Current Strategies for the Delivery of Therapeutic Proteins and Enzymes to Treat Brain Disorders

Brain diseases and injuries are growing to be one of the most deadly and costly medical conditions in the world. Unfortunately, current treatments are incapable of ameliorating the symptoms let alone curing the diseases. Many brain diseases have been linked to a loss of function in a protein or enzyme, increasing research for improving their delivery. This is no easy task due to the delicate nature of proteins and enzymes in biological conditions, as well as the many barriers that exist in the body ranging from those in circulation to the more specific barriers to enter the brain. Several main techniques are being used (physical delivery, protein/enzyme conjugates, and nanoparticle delivery) to overcome these barriers and create new therapeutics. This review will cover recently published data and highlights the benefits and deficits of possible new protein or enzyme therapeutics for brain diseases

PACAP-38 Signaling in \u3ci\u3eTetrahymena thermophila\u3c/i\u3e Involves NO and cGMP

Chemorepellents are signaling molecules, which have been shown to be important for mammalian neuronal development, and are presumed to have a role in protozoan defense. Tetrahymena thermophila represent a good model system in which to study repellents because of their ease of use in biochemical, behavioral, electrophysiological, and genetic analyses. In this study, we have used Tetrahymena as a model in which to study the chemorepellent, PACAP. Using behavioral and biochemical (EIA) assays, we have found that the NO/cGMP pathway plays an important role in PACAP signaling. An increase in intracellular calcium is also critical for PACAP avoidance, which appears to be mediated through a pertussis toxin-sensitive G-protein

Investigating Novel Syntheses of a Series of Unique Hybrid PLGA-Chitosan Polymers for Potential Therapeutic Delivery Applications

Discovering new materials to aid in the therapeutic delivery of drugs is in high demand. PLGA, a FDA approved polymer, is well known in the literature to form films or nanoparticles that can load, protect, and deliver drug molecules; however, its incompatibility with certain drugs (due to hydrophilicity or charge repulsion interactions) limits its use. Combining PLGA or other polymers such as polycaprolactone with other safe and positively-charged molecules, such as chitosan, has been sought after to make hybrid systems that are more flexible in terms of loading ability, but often the reactions for polymer coupling use harsh conditions, films, unpurified products, or create a single unoptimized product. In this work, we aimed to investigate possible innovative improvements regarding two synthetic procedures. Two methods were attempted and analytically compared using nuclear magnetic resonance (NMR), fourier-transform infrared spectroscopy (FT-IR), and dynamic scanning calorimetry (DSC) to furnish pure, homogenous, and tunable PLGA-chitosan hybrid polymers. These were fully characterized by analytical methods. A series of hybrids was produced that could be used to increase the suitability of PLGA with previously non-compatible drug molecule

Calibration of PMP Condensation Particle Number Counters - Effect of Material on Linearity and Counting Efficiency

Recently the particle number method was proposed to the light duty regulation, so the proper calibration of Particle Number Counters (PNCs) will be very important. Calibration includes the linearity measurement and the counting efficiency measurement. Labs will have to demonstrate compliance of their PNCs with a traceable standard within a 12 month period prior to the emissions test. Compliance can be demonstrated by: -Primary method: By comparison of the response of the PNC under calibration with that of a calibrated aerosol electrometer when simultaneously sampling electrostatically classified calibration particles, or -Secondary method: By comparison of the response of the PNC under calibration with that of a second PNC which has been directly calibrated by the above method. Compliance testing includes linearity and detection efficiency with particles of 23 nm electrical mobility diameter. A check of the counting efficiency with 41 nm particles is not required. A workshop was organised to investigate the effect of the material on the calibration procedures and the uncertainties of the suggested procedure. GRIMM and TSI provided PNCs and AEA, MATTER, GRIMM, TSI provided five particle generators. The experiments were conducted in the European¿s Commissions laboratories (JRC). Heavy duty diesel engine (w/o aftertreatment) particles were also produced (measurements downstream a thermodenuder) at idle and a medium load mode. The measured data were evaluated by JRC. The results showed that there was an effect of the material used and suggestions were given. In addition the uncertainties of the procedure were quantified. Theoretical calculations showed the corrections that should be applied.JRC.H.4-Transport and air qualit

