Current Nanoscience - Volume 7, Issue 1, 2011

The 2011 inaugural issue of Current Nanosciences is dedicated to the memory of Professor Rui Manuel Ramos Morgado who, if among us, would turn 78 years old this upcoming May 10th. As posthumous acknowledgement and recognition of his outstanding performance as Full Professor at the Faculty of Health Sciences of University Fernando Pessoa, an exceptional scientific work is now published focusing on the emerging field of Novel Nanomedicines for Brain Targeting. During his entire life, Professor Rui M. R. Morgado has inspired many Students and Scholars in the field of Pharmaceutical Technology to pursue their academic and scientific careers a step further, making him an exceptional individual worthy of our admiration, emulation, and homage being paid in these pages. An enjoyable element of publishing this tribute to him comes from the key element of Brain Targeting. As a part of the central nervous system, the brain is protected by the blood brain barrier (BBB) which controls its homeostasis and transport of endogenous and exogenous molecules, by controlling their selective and specific uptake, efflux, and metabolism. Thus, some pharmacologically active drug molecules have difficulties in reaching the brain because they are unable to cross the BBB. The drugs existing in the pharmaceutical market to treat brain diseases, such as stroke, depression, schizophrenia, epilepsy, Alzheimer's and Parkinson's disease, migraine headache, and also other brain inflammations and infections, show a lack of selectivity against neuronal targets, mainly due to the poor penetration of BBB. Failure of the treatment is often reported. Therefore, the scientific research in this field has been focused on the development of strategies to target and deliver several drugs to the brain. These include both carrier- and receptor-mediated transport systems. This special issue will provide a theoretical and practical guidance for academic scientists and students, and also researchers in developing novel drug delivery systems - Nanomedicines - to the brain. The biology and physiology of BBB, the evolution of brain therapy, targeting and delivery will be briefly discussed, and also how to select the most suitable system to obtain stable and scalable formulations for achieving desired pharmacokinetic profiles. A special manuscript is devoted to inflammatory neurological disorders and in a more detail, the several approaches for delivering drugs locally and systemically using carriermediated transport systems and receptor-mediated non-viral systems. This hot special issue gathers contributions from worldwide experts in the field of brain delivery and targeting from Portugal, India, USA, Japan, China, Canada, and Italy. Recognised acknowledgements are also addressed to all the contributors, who have devoted their efforts in undertaking some of their finest work to a timetable that has been quite challenging, and to the manuscript reviewers for their help in making this issue a success. My sincere thanks to Prof. Dr. Maria Jose Sa, neurologist at Hospital Sao Joao in Porto and Associate Professor at the Faculty of Health Sciences, for kindly accepted the invitation to contribute with her expertise in Neurological Diseases, allowing opening this issue with a comprehensive lecture in the field. I hope this special issue will please readers and inspire them with future strategies for exploiting this exciting research field.

Central nervous system (CNS) inflammation and neurological diseases are clinical conditions requiring a multifaceted spectrum of immunotherapies. The present paper reviews the etiopathogeny of demyelinating diseases located in the CNS (e.g., multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica), and in the peripheral nervous system (e.g., acute/chronic idiophathic inflammatory polyradiculoneuritis, and other dysimmune neuropathies). The pharmacological treatments here discussed include non-specific strategies (e.g., glucocorticoids, intravenous immunoglobulin) and others more specific, such as human IFNβ, glatiramer acetate, mitoxantrone, monoclonal antibodies, fingolimod, laquinimod, cladribine, fumarate, teriflunomide. The immunotherapies are described in terms of their specific and/or multiple activity in the disease stage of development (i.e., initiation, central/peripheral activation, molecular stimulation and immune effector responses during early, transitional and late phases). In the light of the current pharmacological treatments, novel site specific approaches using nanoparticles are briefly addressed.

In last few years, scientists have been constantly engaged in the research to develop an effective drug delivery system to the brain. The blood brain barrier (BBB) is a formidable obstacle for a large number of drugs. As a consequence, it prevents effective treatment of many severe and life threatening diseases associated with brain. The BBB is a tight junction of brain capillary endothelial cells (BCECs), that abolishes aqueous paracellular pathway across the cerebral endothelium and it is also a rate-limiting factor in determining permeation of a drug into brain. Many attempts have been envisaged to overcome the BBB following drug transport. The most commonly used attempts are chemical modification of drug molecule or transient opening of BBB by osmotic methods. But none of these methods decisively proved their potential in drug delivery to brain. Other alternative strategies are to use carrier systems, e.g. liposomes, polymeric nanoparticles, solid lipid nanoparticles, colloidosomes, dendrimers, to delivery drug to brain.

