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Today, 12 Ιουλίου 2016, 4:09:44 μμ
Gene Electrotransfer in 3D Reconstructed Human Dermal Tissue
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Gene electrotransfer into the skin is of particular interest for the development of medical applications including DNA vaccination, cancer treatment, wound healing or treatment of local skin disorders. However, such clinical applications are currently limited due to poor understanding of the mechanisms governing DNA electrotransfer within human tissue. Nowadays, most studies are carried out in rodent models but rodent skin varies from human skin in terms of cell composition and architecture. We used a tissue-engineering approach to study gene electrotransfer mechanisms in a human tissue context. Primary human dermal fibroblasts were cultured according to the self-assembly method to produce 3D reconstructed human dermal tissue. In this study, we showed that cells of the reconstructed cutaneous tissue were efficiently electropermeabilized by applying millisecond electric pulses, without affecting their viability. A reporter gene was successfully electrotransferred into this human tissue and gene expression was detected for up to 48h. Interestingly, the transfected cells were solely located on the upper surface of the tissue, where they were in close contact with plasmid DNA solution. Furthermore, we report evidences that electrotransfection success depends on plasmid mobility within tissue- rich in collagens, but not on cell proliferation status. In conclusion, in addition to proposing a reliable alternative to animal experiments, tissue engineering produces valid biological tool for the in vitro study of gene electrotransfer mechanisms in human tissue.
Gene Electrotransfer: A Mechanistic Perspective
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Gene electrotransfer is a powerful method of DNA delivery offering several medical applications, among the most promising of which are DNA vaccination and gene therapy for cancer treatment. Electroporation entails the application of electric fields to cells which then experience a local and transient change of membrane permeability. Although gene electrotransfer has been extensively studied in in vitro and in vivo environments, the mechanisms by which DNA enters and navigates through cells are not fully understood. Here we present a comprehensive review of the body of knowledge concerning gene electrotransfer that has been accumulated over the last three decades. For that purpose, after briefly reviewing the medical applications that gene electrotransfer can provide, we outline membrane electropermeabilization, a key process for the delivery of DNA and smaller molecules. Since gene electrotransfer is a multipart process, we proceed our review in describing step by step our current understanding, with particular emphasis on DNA internalization and intracellular trafficking. Finally, we turn our attention to in vivo testing and methodology for gene electrotransfer.
Dry Powder form of Polymeric Nanoparticles for Pulmonary Drug Delivery
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Delivery to the lungs is an efficient way to deliver drugs directly to the site of action or to the blood circulation. Because of limitations of direct administration of free drugs, particulate drug delivery systems such as DPI formulations based on nanoparticles (NPs) have been of interest for pulmonary drug delivery. The prolonged residence of NPs in the lungs due to ability to escape from the clearance mechanisms such as mucociliary escalator, macrophage uptake (a size of 1–2 m is ideal for macrophage phagocytosis), and translocation to the systemic circulation is amongst the key advantages of NPs. By this approach, the controlled pulmonary delivery of drugs, peptides, proteins, genes, siRNA, and vaccines is possible. Both natural (albumin, gelatin, alginate, collagen, cyclodextrin, and chitosan) and synthetic (poly (lactide-co-glycolide) (PLGA), polyacrylates and polyanhydrides) polymers have been used in formulation of pulmonary nanovectors. As direct pulmonary administration of NPs is not feasible, by using the safe excipients, NPs could be converted to dry powder inhaler (DPI) formulations. These can provide a promising deposition and stability of NPs. In this article, the DPI formulations based on polymeric nanoparticles have been reviewed and categorized based on the polymer type used for preparation of NPs.
Recent Development in Identification of Potential Novel Therapeutic Targets Against Trypanosomatids
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Trypanosomatids continue to cause suffering among human and wide range of animal population and have enormous health, social and economic impact. The present constraints in control of trypanosomosis are availability of limited number of effective drugs with narrow safety index, nonavailability of vaccines due to immune evasion mechanisms developed by the parasite and drug resistance problem. The kinetoplastids/ trypanosomatids possess unique kinetoplast DNA structure and express hundreds of membrane transport proteins that allow them to take up nutrients, establish ion gradients, efflux metabolites, translocate compounds from one intracellular compartment to another, and take up or export drugs. In this context, there is urgent need of application of innovative strategies for identification of novel therapeutic drug targets affecting metabolic pathways essential for survival of the parasites using modern molecular approaches (functional/genomics/ proteomics/bioinformatics). In this review we have discussed existing drugs in use for treatment and outline of emerging approaches in identification and evaluation of potential novel therapeutic targets against trypanosomatids.
