Current Pharmaceutical Design - Volume 22, Issue 22, 2016

There is a broad range of biological, chemical and physical hurdles for drugs to reach the brain. Nanoparticulate drug delivery systems hold tremendous potential for diagnosis and treatment of brain disorders, including the capacity of crossing the blood–brain barrier and accessing to the brain after systemic administration. Thus, nanoparticles enable the delivery of a great variety of drugs including anticancer drugs, analgesics, anti- Alzheimer's drugs, protease inhibitors, and several macromolecules into the brain. Moreover, nanoparticles may importantly reduce the drug's toxicity and adverse effects due to an alteration of the body distribution. A very critical and important requirement for nanoparticulate brain delivery is that the employed nanoparticles are biocompatible and, moreover, rapidly biodegradable. Therefore, nanocarriers fabricated from natural polymers including polysaccharides and proteins are particularly interesting. Meeting requirements such as low cytotoxicity, abundant surface functional groups, high drug binding capacity and significant uptake into the targeted cells, natural polymer-based nanocarriers represent promising candidates for efficient drug and gene delivery to the brain. The current review highlights the latest advances achieved in developing drug-loaded polysaccharide and protein nanocarriers for brain delivery. The nanoparticles are discussed with respect to their formulation aspects, advantages, limitations, as well as the major outcomes of the in vitro and in vivo investigations. Modification of the nanoparticle surface with specific brain targeting ligands or by coating with certain surfactants for enhanced brain delivery is also reviewed. In addition, the mechanisms of the nanoparticle-mediated drug transport across the BBB are also discussed in this review.

Background: Treatment by the pulmonary route can be used for drugs that act locally in the lungs (e.g. lung cancer) or non-invasive administration of drugs that act systemically (e.g. diabetes). The potential of using drug delivery systems (DDS) formed from non-ionic surfactants or natural products for pulmonary drug delivery are reviewed. Methods: The effectiveness of each DDS depends on it ability to not only entrap the relevant drug and alter its bio distribution, but also its ability to withstand the physical stresses during nebulization and for the nebuliser to produce aerosol particles with the size for deposition in the appropriate part of the lungs. Different methods must be used to prepare nanoparticles (NP) using non-ionic surfactants, or biocompatible polymers from natural proteins or sugars, and the aqueous solubility of the drug also influences the manufacture method. Results: NP produced using non-ionic surfactants, proteins such as collagen, albumin or gluten, and polysaccharides such as chitosan, hyaluronate, cellulose, carrageenans, alginate or starch has successfully delivered different types of drugs given by the pulmonary route. Drug entrapment efficiency depends on the DDS constituents and the manufacture method used. Large scale manufacture of DDS from natural products is technically challenging but changing from batch manufacture to continuous manufacturing processes has addressed some of these issues, and inclusion of a spray drying step has been beneficial in some cases. Conclusion: DDS for lung delivery can be produced using natural products but identifying a cost effective manufacture method may be challenging and the impact of using different type of nebulisers on the physiochemical characteristics of the aerosolised formulation should be an essential part of formulation development. This would ensure that some of the development work e.g. stability studies do not have to be repeated as they will identify if a carrier to protect the DDS from the physical trauma caused by nebulisation.