Due to the presence of the blood brain barrier (BBB) and the intrinsic complex structure of brain, there are several challenges to overcome in the treatment of brain diseases, for both diagnosis and targeting. The advancement of fast-growing nanotechnology provides many novel tools and creative ideas that can be used to solve these challenges. In the past decades, nanoparticles have been successfully employed as carriers for targeting drug delivery. The nanoparticles can deliver magnetic/imaging agent or a drug molecule specifically to the target site with a much higher concentration, and thus improve the efficiency of detection and treatment of the disease than traditional methods. Recently, the application of magnetic nanoparticles for diagnosis and targeting in brain has attracted significant attention. Many breakthroughs in this field have been demonstrated, and new inspiring conceptual ideas have been proposed. This review describes recent exciting advancements in magnetic nanoparticle based diagnosis and targeting drug delivery for the treatment of brain diseases. The mechanisms of magnetic nanoparticles-assisted diagnosis are discussed as well as the advantages of using nanoparticlesbased approaches for targeting drug delivery through brain barrier.

The treatment of brain tumors including glioblastoma multiformes (GBMs) remains a challenge. The main option is still surgery to remove the bulk of the tumor and adjuvant treatments for the infiltrating parts. The blood brain barrier (BBB), however, restricts the access of chemotherapeutic agents to the tumor. The use of nanoparticle-based drug delivery systems (DDSs) has an increasing impact on disease diagnosis and therapy. By altering their size, composition, and surface chemistry, nanoparticles can be developed into a universal platform with multifunctional capabilities to meet the tunable requirements of different DDS. Thus, nanoparticles have the potential for targeted delivery of therapeutic cargo to brain tumors combined with simultaneous detection and imaging functions, providing a new strategy for effective therapy. The purpose of this article is to provide an updated review on the current progression and future possibilities of treating brain tumors with nanoparticles.

The blood-brain barrier (BBB) exerts its central nervous system (CNS) protective function as it hinders the delivery of diagnostic and therapeutic agents to the brain. Gene therapy could be applied in conquering brain diseases such as neurodegenerative diseases and brain tumors by up- or down-regulating expression of diseased proteins. With the development of nanotechnology during the last thirty years, the nanocarriers for delivering drugs including gene medicines make it possible to transport drugs across the BBB. The nonviral nano-scaled gene delivery systems hold great promise for treating brain diseases due to their safety and convenience. Several brain targeting strategies, such as adsorptive- and receptor-mediated pathways have been developed to improve the brain targeting efficiency of non-viral gene delivery systems. In this review, the non-viral nanocarriers are focused for gene delivery and several possible strategies are discussed to achieve brain targeting effects. Finally, the applications of gene therapy in several brain diseases will be introduced.

The present study investigates the prospective of surface engineered solid lipid nanoparticles as vectors to bypass BBB and provide improved therapeutic efficacy of encapsulated anti-cancer drug Methotrexate (MTX). MTX loaded SLNs were prepared and conjugated with cationic bovine serum albumin (CBSA). Ligand conjugated and unconjugated formulations were characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, particle size/polydispersity index and zeta-potential analysis. In vitro, the SLNs exhibited a biphasic pattern illustrated by an initial rapid release followed by rather sustained release profile of the drug. Furthermore, hemolytic studies elucidated the formulations to be biocompatible when compared to MTX. Transendothelial transport study on brain capillary endothelial cells (BCs) depicted CBSA conjugated SLNs to undergo transcytosis to a greatest extent. These SLNs were preferably taken up by BCs and Human neuroglial culture (HNGC)-1 tumor cells as evaluated against unconjugated SLNs and plain MTX. Furthermore, cytotoxicity studies were performed on HNGC1 tumor cells. CBSA conjugated SLNs exhibited more potent cytotoxic effect on HNGC1 cells than free MTX. The results clearly indicate prospective of CBSA conjugated SLNs loaded with MTX in brain cancer chemotherapy with augmented ability to bypass blood brain barrier.

In the field of biomedical sciences, nanotechnology has emerged as a novel approach to design and develop drug delivery carriers (i.e. nanoparticles). The inspiration of nanoparticles as delivery vehicles for drugs or genes arose from the concept of viral mediated delivery. Researchers envied the enhanced transport efficiency of viruses but required a delivery method that did not incorporate the virus- induced pathological, immunological and oncological side-effects. Thus, bio-mimicked nanoparticles were prepared from synthetic polymers for efficient delivery of therapeutic molecules. However, biotherapeutics delivery across blood-brain-barrier is still a challenging task due to the inherent neuroprotective mechanism of the human brain. Recent studies suggest that cationic cell penetrating peptides can be used in designing targeted nanoparticles. This review describes the anatomical and physiological barriers of the brain with their special features and limitations for drug delivery and role of cationic cell penetrating peptides in designing nanoparticles for targeted biotherapeutics delivery to the brain. It emphasises the use of polymeric nanoparticles and their characteristics with respect to size, surface tolerability and multifunctionality. These properties aid them to cross the biological barriers of the brain. The multifunctionality of nanoparticles has been further explored with the application of cell penetrating peptides conjugated with nanoparticles for delivery at specialized location. The utilization of peptides on nanoparticles has encouraged and facilitated the approach of using non-invasive techniques not only to deliver drugs but also genes and proteins with minimal side-effects and toxicity when compared to conventional invasive techniques of therapeutic delivery to the brain. This technology has shown to be promising as a possible treatment method for a number of neurological disorders in both in vitro and in vivo models.