Polymer-based Drug Delivery Systems Applied to Insects Repellents Devices: A Review
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Insects-borne diseases constitute a public health concern. Since there is no vaccine or curative treatment for many of these diseases, individual protection is the main approach to prevent them. Nowadays, the search for replacing synthetic molecules for insect repellents from natural sources, such as essential oils, is increasing. However, most of them present low efficiency compared to synthetic repellents. Therefore, decreasing skin permeation of synthetic repellents or yet, increasing effectiveness of natural repellents are challenges that must be overcome during the development of novel insect repellent formulations. In this context, polymer-based formulations allow entrapping active ingredients and provide release control. Encapsulation into polymeric micro/nanocapsules, cyclodextrins, polymeric micelles or hydrogels constitutes an approach to modify physicochemical properties of encapsulated molecules. Such techniques, applied in topical formulations, fabrics modification for personal protection, or food packaging have proved to be more effective in increasing repellency time and also in reducing drug dermal absorption, improving safety profiles of these products. In this work, the main synthetic and natural insect repellents are described as well as their polymeric carrier systems and their potential applications.
Biodegradable Polymeric Nanoparticles as the Delivery Carrier for Drug
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Background: Drug research and development has entered into the new epoch of innovation formulation, and the drug delivery system has been in the forefront of pharmaceutical innovation. Nanotechnology is widely used in fiber and textiles, electronics, space, agriculture, forensic science and medical therapeutics. It increasingly plays a significant role in drug delivery system. Compared with traditional delivery system, the nanoparticle drug delivery system has lots of merits, such as the high drug loading ability, the excellent biocompatibility, low toxicity, controlled and targeted drug release. </p><p> Methods: We undertook a structured research of biodegradable polymeric nanoparticles used as delivery carrier for drug using a focused review question and inclusion/exclusion criteria. We have searched the bibliographic databases for peerreviewed research literature. The outstanding characteristics of the screened papers were described respectively, and a systematic content analysis methodology was used to analysis the findings. </p><p> Results: Seventy-three papers were included in the review, the majority defined leadership and governance approaches that had impacted upon the polymeric nanoparticles as the delivery carrier for drug in therapeutic applications and developments. Seven papers outlined the superiority characteristics of polymeric nanoparticles that applied in the field of vaccine. Forty-seven papers overviewed the application prospects of polymeric nanoparticles used as drug delivery carrier for cancer. These included current advances in research and clinical applications of polymeric nanoparticles. The review identified the drug delivery carrier of biodegradable polymeric nanoparticles, and we described the synthesis methods, applications and challenges of polymeric nanoparticles. </p><p> Conclusion: The findings of this review identified that the biodegradable polymeric nanoparticles were used as delivery carrier for drug currently. It also indicates that the biodegradable polymeric nanoparticles play an important role in the drug delivery. </p><p>
Characterization of pDNA-TMC Nanoparticle Interaction and Stability
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Formulation of nanoparticulate DNA vaccines requires the assessment of stability and integrity of the components implicated. Stability of cationic nanoparticles made of N-trimethyl chitosan and chondroitin sulfate (TMC nanoparticles) was investigated in aqueous solution and after freeze-drying by characterization of their size, polydispersity index (PDI), and zeta potential. Furthermore, the structural integrity of plasmid DNA (pDNA) on adsorption to the nanoparticle surface was investigated. Agarose gel electrophoresis showed DNA retention when applied with the nanocarrier, suggesting that pDNA adsorption on nanoparticles took place. In circular dichroism (CD) spectra, ellipticity of pDNA decreased at 280 nm and increased at 245 nm, and the maximum wavelength shifted from 275 nm to 285 nm when nanoparticles were present. Once released from the particles, the secondary structure of the plasmid was retained in its native form. pDNA release from pDNA-TMC nanoparticles was indicated by a rise in zeta potential from initially -32 mV (pDNA adsorbed to particles) to 14 mV during one hour, and to 36 mV after 24 hours. Unloaded TMC nanoparticles remained stable in suspension for 24 hours, maintaining diameters of around 200 nm, and zeta potential values of approximately 38 mV. Freeze-drying with sucrose could ensure storage for 30 days, with minimal increase in size (291 nm) and charge (62 mV). In conclusion, TMC nanoparticles may potentially be freeze-dried in the presence of sucrose to be stored for prolonged periods of time. Furthermore, pDNA was successfully adsorbed to the cationic nanoparticles and remained intact after being released.
