Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease.
A central issue in the understanding of the pathogenesis of nonalcoholic fatty liver disease is the problem of the underlying mechanisms which are not fully understood. In the setting of excessive central adiposity, insulin resistance is the major underlying cause of fat accumulation in hepatocytes. Because of the difficulties with human trials, several animal models have been developed for this purpose mainly characterized as follows: genetically disturbed or murine fatty liver, methionine-choline deficient diet fed or murine steatohepatitis, and high-fat or sucrose diet fed models. Although these animal models have provided useful information, none of them accurately reflect genetic, metabolic and biochemical characteristics of the human disease.
Drug Delivery to Stem Cells in Regenerative Medicine
Translation of nanoscale discoveries from the laboratory to the clinic promises new diagnostic tools, drug targeting modalities, gene therapy platforms, and tissue constructs for patients. Tissue morphogenesis during fetal development is highly dependent on spatial and temporal expression of multiple morphogens targeting different progenitor cells. During fetal development, mesenchymal stem cells (MSCs) and endothelial colony forming cells (ECFCs) are implicated in bone formation coupled by paracrine signalling between the two progenitor cells. The invading ECFCs secrete osteogenic morphogens (BMP2) to stimulate cell differentiation and mineralization whereas the differentiating MSCs release vasculogenic morphogens (VEGF) to further stimulate capillary formation for the metabolically active osteoblasts. I will present in my seminar novel drug delivery strategies and tissue models for timed and localized release of morphogens using self-assembled nanogels in a micro-patterned co-culture system to stimulate paracrine signalling and coupling osteogenesis to vasculogenesis.
Esmaiel Jabbari, University of South Carolina, USA
Strategy in crystallization process to ensure solid state stability of drug substance
Crystallization of pharmaceutical ingredients, primarily those that possess several polymorphic forms, particle size and morphology critical properties, are among the most serious and least understood manufacturing procedure. Many processes and product failures can be traced to a poor understanding or lack control of the crystallization procedures. Clearly the pharmaceutical industry requires to getting more competitive and robust process by the knowledge of molecular complexity and solid form challenges, due to the impact of material properties for production efficiency related to the solid implication on drug product formulation.The content of this presentation is focused on reporting real case examples from the lab and development scale to production, throughout in-process crystallization measurements and control by means also of PAT approaches. Process understanding using in-process techniques in development scale, such as automated batch reactor vessels equipped with Reaction Calorimetry, ATR/FT-IR Spectroscopy, Focus Beam Reflectance (FBRM) probes plus temperature and pH sensors, were suitable methods to reach the desired active ingredient requirements, and then define a suitable tool in control the Critical Quality Attributes with as well benefits in process cycle time reduction. A variety of in situ analytical methods applied, combined with chemometric tools for the analysis of multivariate process information, have provided a basis for future improvement in modelling, simulation and control of crystallization procedures. These on-line recorded data together with chemical properties parameters assessed by off-line controlling techniques, are the starting point for intended processes for high quality products.
