Molecular targets in arthritis and recent trends in nanotherapy

Due to its severity and increasing epidemiology, arthritis needs no description. There are various forms of arthritis most of which are disabling, very painful, and common. In spite of breakthroughs in the field of drug discovery, there is no cure for arthritis that can eliminate the disease permanently and ease the pain. The present review focuses on some of the most successful drugs in arthritis therapy and their side effects. Potential new targets in arthritis therapy such as interleukin-1β, interleukin-17A, tumor necrosis factor alpha, osteopontin, and several others have been discussed here, which can lead to refinement of current therapeutic modalities. Mechanisms for different forms of arthritis have been discussed along with the molecules that act as potential biomarkers for arthritis. Due to the difficulty in monitoring the disease progression to detect the advanced manifestations of the diseases, drug-induced cytotoxicity, and problems with drug delivery; nanoparticle therapy has gained the attention of the researchers. The unique properties of nanoparticles make them highly attractive for the design of novel therapeutics or diagnostic agents for arthritis. The review also focuses on the recent trends in nanoformulation development used for arthritis therapy. This review is, therefore, important because it describes the relevance and need for more arthritis research, it brings forth a critical discussion of successful drugs in arthritis and analyses the key molecular targets. The review also identifies several knowledge gaps in the published research so far along with the proposal of new ideas and future directions in arthritis therapy.

Novel protein and atenolol co-encapsulated nanocapsules to impede cardiomyocyte apoptosis

 The research conducted was based on regenerating the dying heart cells (cardiomyocytes) by employing novel therapeutic proteins and their respective co-encapsulated nanoformulation with an antihypertensive drug. This promising therapeutic strategy to revive the heart can help in the treatment of several cardiac pathologies such as myocardial infarction and drug induced cardiotoxicity.

Hydrogel properties of electrospun polyvinylpyrrolidone and polyvinylpyrrolidone/poly(acrylic acid) blend nanofibers

Hydrogel nanofibers with high water-absorption capacity and excellent biocompatibility offer wide use in biomedical areas. In this study, hydrogel nanofibers from polyvinylpyrrolidone (PVP) and PVP/poly(acrylic acid) (PAA) blend were prepared by electrospinning and by subsequent heat treatment. The effects of post-electrospinning heat treatment and PVP/PAA ratio on hydrogel properties of the nanofibers were examined. Heat treatment at a temperature above 180°C was found to play a key role in forming insoluble and water-absorbent nanofibers. Both PVP and PVP/PAA nanofibers showed high morphology stability in water and excellent water retention capacity. The swelling ratio of PVP/PAA nanofibers declined with increasing heating temperature and decreasing PVP/PAA unit ratio. In comparison with dense casting films, these nanofiber membranes showed nearly doubled swelling ratio.

Can cancer therapy be achieved by bridging apoptosis and autophagy: A method based on microRNA-dependent gene therapy and phytochemical targets

A failure of a cell to self destruct has long been associated with cancer progression and development. The fact that tumour cells may not instigate cell arrest or activate cell death mechanisms upon cancer drug delivery is a major concern. Autophagy is a mechanism whereby cell material can be engulfed and digested while apoptosis is a self-killing mechanism, both capable of hindering multiplication after cell injury. In particular situations, autophagy and apoptosis seem to co-exist simultaneously or interdependently with the aid of mutual proteins. This review covers roles of microRNAs and chemopreventive agents and makes an attempt at outlining possible partnerships in maximizing cancer cell death with minimal normal cell damage.

Coassembled nanostructured bioscaffold reduces the expression of proinflammatory cytokines to induce apoptosis in epithelial cancer cells

The local inflammatory environment of the cell promotes the growth of epithelial cancers. Therefore, controlling inflammation locally using a material in a sustained, non-steroidal fashion can effectively kill malignant cells without significant damage to surrounding healthy cells. A promising class of materials for such applications are the nanostructured scaffolds formed by epitope containing minimalist self-assembled peptides (SAPs), as they are bioactive on a cellular length scale, whilst presenting as an easily handled hydrogel. Here, we show that the assembly process distributes an anti-inflammatory polysaccharide, fuccoidan, localised to the nanofibers to function as an anti-inflammatory biomaterial for cancer therapy. We show that it supports healthy cells, whilst inducing apoptosis in cancerous endothelial cells, as demonstrated by the downregulation of the proinflammatory gene and protein expression pathways associated with epithelial cancer progression. Our findings highlight an innovative material approach with potential applications as local epithelial cancer immunotherapy and drug delivery vehicles.

