent for Efficient Removal of Azo Dyes.

In this work, chitosan/magnetite nanoparticles (ChM) were quickly synthesized according to our previous report based on co-precipitation reaction under ultrasound (US) irradiation. Besides ChM was in-depth structurally characterized, showing a crystalline phase corresponding to magnetite and presenting a spheric morphology, a "nanorod"-type morphology was also obtained after increasing reaction time for eight minutes. Successfully, both morphologies presented a nanoscale range with an average particle size of approximately 5-30 nm, providing a superparamagnetic behavior with saturation magnetization ranging from 44 to 57 emu·g-1. As ChM nanocomposites have shown great versatility considering their properties, we proposed a comparative study using three different amine-based nanoparticles, non-surface-modified and surface-modified, for removal of azo dyes from aqueous solutions. From nitrogen adsorption-desorption isotherm results, the surface-modified ChMs increased the specific surface area and pore size. Additionally, the adsorption of anionic azo dyes (reactive black 5 (RB5) and methyl orange (MO)) on nanocomposites surface was pH-dependent, where surface-modified samples presented a better response under pH 4 and non-modified one under pH 8. Indeed, adsorption capacity results also showed different adsorption mechanisms, molecular size effect and electrostatic attraction, for unmodified and modified ChMs, respectively. Herein, considering all results and nanocomposite-type structure, ChM nanoparticles seem to be a suitable potential alternative for conventional anionic dyes adsorbents, as well as both primary materials source, chitosan and magnetite, are costless and easily supplied.

Magnetic Hybrid Wax Nanocomposites as Externally Controlled Theranostic Vehicles: High MRI Enhancement and Synergistic Magnetically Assisted Thermo/Chemo Therapy.

To fight against cancer, smarter drugs and drug delivery systems are required both to boost the efficiency of current treatments while reducing deleterious side effects, and combine diagnosis/monitoring with therapy (theranosis) in the search for the final goal of personalized medicine. This work presents the design, preparation, and proof-of-principle validation of a novel hybrid organic-inorganic nanocomposite joining together non-invasive imaging capabilities through magnetic resonance imaging and externally actuated therapeutic properties through a combination of chemo- and thermotherapy. The lipidic matrix of the nanocomposite was composed of carnauba wax, which was simultaneously dual loaded with magnetite nanoparticles and the anticancer drug Oncocalyxone A. Obtained formulations were fully characterized and showed outstanding performances as T2 -contrast agents in magnetic resonance imaging (r2 >800 mm-1 s-1 ), heat generating sources in magnetic hyperthermia (specific absorption rate, SAR>200 W g-1 Fe ), and magnetically responsive drug delivery vehicles. The potential of the designed formulations as theranostic agents was validated in vitro and results indicated a synergistic thermo/chemotherapeutic effect derived from heat generation and controlled drug delivery to cancer growth. Thereby, this external control over the drug delivery profile and the integrated imaging capability open the door to personalized cancer medicine and real-time monitoring of tumor progression.

The Combination of Dimorphandra gardneriana Galactomannan and Mangiferin Inhibits Herpes Simplex and Poliovirus.

BACKGROUND: Herpes simplex virus (HSV) and poliovirus (PV) are both agents of major concern in the public health system. It has been shown that Dimorphandra gardneriana galactomannans can be used as solubilizer vehicles in the manufacturing of medicine. Mangiferin is the major constituent of Mangifera indica and presents multiple medicinal and biological activities. OBJECTIVE: This study assayed the effect of D. gardneriana galactomannan combined with mangiferin (DgGmM) against HSV-1 and PV-1. METHODS: The DgGmM cytotoxicity was evaluated by the colorimetric MTT method and the antiviral activity by plaque reduction assay, immunofluorescence and polymerase chain reaction (PCR), in HEp-2 cells. RESULTS: The DgGmM showed a 50% cytotoxic concentration (CC50) > 2000 µg/mL. The 50% inhibitory concentrations (IC50) for HSV-1 and PV-1 were, respectively, 287.5 µg/mL and 206.2 µg/mL, with selectivity indexes (SI) > 6.95 for the former and > 9.69 for the latter. The DgGmM time-ofaddition protocol for HSV-1 showed a maximum inhibition at 500 µg/mL, when added concomitantly to infection and at the time 1 h post-infection (pi). While for PV-1, for the same protocol, the greatest inhibition, was also observed concomitantly to infection at 500 µg/mL and at the times 4 h and 8 h pi. The inhibition was also demonstrated by the decrease of fluorescent cells and/or the inhibition of specific viral genome. CONCLUSION: These results suggested that the DgGmM inhibited HSV-1 and PV-1 replication, with low cytotoxicity and high selectivity and, therefore, represents a potential candidate for further studies on the control of herpes and polio infections.