Background: Engineered magnetic nanoparticles (MNPs) possess unique properties and hold great potential in biomedicine and clinical applications. With their magnetic properties and their ability to work at cellular and molecular level, MNP have been applied both in-vitro and in-vivo in targeted drug delivery and imaging. Focusing on Iron Oxide Superparamagnetic nanoparticles (SPIONs), this paper elaborates on the recent advances in development of hybrid polymeric-magnetic nanoparticles. Their main applications in drug delivery include Chemotherapeutics, Hyperthermia treatment, Radio-therapeutics, Gene delivary, and Biotheraputics. Physiochemical properties such as size, shape, surface and magnetic properties are key factors in determining their behavior. Additionally tailoring SPIONs surface is often vital for desired cell targetting and improved efficiency. Polymer coating is specifically reviewed with brief discussion of SPIONs administration routes. Commonly used drug release models for describing release mechanisms and the nanotoxicity aspects are also discussed. Methods: This review focus on superparamagnetic nanoparticles coated with different types of polymers starting with the key physiochemical features that dominate their behavior. The importance of surface modification is addressed. Subsequently, the major classes of polymer modified iron oxide nanoparticles is demonstrated according to their clinical use and application. Clinically approved nanoparticles are then addressed and the different routes of administration are mentioned. Lastly, mathematical models of drug release profile of the common used nanoparticles are addressed. Results: MNPs emerging in recent medicine are remarkable for both imaging and therapeutics, particularly, as drug carriers for their great potential in targeted delivery and cancer treatment. Targeting ability and biocompatibility can be improved though surface coating which provides a mean to alter the surface features including physical characteristics and chemical functionality. The use of biocompatible polymers can prevent aggregation, increase colloidal stability, evades nanoparticles uptake by RES, and can provide a surface for conjugation of targeting ligands such as peptide and biomolecules with high affinity to target cells. Conclusion: Great efforts to bring MNPs from lab testing stage to clinic are needed to understand their physicochemical properties and how they behave in vivo, which resulted in few of them to exist in the market today. Although magnetic nanoparticles have not yet fully reached their optimal safety and efficiency due to the challenges they face in vivo, their shortcomings can be overcome through improvement of magnetictargeted carrier by pre-clinical trials and continuous studies.

The use of nanodevices to transport active compounds like small-molecular drugs, peptides, or genes found an increased attention throughout the different fields of natural sciences. Moreover, recent research trends are focused on the employment of smart nanocarriers able to react on certain internal or external applied stimuli, in order to achieve temporal and site-specific drugs/gene release. In contrast to traditional biodegradable nanocarriers that slowly release drugs inside the cells, these smart nanosystems are able to quickly release or even dump drugs in response to a specific biological signal in the target cancer cells such lower pH, high redox potential or over expression of enzymes or to external stimuli such as temperature, light, ultrasounds and magnetic field. This review gives a brief overview about some types of stimuli-responsive nanocarriers, with the main focus on magnetic fieldresponsive devices obtained from natural polymers. The concept of magnetic field-sensitive nanocarriers, their advantages and disadvantages, the methods of preparation and applications in various fields of drug delivery will be explored, giving an exhaustive collection of the findings of recent investigations.

Cancer has become one of the main causes of death in developed countries, and it is expected to be declared as the disease with the highest worldwide morbidity and mortality indexes in the coming decades. Nanomedicine aims to overcome some problems related to this prevalent disease, particularly the lack of efficient diagnostic and therapeutic tools. The most recent scientific advances, which have conducted to a more personalized medicine, were focused on the production of nanocarriers involved into the transport and the delivery of drugs to targeted cells. A wide variety of nanocarriers composed by different materials have been designed for their use as drug delivery systems. Polysaccharides have emerged as very useful biopolymers among all raw materials used in the preparation of these nanoplatforms. They are highly stable, non-toxic and biodegradable molecules, and also present some chemical properties which are very difficult to reproduce using artificial polymers. Anionic polymers, such as hyaluronic acid, heparin or alginate, present some structural and chemical characteristics which make them ideal polymers to prepare nanosystems with anticancer applications. This review will focus on the description of some anionic polysaccharides and the possibilities they offer towards the preparation of nanosystems with applications in cancer treatment and diagnostics.

Chitosan nanogels present a very interesting combination of valuable characteristics for drug delivery; those derived from their nanometric size, such as, large surface area, rapid stimuli-response, and easy functionalization; and those emerged especially from their biocompatibility, biodegradability and mucoadhesive nature. Due to this, chitosan nanogels have reached a prominent position as nanocarriers and have originated accelerated research worldwide. Diverse methods to prepare chitosan nanogels have been reported, showing a dependence on final swelling, drug encapsulation capability and release properties with different synthesis variables, in such a way that they can be exploited to be modulated. The present review describes the properties of chitosan nanogels, along with the different methods of crosslinking and confining chitosan in nanosized particles, and the various fields of drug delivery where they have been applied. This work aims to emphasize the connection between the characteristics of chitosan and the synthetic variables with the final properties of chitosan nanogels in order to enhance controlled drug loading and a sustained release.