EBV-Related Malignancies, Outcomes and Novel Prevention Strategies
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Background: Epstein Barr Virus (EBV) is a common gamma herpes virus with a high prevalence in adults worldwide. Infection is mostly latent in affected individuals. EBV has been linked mostly with lymphoid malignancies but its association with epithelial and other non-lymphoid malignancies has also been described. </p><p> Methods: Using MEDLINE, the terms “Epstein Barr Virus AND Malignancy”; “EBV mechanisms”; EBV treatment AND outcomes”; and “EBV prevention” were combined to find articles pertinent to this review. The search was limited to more recent publications between January 1, 2000 and August 1, 2015. </p><p> Results: In this review, we describe current knowledge about the pathogenesis of EBV-related malignancies and evaluate their therapeutic options and outcomes. Current and prospective novel preventive options are also critically reviewed. </p><p> Conclusions: EBV infection is a very common viral infection worldwide and has been implicated in various malignancies including lymphomas, gastric cancer, and nasopharangeal cancer. Patients with EBV positive PTLD and NK/T-cell lymphoma tend to have a better prognosis than EBV negative patients. On the other hand, patients with EBV positive HL or DLBCL tend to have a poorer prognosis especially in elderly patients. Further research is needed to better understand if EBV status is a true prognostic indicator in most malignancies. Treatment approaches remain similar for EBV positive and EBV negative malignancies while the use of novel agents remain under investigation. EBV vaccination trials are underway and these remain a potentially effective strategy to prevent EBV-related malignancies and the associated sequela. </p><p>
Cubosomes: Innovative Nanostructures for Drug Delivery
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Background: Some amphiphilic lipids can self-assemble to form bicontinuous cubic liquid crystalline materials in aqueous media. These cubic structures have gained considerable attention since they impart unique properties of practical interest. Cubosomes, being dispersions of an inverted type bicontinuous cubic phase, separate two continuous aqueous regions with a lipid bilayer having the propensity to incorporate drugs of varying polar characteristics. These novel versatile materials possess the properties to form a section of the next generation of advanced biocompatible nanoparticles. </p><p> Methods: This review chiefly considers the scope and importance of cubosomes as a proficient drug delivery vehicle. In addition, it also takes into account the various methods of preparation, the drug loading and release behavior as well as different methods of characterization. Their current advances in various arenas ranging from sustained drug release, burn management, melanoma therapy, vaccine delivery, protein delivery, cosmeceutical and theranostic applications are briefly summarized in this overview. </p><p> Results: The drug release from cubosomal dispersions have shown enhancement in bioavailability by solubilisation of poorly water soluble drugs, decrease in adverse effects, enhancement of intracellular penetration, protection against degradation, possibility of sustained drug release and the biodegradable nature of lipids is an added advantage. </p><p> Conclusion: Recognizing the desirable properties of cubosomes, it has been proposed as a novel carrier for drug delivery systems. Their unique solubilizing, encapsulating, transporting and protecting capabilities make them an attractive vehicle for numerous in vivo drug delivery routes. </p><p>
A Novel Monocyte-based Pyrogen Test Based on the Mechanism of Human Fever Reaction
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Background: Given that pharmacopoeia pyrogen tests, rabbit pyrogen test, and limulus amoebocyte lysate (LAL) test have some shortcomings, supplements for pyrogen tests are necessary. </p><p> Objective: This study aimed to develop a novel monocyte-based pyrogen test. </p><p> Method: The human promyelocytic leukemia cell line (HL-60), which was selected for its high sensitivity to pyrogens, such as lipopolysaccharide (LPS), zymosan, and lipoteichoic acid (LTA), was evaluated for interleukin- 6 (IL-6) production with IL-6 ELISA kit. The important parameters of the assay were researched, and a novel pyrogen test was developed. The linearity, reproducibility, and accuracy of the assay were verified, and the assay was compared with the LAL test by assessing the response to samples containing pyrogen. </p><p> Results: HL-60/IL-6 assay was developed as a novel monocyte-based pyrogen test. The linearity between the pyrogen concentration and IL-6 amount was good (R<sup>2</sup> > 0.96), and the RSD of the assay was not more than 20%. The recovery of pyrogens in biological products, such as monoclonal antibody, vaccine, and blood products, ranged from 50% to 200%. The pyrogen level detected by the assay was similar to that detected by LAL. </p><p> Conclusion: The developed HL-60/IL-6 assay was a good supplement to traditional pyrogen tests for the detection of pyrogens, such as LPS, zymosan, and LTA.