Magnetic nanosystem for cancer therapy using oncocalyxone a, an antitomour secondary metabolite isolated from a Brazilian plant.

This paper describes the investigation and development of a novel magnetic drug delivery nanosystem (labeled as MO-20) for cancer therapy. The drug employed was oncocalyxone A (onco A), which was isolated from Auxemma oncocalyx, an endemic Brazilian plant. It has a series of pharmacological properties: antioxidant, cytotoxic, analgesic, anti-inflammatory, antitumor and antiplatelet. Onco A was associated with magnetite nanoparticles in order to obtain magnetic properties. The components of MO-20 were characterized by XRD, FTIR, TGA, TEM and Magnetization curves. The MO-20 presented a size of about 30 nm and globular morphology. In addition, drug releasing experiments were performed, where it was observed the presence of the anomalous transport. The results found in this work showed the potential of onco A for future applications of the MO-20 as a new magnetic drug release nanosystem for cancer treatment.

Potential inhibitory effect of LASSBio-596, a new thalidomide hybrid, on inflammatory corneal angiogenesis in rabbits.

AIMS: Evaluate the effect of LASSBio-596, structurally designed as a new hybrid of thalidomide, on inflammatory corneal angiogenesis. METHODS: Eighteen rabbits were submitted to an alkaline cauterization in the right cornea. The animals were randomly allocated to three groups: vehicle, dexamethasone and LASSBio-596. Drugs were administered by eyedrops 3 times a day for 21 days. Evaluations were performed on days 3, 6, 9, 12, 15, 18 and 21 after cauterization. At these time points, digital images of the cornea were captured in a standard fashion. The angiogenic response was measured using software that was developed specifically for this purpose. It calculated the following parameters: neovascularization area (NA), total vascular length (TVL) and blood vessel number (BVN). RESULTS: It was observed that dexamethasone significantly decreased NA, TVL and BVN during all assessments. From the NA the angiogenesis rate (AR) was calculated in each group. Therefore, dexamethasone completely inhibited the inflammatory corneal angiogenesis with an AR of -0.001 ± 0.006 mm(2)/day, which was significantly lower (p < 0.001) than that observed after treatment with vehicle (0.078 ± 0.024 mm(2)/day) and LASSBio-596 (0.054 ± 0.012 mm(2)/day). Although LASSBio-596 reduced angiogenesis in relation to vehicle, according to NA, TVL and BVN values, this difference was not statistically significant. However, it was found that the AR as measured in the LASSBio-596 group was significantly lower (p < 0.05) than that seen in control animals, indicating a potential antiangiogenic effect. CONCLUSION: We conclude that topical application of LASSBio-596 at 1.0% has a potential inhibitory effect on inflammatory corneal angiogenesis in rabbits.

Solubilisation capacity of Brij surfactants.

The aim of this study was to investigate the potential of selected Brij non-ionic surfactants for enhancing the solubility of poorly water-soluble drugs. Griseofulvin was selected as a model drug candidate enabling comparisons to be made with the solubilisation capacities of other poly(ethylene oxide)-based copolymers. UV/Vis and (1)H NMR spectroscopies were used to quantify the enhancement of solubility of griseofulvin in 1 wt% aqueous micellar solutions of Brij 78 (C(18)H(37)E(20)), Brij 98 (C(18)H(35)E(20)) and Brij 700 (C(18)H(37)E(100)) (where E represents the OCH(2)CH(2) unit of the poly(ethylene oxide) chain) at 25, 37 and 40 °C. Solubilisation capacities (S(cp) expressed as mg griseofulvin per g Brij) were similar for Brij 78 and 98 (range 6-11 mg g(-1)) but lower for Brij 700 (3-4 mg g(-1)) as would be expected for the surfactant with the higher ethylene oxide content. The drug loading capacity of micelles of Brij 78 was higher than many di- and triblock copolymers with hydrophilic E-blocks specifically designed for enhancement of drug solubility.