Similarity between the in vitro activity and toxicity of two different fungizone™ / lipofundin™ admixtures

Amphotericin B (AmB), an antifungal agent that presents a broad spectrum of activity, remains the gold standard in the antifungal therapy. However, sometimes the high level of toxicity forbids its clinical use. The aim of this work was to evaluate and compare the efficacy and toxicity in vitro of Fungizon™ (AmB-D) and two new different AmB formulations. Methods: three products were studied: Fungizon™, and two Fungizon™ /Lipofundin™ admixtures, which were diluted through two methods: in the first one, Fungizon™ was previously diluted with water for injection and then, in Lipofundin™ (AmB-DAL); the second method consisted of a primary dilution of AmB-D as a powder in the referred emulsion (AmB-DL). For the in vitro assay, two cell models were used: Red Blood Cells (RBC) from human donors and Candida tropicallis (Ct). The in vitro evaluation (K+ leakage, hemoglobin leakage and cell survival rate-CSR) was performed at four AmB concentrations (from 50 to 0.05mg.L-1). Results: The results showed that the action of AmB was not only concentration dependent, but also cellular type and vehicle kind dependent. At AmB concentrations of 50 mg.L-1, although the hemoglobin leakage for AmB-D was almost complete (99.51), for AmB-DAL and AmB-DL this value tended to zero. The p = 0.000 showed that AmB-D was significantly more hemolytic. Conclusion: The Fungizon™- Lipofundin™ admixtures seem to be the more valuable AmB carrier systems due to their best therapeutic index presented

Modificação de membranas de quitosana por plasma para uso biológico

Chitosan membranes have been modified by plasma, utilizing the following gases: nitrogen (N2), methane (CH4), argon (Ar), oxygen (O2) and hydrogen. The modified membranes by plasma were compared to the unmodified ones. The membranes were characterized by absorption assay, contact angle, atomic force microscopy (AFM). Also, permeability assay of sodium sulfamerazine from such membranes were carried out. Through the absorption assay and contact angle it was possible to obtain information of the wettability of the membranes and what changes the plasma treatment can promote in relation to it. The plasma treatment using oxygen promoted increase of the wetability and swelling while the samples treated with methane decrease of the wetability and swelling. Through the Optical Emission Spectroscopy (OES) it was possible to identify which species were present in the plasma during the treatment. And through the AFM analysis it was possible to observe the changes nanotopography occurred on the surface of the samples. Permeability assay were archived for all treated membranes and compared to no treated ones. Due to that assay it was possible verify which the plasma treatment increased the permeability spectrum of the membranes which has varied from 1,4548 *10-5cm2.min-1 to 2,7713*10-5cm2.min-1. Chitosan membranes with permeability varied are importance in systems drug delivery, to liberate a wide variety of drugs

Síntese e caracterização do poli(ácido láctico) para potencial uso em sistemas de liberação controlada de fármacos

With the advances in medicine, life expectancy of the world population has grown considerably in recent decades. Studies have been performed in order to maintain the quality of life through the development of new drugs and new surgical procedures. Biomaterials is an example of the researches to improve quality of life, and its use goes from the reconstruction of tissues and organs affected by diseases or other types of failure, to use in drug delivery system able to prolong the drug in the body and increase its bioavailability. Biopolymers are a class of biomaterials widely targeted by researchers since they have ideal properties for biomedical applications, such as high biocompatibility and biodegradability. Poly (lactic acid) (PLA) is a biopolymer used as a biomaterial and its monomer, lactic acid, is eliminated by the Krebs Cycle (citric acid cycle). It is possible to synthesize PLA through various synthesis routes, however, the direct polycondensation is cheaper due the use of few steps of polymerization. In this work we used experimental design (DOE) to produce PLAs with different molecular weight from the direct polycondensation of lactic acid, with characteristics suitable for use in drug delivery system (DDS). Through the experimental design it was noted that the time of esterification, in the direct polycondensation, is the most important stage to obtain a higher molecular weight. The Fourier Transform Infrared (FTIR) spectrograms obtained were equivalent to the PLAs available in the literature. Results of Differential Scanning Calorimetry (DSC) showed that all PLAs produced are semicrystalline with glass transition temperatures (Tgs) ranging between 36 - 48 °C, and melting temperatures (Tm) ranging from 117 to 130 °C. The PLAs molecular weight characterized from Size Exclusion Chromatography (SEC), varied from 1000 to 11,000 g/mol. PLAs obtained showed a fibrous morphology characterized by Scanning Electron Microscopy (SEM)

Desenvolvimento de uma formulação cólon específica visando o tratamento da colite ulcerativa