PLGA-PEG-ANG-2 Nanoparticles for Blood-Brain Barrier Crossing: Proof-of-Concept Study

The treatment of diseases that affect the central nervous system (CNS) represents a great research challenge due to the restriction imposed by the blood-brain barrier (BBB) to allow the passage of drugs into the brain. However, the use of modified nanomedicines engineered with different ligands that can be recognized by receptors expressed in the BBB offers a favorable alternative for this purpose. In this work, a BBB-penetrating peptide, angiopep-2 (Ang-2), was conjugated to poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles through pre- and post-formulation strategies. Then, their ability to cross the BBB was qualitatively assessed on an animal model. Proof-of-concept studies with fluorescent and confocal microscopy studies highlighted that the brain-targeted PLGA nanoparticles were able to cross the BBB and accumulated in neuronal cells, thus showing a promising brain drug delivery system

Nanomedicine in Alzheimer's disease: Amyloid beta targeting strategy

The treatment of Alzheimer's disease (AD) is up to today one of the most unsuccessful examples of biomedical science. Despite the high number of literature evidences detailing the multifactorial and complex etiopathology of AD, no cure is yet present on the market and the available treatments are only symptomatic. The reasons could be ascribed on two main factors: (i) lack of ability of the majority of drugs to cross the blood-brain barrier (BBB), thus excluding the brain for any successful therapy; (ii) lack of selectivity and specificity of drugs, decreasing the efficacy of even potent anti-AD drugs. The exploitation of specifically engineered nanomedicines planned to cross the BBB and to target the most “hot” site of action (i.e., β-amyloid) is one of the most interesting innovations in drug delivery and could reasonably represent an promising choice for possible treatments and even early-diagnosis of AD. In this chapter, we therefore outline the most talented approaches in AD treatment with a specific focus on the main advantages/drawbacks and future possible translation to clinic application

Interleukin-15 and its receptor augment dendritic cell vaccination against the neu oncogene through the induction of antibodies partially independent of CD4 help

Interleukin-15 (IL-15) stimulates the diffrentiation and proliferation of T, B, and natural killer cells; enhances CD8+ cytolytic T-ceII activity; helps maintain CD44hiCD8+ memory T cells; and stimulates immunoglobulin synthesis by B cells. IL-15 is trans-presented to effector cells by its receptor, IL-15Rα, expressed on dendritic cells (DC) and monocytes. We examined the antitumor effect of adenoviral-mediated gene transfer of IL-15 and IL-15Rα to augment a DC vaccine directed against the NEU (ErbB2) oncoprotein. Transgenic BALB-neuT mice vaccinated in late-stage tumor development with a DC vaccine expressing a truncated NEU antigen, IL-I5, and its receptor (DCAd.Neu+Ad-mIL-15+Ad.mlL-15Rα) were protected from mammary carcinomas, with 70% of animals tumor-free at 30 weeks compared with none of the animals vaccinated with NEU alone (DC Ad.Neu). The combination of neu, IL-15, and IL-15Rα gene transfer leads to a significaintly greater anti-NEU antibody response compared with mice treated with DCAd.Neu or DCAd.Neu combined with either IL-15 (DCAd.Neu+Ad.mlL-15) or lL-15Rα (DC Ad.Neu+Ad.mlL-15Rα). The antitumor effect was antibody mediated and involved modulation of NEU expression and signaIing. Depletion of CD4 + cells did not abrogate the antitumor effect of the vaccine, nor did it inhibit the induction of anti-NEU aritibodies. Coexpression of IL-15 and IL-15Rα in an anticancer vaccine enhanced immune responses against the NEU antigen and may overcome impaired CD4+ T-helper function