Effect of water-soluble polymers, polyethylene glycol and poly(vinylpyrrolidone), on the gelation of aqueous micellar solutions of Pluronic copolymer F127.

The micellization of F127 (E(98)P(67)E(98)) in dilute aqueous solutions of polyethylene glycol (PEG6000 and PEG35000) and poly(vinylpyrrolidone) (PVP K30 and PVP K90) is studied. The average hydrodynamic radius (r(h,app)) obtained from the dynamic light scattering technique increased with increase in PEG concentration but decreased on addition of PVP, results which are consistent with interaction of the micelles with PEG and the formation of micelles clusters, but no such interaction occurs with PVP. Tube inversion was used to determine the onset of gelation. The critical concentration of F127 for gelation increased on addition of PEG and of PVP K30 but decreased on addition of PVP K90. Small-angle X-ray scattering (SAXS) was used to show that the 30 wt% F127 gel structure (fcc) was independent of polymer type and concentration, as was the d-spacing and so the micelle hard-sphere radius. The maximum elastic modulus (G(max)(')) of 30 wt% F127 decreased from its value for water alone as PEG was added, but was little changed by adding PVP. These results are consistent with the packed-micelles in the 30 wt% F127 gel being effectively isolated from the polymer solution on the microscale while, especially for the PEG, being mixed on the macroscale.

The effect of water-soluble polymers, PEG and PVP, on the solubilisation of griseofulvin in aqueous micellar solutions of Pluronic F127.

The purpose of this study was to investigate the possibility of enhancing the solubilisation capacity of micellar solutions of Pluronic F127 for the poorly water-soluble drug griseofulvin by co-formulating with a water-soluble polymer. The effect of the addition of the polyethylene glycols PEG6000 and 35000, and the poly(vinylpyrrolidone)s PVP K30 and K90, on the solubilisation capacity of 1wt% solutions of Pluronic F127 was related to the effect of these additives on particle size as determined by dynamic light scattering measurements. The addition of PEG35000 to 1wt% F127 solutions significantly increased the solubility capacity expressed in terms of unit weight of F127; PVP K90 had a smaller effect but no enhancement was noted following the addition of PEG6000 or PVP K30. Solubilisation enhancement was thought to be a consequence of the association of the polymers with the E-blocks of the micelle corona so providing an expanded region of reduced polarity for drug solubilisation.

The effect of polymeric additives on the solubilisation of a poorly-soluble drug in micellar solutions of Pluronic F127.

The solubilisation of griseofulvin in 1wt% aqueous micellar solutions of Pluronic F127 at 37°C has been modified by adding polyethylene glycol PEG 35000 or poly(vinylpyrrolidone) PVP K30. The solubilisation capacity expressed in terms of unit weight of F127 is increased by the addition of 0.5wt% PEG 35000 to a value approaching double that of a 2.5wt% solution of F127 alone, but there is no advantage in adding 0.5wt% PVP K30.

The effect of n-, s- and t-butanol on the micellization and gelation of Pluronic P123 in aqueous solution.

In dilute aqueous solution unimers of copolymer P123 (E(21)P(67)E(21)) associate to form micelles, and in more concentrated solution micelles pack to form high-modulus gels. We are interested in the use of the system as a templating agent in the synthesis of mesoporous materials, and the possibility of determining gel structure, hence mesoporosity, by use of n-, s- or t-butanol. Dynamic light scattering from clear dilute solutions has been used to confirm micellization, visual observation of mobility (tube inversion) to detect gel formation in concentrated solutions, oscillatory rheometry to confirm gel formation and provide values of elastic moduli over a wide temperature range, and small-angle X-ray scattering to determine gel structure. As expected, clear cubic gels (fcc) formed at moderate concentrations and temperatures, e.g. 30 wt.% P123, 20°C, and clear hexagonal gels at higher concentrations and temperatures. The transition on heating from cubic to hexagonal gel involved an intermediate turbid phase in which cubic and hex structures coexisted. Considering cubic gels of 35 wt.% P123 in 5 wt.% butanol/water, those in n-butanol/water had the lowest critical temperatures for gel formation and the highest maximum values for the dynamic elastic modulus (G') of the gels, a result consistent with n-butanol/water being the poorest solvent for P123.

Xylan from corn cobs, a promising polymer for drug delivery: production and characterization.