While in the latest years carbon nanotubes have found wide exploitation in nanomedicine, to date biomedical applications of boron nitride nanotubes (BNNTs) are almost totally unexplored. BNNTs are structural analogues of carbon nanotubes: alternating B and N atoms entirely substitute for C atoms in a graphitic-like sheet, with almost no change in atomic spacing. Despite this structural similarity, BNNTs present superior chemical and physical properties that render them more amenable for a plenty of applications in the biomedical field. In this review, we summarize the major findings of the studies about the interactions between BNNTs and living matter, with special attention on the potential applications to the neuronal system, which range from the treatment of neuronal diseases, to the stimulation of neurons, up to the exploitation of BNNTs as structural reinforcement agents for tissue engineering.

Targeting imaging and enhanced radiotherapy are very important issues for decrease in diagnosis and therapy. Functionalized gold nanostructures show low toxicity and excellent optical properties, and thus, they can be used as the contrast agent in cancer cell imaging. Furthermore, gold nanostructures can enhance radiotherapy due to strong photoelectric absorption and second electron caused by gamma or X-ray irradiation. This critical review provides a recent progress in fabrication, optical properties (especially, fluorescence of nanoclusters), surface modification, targeting imaging, and enhanced radiotherapy of gold nanostructures. It will interest the radiation medicine, chemistry, spectroscopy, biochemistry, biophysics, and nanoscience communities.

Brain disorders including neurological disorders, inflammatory and infectious conditions of brain, brain cancer and brain stroke pose a significant challenge globally. The blood brain barrier (BBB) an important physiological barrier limits access of drug to the site of action. While passive diffusion and endogenous carrier mediated transport are two important mechanisms for the transport of substances across the BBB into the luminal side, efflux transporters severely limit drug concentration. Drug delivery strategies must address on one hand methods to bypass the BBB and on the other hand methods to overcome efflux transporters. Lipid based nanocarriers, liposomes and solid lipid nanoparticles are widely investigated for brain targeting. Emulsion based lipid nanocarriers like microemulsions (ME) and nanoemulsions (NE) provide an additional advantage of greater bypass of the reticulo-endothelial system with improved brain targeting. More recently the promise of ME and NE for brain delivery has been cited. Oil, surfactants and water are the primary components of ME and NE. ME may additionally comprise cosurfactants. The reviews discusses the development of ME/NE, design of functional ME/NE by appropriate selection of primary ME/NE components which could provide improved brain delivery by functioning as stealth agent, absorption enhancer, efflux transporter inhibitor or even facilitate receptor mediated endocytosis. Engineering functional ME/NE into multifunctional ME/NE as a strategy to further enhance brain targeting is also presented. Functional and multifunctional excipients have been discussed. The possible routes of delivery namely intravenous, oral and intranasal and therapeutic applications of ME/NE designed for brain targeting is also reviewed.

Layered double hydroxides (LDHs) and anionic clay are nano-ordered layered compounds and are well known for their ability to intercalate anionic compounds. Most LDHs are prepared conventionally only with di- and tri-valent cations. Alumina-silicate structures are very familiar in the literature as cationic clay or zeolite structure, however, there is no data for alumina-silicate as anionic clay. In this study, a new series of Zn-Al-Si LDHs with various Zn/Al/Si ratios, consisting of di-, tri-, and tetra-valent cations, were prepared and characterized by energy-dispersive X-ray spectrometry (SEM/EDS), X-ray powder diffraction (XRD), infrared spectra (IR), thermal analyses (TG, DTG and DTA), and scanning electron microscopy (SEM). Characterization of the samples containing molar percentages of aluminum and silicon 20∼40 % revealed formation of well crystallized phases, layered structures and no excess phases. XRD results and thermal analyses indicated that the carbonate anions have two orientations inside the interlayer region. After intercalation reactions with organic acids, mono- and di-carboxylic acids, the interlayer spacing of Zn-Al-Si LDH increased and organic-inorganic nano-hybrid materials formed. SEM images showed that the morphology of Zn-Al-Si LDH before and after intercalation reactions is plate-like structure. The results presented in this work conclude that the formation of the layer double hydroxide is not limited to the reactions between di- and trivalent cations, although these are the only reactions reported by many researchers.