Micro and nanoparticulate systems as drug delivery carriers have achieved successful therapeutic use by enhancing efficacy and reducing toxicity of potent drugs. The improvement of pharmaceutical grade polymers has allowed the development of such therapeutic systems. Microencapsulation is a process in which very thin coatings of inert natural or synthetic polymeric materials are deposited around microsized particles of solids or around droplets. Products thus formed are known as microparticles. Xylan is a natural polymer abundantly found in nature. It is the most common hemicellulose, representing more than 60% of the polysaccharides existing in the cell walls of corn cobs, and is normally degraded by the bacterial enzymes present in the colon of the human body. Therefore, this polymer is an eligible material to produce colon-specific drug carriers. The aim of this study was to evaluate the technological potential of xylan for the development of colon delivery systems for the treatment of inflammatory bowel diseases. First, coacervation was evaluated as a feasible method to produce xylan microcapsules. Afterwards, interfacial cross-linking polymerization was studied as a method to produce microcapsules with hydrophilic core. Additionally, magnetic xylan-coated microcapsules were prepared in order to investigate the ability of producing gastroresistant systems. Besides, the influence of the external phase composition on the production and mean diameter of microcapsules produced by interfacial cross-linking polymerization was investigated. Also, technological properties of xylan were determined in order to predict its possible application in other pharmaceutical dosage forms

Desenvolvimento e caracterização de nanocápsulas de poli (L-lactídeo) contendo benzocaína

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Caracterização físico-química de complexo de inclusão entre hidroximetilnitrofurazona e hidroxipropil-beta-ciclodextrina

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Micro and nanosystems for delivering local anesthetics

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-beta-cyclodextrin inclusion complex

Ropivacaine (RVC) is an enantiomerically pure local anesthetic (LA) largely used in surgical procedures, which presents physico-chemical and therapeutic properties similar to those of bupivacaine (BPV), but associated to less systemic toxicity This study focuses on the development and pharmacological evaluation of a RVC in 2-hydroxypropyl-beta-cyclodextrin (HP-P-CD) inclusion complex. Phase-solubility diagrams allowed the determination of the association constant between RVC and HP-beta-CD (9.46 M-1) and showed an increase on RVC solubility upon complexation. Release kinetics revealed a decrease on RVC release rate and reduced hemolytic effects after complexation. (onset at 3.7 mM and 11.2 mM for RVC and RVCHP-beta-CD, respectively) were observed. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray analysis (X-ray) showed the formation and the morphology of the complex. Nuclear magnetic resonance (NMR) and job-plot experiments afforded data regarding inclusion complex stoichiometry (1:1) and topology. Sciatic nerve blockade studies showed that RVCHP-beta-CD was able to reduce the latency without increasing the duration of motor blockade, but prolonging the duration and intensity of the sensory blockade (p < 0.001) induced by the LA in mice. These results identify the RVCHP-beta-CD complex as an effective novel approach to enhance the pharmacological effects of RVC, presenting it as a promising new anesthetic formulation. (c) 2007 Elsevier B.V All rights reserved.

Stability and Local Toxicity Evaluation of a Liposomal Prilocaine Formulation

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Encapsulation of Local Anesthetic Bupivacaine in Biodegradable Poly(DL-lactide-co-glycolide) Nanospheres: Factorial Design, Characterization and Cytotoxicity Studies

Local anesthetic agents cause temporary blockade of nerve impulses productiong insensitivity to painful stimuli in the area supplied by that nerve. Bupivacaine (BVC) is an amide-type local anesthetic widely used in surgery and obstetrics for sustained peripheral and central nerve blockade. in this study, we prepared and characterized nanosphere formulations containing BVC. To achieve these goals, BVC loaded poly(DL-lactide-co-glycolide) (PLGA) nanospheres (NS) were prepared by nanopreciptation and characterized with regard to size distribution, drug loading and cytotoxicity assays. The 2(3-1) factorial experimental design was used to study the influence of three different independent variables on nanoparticle drug loading. BVC was assayed by HPLC, the particle size and zeta potential were determined by dynamic light scattering. BVC was determined using a combined ultrafiltration-centrifugation technique. The results of optimized formulations showed a narrow size distribution with a polydispersivity of 0.05%, an average diameter of 236.7 +/- 2.6 nm and the zeta potential -2.93 +/- 1,10 mV. In toxicity studies with fibroblast 3T3 cells, BVC loaded-PLGA-NS increased cell viability, in comparison with the effect produced by free BVC. In this way, BVC-loaded PLGA-NS decreased BVC toxicity. The development of BVC formulations in carriers such as nanospheres could offer the possibility of controlling drug delivery in biological systems, prolonging the anesthetic effect and reducing toxicity.