Although many authors have reported several beneficial effects ascribed to xylan, such as inhibitory action on mutagenicity activity, antiphlogistic effects, and mitogenic and comitogenic activities, few papers have investigated a systematic study on the technological properties of this polymer. The aim of the present work was to evaluate xylan as a promise raw material for the pharmaceutical industry. The water-insoluble xylan samples were extracted from corn cobs following several steps. The obtained powered sample was analyzed by infrared and RMN spectroscopy, and characterized regarding their particle size, bulk and tap densities, compressibility index, compactability, Hausner ratio, and angle of repose. According to the results, infrared and RMN spectroscopy were shown to be able to evaluate the xylan structural conformation and composition, respectively. In addition, rheological data demonstrated that xylan powder obtained from corn cobs may be characterized as a material with low density and very cohesive flow properties.

Insecticidal action of sodium anacardate from Brazilian cashew nut shell liquid against Aedes aegypti.

Aedes aegypti is the major vector of 1 of the most concerning arboviruses of the world, the dengue fever. The only effective way of reducing the incidence of dengue fever is to control the vector mosquito, mainly by application of insecticides to its breeding places. This study was aimed at assessing the insecticidal activity of sodium anacardate, isolated from Brazilian cashew nut shell liquid (CNSL), against the eggs, 3rd instars or pupae of Ae. aegypti. In addition, the acute toxicity of sodium anacardate to mice was also investigated. Sodium anacardate showed toxicity against Ae. aegypti eggs (median effective concentration [EC50] = 162.93 +/- 29.93 microg/ml), larvae (median lethal concentration [LC50] = 55.47 +/- 3.0 microg/ml) and pupae (LC50 = 369.78 - 52.30 microg/ml). On the other hand, even at high dose (0.3 g/kg body weight), this compound did not cause any adverse effects on mice, suggesting that this compound is safe to mammals. Therefore, sodium anacardate may be a viable low-cost alternative to help combat Ae. aegypti.

Solubilisation of griseofulvin, quercetin and rutin in micellar formulations of triblock copolymers E62P39E62 and E137S18E137.

The solubilisation of two poorly soluble flavonoids, quercetin and rutin, in micellar solutions of mixtures of a block copolymer of ethylene oxide and styrene oxide (E(137)S(18)E(137)) with one of ethylene oxide and propylene oxide (E(62)P(39)E(62)) has been studied at 25 and 37 degrees C. Solubilisation capacities were higher than those for the model poorly water-soluble drug griseofulvin and comparable with published values for the solubilisation of rutin by beta-cyclodextrin.

Interaction of polysaccharide-protein complex from Agaricus blazei with Langmuir and Langmuir-Blodgett films of phospholipids.

The use of natural substances in health applications may be hampered by the difficulties in establishing the mechanisms of action, especially at molecular-level. The protein-polysaccharide complex extracted from the mushroom Agaricus blazei Murill, referred to as CAb, has been considered for treating various diseases with probable interaction with cell membranes. In this study, we investigate the interaction between CAb and a cell membrane model represented by a Langmuir monolayer of dimyristoyl phosphatidic acid (DMPA). CAb affects the structural properties of DMPA monolayers causing expansion and increasing compressibility. In addition, interaction with DMPA polar heads led to neutralization of the electrical double layer, yielding a zero surface potential at large areas per molecule. CAb remained at the interface even at high surface pressures, which allowed transfer of Langmuir-Blodgett (LB) films onto solid supports with the CAb-DMPA mixture. The mass transferred, according to quartz crystal microbalance (QCM) measurements, increased linearly with the number of deposited layers. With UV-vis absorption, fluorescence and FTIR spectroscopies, we confirmed that the LB films contain polysaccharides, proteins and DMPA. Therefore, the CAb biological action must be attributed not only to polysaccharides but also to proteins in the complex.

Solubilisation of griseofulvin in aqueous micellar solutions of diblock copolymers of ethylene oxide and 1,2-butylene oxide with lengthy B-blocks.

The influence of hydrophobic-block length on solubilisation capacity was examined for micelles of E(m)B(n) copolymers (E=oxyethylene, B=oxybutylene, subscripts denote number-average block lengths in repeat units) with B-block lengths in the range of 30-76 and with E-blocks of sufficient length to ensure the formation of spherical micelles. Griseofulvin was used as a model poorly-water-soluble drug known to be almost exclusively solubilised in the micellar core. Combination of solubilisation data with those of a previous study has shown that the amount of drug solubilised per gram of hydrophobe is essentially independent of B-block length when this exceeds about 15 B units, suggesting that core size is not a major influence on solubilisation.