Despite an Extensive Sequence Analysis Identification of Functional Candidates Amongst Hypothetical Proteins of Neisseria gonorrhoeae
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Background: Neisseria gonorrhoeae is a Gram-negative, obligate human specific pathogenic bacteria, predominantly causing a sexually transmitted infection known as gonorrhoea. The frequent emergence of new multiple drug resistant strain needs an extensive study of its genome for the development of new drug/vaccine target. </p><p> Objective: Here, our aim is to predict the function of all hypothetical proteins (HPs) of Neisseria gonorrhoeae genome using modern bioinformatic-tools. </p><p> Method: We have analyzed the genome sequence of N. gonorrhoeae and found that ~43% of genes are listed as conserved HP, for which no biochemical evidences are reported. To predict their possible functions using various bioinformatics tools and databases we have annotated amino acid sequences of all HPs from N. gonorrhoeae genome. </p><p> Results: We found proteins of unknown functions belonging to various classes. Functions of 478 proteins were annotated and we observed that out of these proteins 48% are enzymes, 10% as transporter, 5% proteins as nucleic acid-binding proteins and 11% sequences contain a domain of unknown function. </p><p> Conclusion: Functional annotation and identification of functionally important regions in the HPs from N. gonorrhoeae may be helpful for better understanding of its virulence mechanism, adaptability in host system, tolerance for host immune system and emergence of novel therapeutic intervention. </p><p>
The Gender Bender effect in Periodontal Immune Response
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Background: The gender and sex of an individual is known to have a significant bearing on the immune system, responsible for protection against infections and disease. Contemporary evidence suggests there exists a sexual dimorphism in the hetero immune as well as autoimmune responses in human beings and females show stronger and more vigorous immune responses to antigenic stimulations, e.g infectious diseases and vaccination. The evidence supportive to gender based heterogeneity in immune responses specifically in context of periodontal disease, is mounting in contemporary literature. </p><p> Method: A thorough and methodical search for related scientific publications have been accomplished by using different key words and terms like sex or gender based immune differences in periodontal disease, both by manual methods and on various electronic databases. Primary research articles, narrative and systematic reviews of good quality, relevant to the subject were included. </p><p> Results: The aggregate effects of the factors related to gender such as the steroid hormones as well as gene based differences in both sexes as supported by published literature are in line with the observed variation in susceptibility for chronic periodontitis in both genders , with males showing more risk for disease than women. </p><p> Conclusion: Gender as a risk factor for periodontal disease needs to identified, its underlying mechanisms to contribute needs to be revealed, so that novel strategies for risk assessment, disease identification and individualized therapeutic approaches can be developed for optimized patient care. </p><p>
Controlled Drug Delivery Using Microdevices
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Therapeutic drugs administered systematically are evenly distributed to the whole body through blood circulation and have to cross many biological barriers before reaching the pathological site. Conventional drug delivery may make drugs inactive or reduce their potency as they may be hydrolyzed or degraded enzymatically and are rapidly excreted through the urinary system resulting in suboptimal concentration of drugs at the desired site. Controlled drug delivery aims to localize the pharmacological activity of the drug to the desired site at desired release rates. The advances made by micro/nanofluidic technologies have provided new opportunities for better-controlled drug delivery. Various components of a drug delivery system can be integrated within a single tiny micro/nanofluidic chip. This article reviews recent advances of controlled drug delivery made by microfluidic/nanofluidic technologies. We first discuss microreservoir-based drug delivery systems. Then we highlight different kinds of microneedles used for controlled drug delivery, followed with a brief discussion about the current limitations and the future prospects of controlled drug delivery systems.
Emerging Immunotargets in Metastatic Renal Cell Carcinoma
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Renal cell carcinoma (RCC) is one of the most immunoresponsive human cancers. High-dose IL-2 and Interferon-α were once the principle therapies for metastatic RCC, however they had harsh-tolerance profiles and limited response rates. In the last decade, targeted therapies have supplanted cytokine therapy due to higher response rates and more favorable toxicity profiles. Emerging immunotherapies targeting the PD-1 receptor and PD-L1 ligand have shown promising results. Likewise, other novel targeted immunotherapies are currently under evaluation. The safety profiles and response rates of new generation immunotherapies are encouraging and justify the progression of clinical trials. However, longer follow-up data are needed to confirm these promising results. In addition, it is still unclear if an optimal sequence or combinations of new immunotherapies paired with current targeted therapies will emerge.
Editorial (Thematic Issue: Molecular Modeling, Molecular Dynamics and Bioinformatics in Pharmaceutical Design)
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Editorial (Thematic Issue: Pulmonary Delivery of Systemic Drugs- from Aerosol Generation to Efficacious Delivery)
Today, 12 Ιουλίου 2016, 4:09:45 μμ
What is the Current Role of Immunotherapy for Colon Cancer?
Today, 12 Ιουλίου 2016, 4:09:45 μμ
Colon cancer is a leading cause of cancer related mortality. Until very recently the only existing options that medical oncologists had to treat metastatic colon cancer were a combination of chemotherapy, anti-EGFR and anti-angiogenic agents. We currently have the first proof that immune therapies could be an effective approach to battle colorectal cancers that carry a mismatch repair machinery deficient phenotype. It is expected that as our knowledge of the different mechanisms of immune-resistance grows, this therapeutic modality might soon be applicable to all patients. However, due to the continuous increase in the cost of oncological drugs, some treatment overheads may soon become prohibitive for many. In this review we will examine the current evidence related to this topic with the objective to provide the reader with concise but practical information about the potential role of immunotherapy in CRC.
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