Marino Nebuloni, Parma University, Italy
Hollow Mesoporous Silica as Potential Platform for Anti-cancer Drug Delivery in Cancer Treatment
Over the last several years, mesoporous silica nanoparticles (MSNs) have been extensively developed in the field of biomedicine as nanocarriers for delivering anti-cancer drugs, due to their biocompatibility and ease of surface functionalization. However, it has certain limitations for being applied in pharmaceuticals, for example this type of material usually has low drug loading capacity. In this study, hollow mesoporous silica nanoparticles (HMSNs) were fabricated in order to increase the drug loading capacity of nanosilica materials. The synthesized HMSNs possessed inner hollow cores that could remarkably raise the total pore volume and thus improve the capacity for cargo loading. HMSNs were synthesized according to the hard-template method with three main steps: (1) forming of solid SiO2 nanoparticles as templates, (2) forming of core-shell structure by coating MSN layers onto the templates, and (3) forming of hollow core structure by etching away the solid template. The HMSNs product was characterized by TEM, XRD, TGA, FTIR and BET. In addition, drug loading capacity of the material was evaluated with doxorubicin (DOX) as model drug. The results indicated remarkable improvement in drug loading capacity, compared to MSN sample. More importantly, MTT assay data showed that the prepared HMSNs were biocompatible nanocarriers and furthermore, the incorporation of DOX into these HMSNs has been proven successful in reducing the toxicity of DOX. In the interest of the system’s biodistribution, the imaging and measurement on mice with tumor cell lines were conducted and the obtained results indicated excellent accumulation of the desired materials at tumor sites. As a part of histological investigation on HMSNs nano-drug-carrier system, long-term toxicity study was also managed by H&E organ staining. Base on the condition of the cells’ components, for examples cellular shrinkage in liver cells, condensation of chromatin or rupture of cell membrane, etc., the conclusion about toxic features from the administration of HMSNs system can be made, which in this report, showed minor in vivo toxicity. These results demonstrated the potential of HMSNs in the delivery of anticancer agents.
Dai Hai Nguyen, Institute of Applied Materials Science, Vietnam Academy of Science and Technology vietnam
Process innovation in the production of smart lipid-polymeric release systems
Liposomes are the most versatile carriers for the delivery of a large variety of both lipophilic and hydrophilic drug molecules, being biocompatible and biodegradable. Despite their great advantages, their tendency to degrade and aggregate in biological fluids as well as in storage conditions drove the research towards new preparative approaches for liposomes stabilization, essentially based on superficial coatings or inclusion in polymeric materials. However the most used techniques, such as spraying, layering, sometimes by exploiting supercritical fluids, require complex and expensive apparatuses. Therefore, this work was developed with the idea to overcome typical liposomes stabilization limits, by choosing the consolidated wet granulation process as a method to obtain granules containing liposomes in a single step, by spraying on powder the liposomal suspension, previously produced by a novel continuous and rapid simil-microfluidic method. Literature highlights, although with only few works, the use of wet granulation as method to stabilize polymeric nanoparticles suspensions, by adding them in the binder phase. Instead, there are not experimental evidences about the use of liposomes suspensions as binder phase in wet granulation for both their stabilization and incorporation in pharmaceutical solid forms. Thus, this novel combination between wet granulation and the use of liposomes suspension spray as binder phase, allowed to reach both easy and cheap liposomes stabilization and the production of smart solid multiparticulate dosage forms, which could be ideal candidates for a combined fast/slow release of active ingredients, enhancers, fortifiers.
Annalisa Dalmoro, University of Salerno, Italy
Controlled release of bacteriophage from PLGA microparticles delivered by microneedle patches to induce innate and adaptive immune system
While vaccines represent the strongest weapons against a contagious disease, several shortcomings still limit their optimal function. This can largely be attributed to the lack of a proper delivery system as well as route of administration for effective activation of the immune system [1-3]. The intradermal route has the potential to be an outstanding route of vaccination due to the localization of potent antigen present cell (APC) and other immune cells in the dermis [4]. MNPs are tiny needles, small enough (100 –1,000 μm) that perforate superficial layers of the skin to deliver a therapeutic agent into the dermis in a relatively painless and invasive manner. MNPs are generally preferred by patients as compared to traditional hypodermic injections. they take advantage of the potent intradermal immune system, which can create stronger responses than what is typical of the muscle or can generate equivalent responses from lower doses. The majority of works with microneedles has involved bolus delivery of drugs and vaccines using either coated or dissolvable microneedles, but introducing microparticles into microneedles in order to sustained release has received less attention [1]. Given these objectives and challenges, we designed a multi-compartment dissolvable and degradable polymeric microneedle patches for the sustained release of fd-OVA.
Rezvan Jamaledin, Italian Institute of Technology, Italy