Diblock copolymers of ethylene oxide and 1,2-butylene oxide in aqueous solution: formation of unimolecular micelles.

The dependence of log(cmc) on hydrophobic block length n was examined for E(m)B(n) copolymers (E=oxyethylene, B=oxybutylene, subscripts denote number-average block lengths in repeat units) with n in the range 30-76. Combination with published data for E(m)B(n) diblock copolymers with shorter E-blocks shows two changes of slope in the log(cmc)-n plot corresponding to the onset of unimolecular micelle formation at n approximately 12 and completion of this process at n approximately 30. The results are discussed with reference to published data for E(m)L(n) and E(m)CL(n) (L from d,L-lactide; CL from epsilon-caprolactone) copolymers, which show similar behaviour.

Mixtures of triblock copolymers E(62)P(39)E(62) and E(137)S(18)E(137) potential for drug delivery from in situ gelling micellar formulations.

The gelation behaviour of concentrated micellar solutions of mixtures of a block copolymer of ethylene oxide and styrene oxide (E(137)S(18)E(137)) with one of ethylene oxide and propylene oxide (E(62)P(39)E(62)) has been investigated. Over a wide range of compositions, up to 90 wt.% E(137)S(18)E(137) in the mixture, gelation resembled that of solutions of E(62)P(39)E(62) alone, i.e. they gelled on heating from ambient to body temperature. In related experiments, using the aromatic drug griseofulvin as a comparative standard, it was demonstrated that solubilisation efficiency of dilute micellar solutions of the mixtures with 80 wt.% or more E(137)S(18)E(137) approached that of solutions of E(137)S(18)E(137) alone. Thus it was shown that the mixed system could have both the satisfactory solubilisation capacity of micellar solutions of E(137)S(18)E(137) and the desirable gelation characteristics of E(62)P(39)E(62), and so have potential for use in drug release applications involving in situ gelation.

Association behavior of mixed triblock copoly(oxyalkylene)s (type EBE and ESE) in aqueous solution.

The micellization of binary mixtures of water-soluble block copolymers E(m)B(n)E(m) and E(m)S(n)E(m) in dilute solution was investigated by light-scattering methods. We use the notation E, B, and S to denote chain units derived, respectively, from ethylene oxide, butylene oxide, and styrene oxide and the subscripts to denote number-average chain lengths in chain units. Two distinct distributions of micelles were formed in solutions of a 50:50 wt % mixture of copolymers E64B20E64 and E137S18E137, which had hydrophobic blocks of similar length but very different hydrophobicity. One distribution of micelles was formed in solutions of a mixture (50:50 wt %) of copolymers E135B20E135 and E82S9E82, which had hydrophobic blocks of different length but similar hydrophobicity. In this case, the properties of the micelles formed in solutions of the mixture were very similar to those of micelles of E82S9E82 alone. This result extended to concentrated solutions, because the hard-gel boundary for the mixture proved to be very similar to that of solutions of E82S9E82 alone.

Controlling the gelation of aqueous micellar solutions of ethylene-oxide-based block copoly(oxyalkylene)s.

Micellar solutions of EmPnEm copolymers may be mobile at ambient temperature and form hard gels on warming to body temperature, whereas micellar solutions of EmSnEm copolymers do not show this effect (E denotes oxyethylene, P oxypropylene and S oxyphenylethylene, and subscripts m and n denote chain lengths). The aim of this study was to combine the desirable gelation characteristics of solutions of the EmPnEm copolymers with the greater solubilising capacities of solutions of the EmSnEm copolymers. Accordingly, the gelation characteristics in aqueous solution of binary mixtures of the triblock copolymer E62P39E62 (Pluronic F87) with E137S18E137, E82S9E82 or E76S5E76 were investigated by rheological techniques. We have shown that 50/50 wt.% mixtures of E62P39E62 with either E137S18E137 or E82S9E82 at a total copolymer concentration of approximately 30 wt.% are fluids of low viscosity at temperature below 22-25 degrees C and gels of high elastic modulus at body temperature.The mixed systems have potential as vehicles for the controlled delivery of solubilised drug from gels formed in situ following subcutaneous injection of a low viscosity aqueous solution.