Background: Now a day’s natural polymer based nanoparticulate system have been widely studied as particulate vehicles in the bio-medical and pharmaceutical area. Alginate, a natural biopolymer show good biodegradability, biocompatibility and non toxic, has received attention to utilise as a carrier for preparation of polymeric nanoparticles. Chemically and physically alginate can modified easily and obtained various structure having various properties, and versatile applications. Various properties and structure such as biodegradability, gelling property, mechanical strength and cell affinity can be obtained through combination of alginate with other biopolymers, immobilization of specific molecules such as sugar molecules and peptide through chemical or physical cross-linking. Conclusion: In this article, we report different method of preparation of alginate nanoparticles, and also focus on recent advances of nanoparticles made of alginate and its modified form in the field of drug delivery applications.

Background: Dextran (DX) is a natural polysaccharide produced in the laboratory by fermentation of sucrose under the effect of the enzyme DX sucrase (1,6-α-D-glucan-α- glucosyltransferase). After harvesting and purification DX is subjected to cracking and separation to obtain the desired molecular weight. Methods: The hydroxyl groups present in DX offer many sites for derivatization allowing the production of functionalized glycoconjugates biocompatible compound. DX and its derivatives are getting increased attention for use in core decoration or as carriers in novel drug delivery systems. This includes, among others, ion-pairing, self-aggregate, protein and drug conjugates. DX carriers and camouflaged particles will be dealt with in this review to give emphasis on the great versatility of this natural biocompatible polysaccharide. Conclusion: With the continuous development in the area of drug delivery, we believe that the unique properties of this versatile nanocarrier platform will elect it as one of the cornerstones of safe nanodelivery systems.

During the last years we have seen an increasing number of reports describing new properties and potential applications of cationic polymers and derived nanostructures. This review gives a summary of their applications in drug delivery, the preparation methods for nano and microstructures and will attempt to give a glimpse on how their structure, chemical composition and properties may be affected or modulated as to make them suitable for an intended application as drug delivery nanocarriers. The compositional complexity with the existence of several reacting groups makes cationic nanostructures critically sensitive to the contribution of thermodynamic and kinetic parameters in the determination of the type and stability of a particular structure and its ability to respond to changes in environmental conditions in the right time frame. Curiously, and contrarily to what could be expected, despite the fact that cationic polymers can form strong electrostatic interactions the contribution of the entropic component has been often found to be very important for their association with negatively charged supramolecular structures. Some general considerations indicate that when considering a complex multimolecular system like a nanocarrier containing an active ingredient it is frequently possible to find conditions under which enthalpic and entropic contributions are compensated leading to stable structures with a marginal thermodynamic stability (free energy change close to zero) which make them able to respond relatively fast to changes in the environmental conditions and therefore suitable for the design of smart drug delivery systems. Like with other nanocarriers, it should always be kept in mind that the properties of cationic nanocarriers will depend not only on their chemical composition but also on the properties of the structures formed by them.

Background: Nanoparticulate delivery systems receive a lot of attention in pharmaceutical research and market due to their in vivo stability, ability to protect entrapped drug, and ease of cellular penetration. The hemocompatibility and the clearance half-life are important parameters of the nanodelivery systems that will be administered through intravenous route. Natural components, like blood plasma proteins are ideal sources of biomaterial for such systems with their long in vivo half-lives. Methods: The aim of this work is to review in vitro, in vivo and clinical findings of nanocarriers based on blood plasma proteins, namely albumin, lipoproteins, fibrin/fibrinogen, transferrin. Plasma protein based nanocarriers loaded with different bioactive molecules (i.e., anti-cancer, antiviral, anti-epileptic drugs, DNA) have been developed using different preparation methods like desolvation, emulsification, nab-technology, complexation methods. Results: Human serum albumin has attracted the most attention in the last decade as nanocarrier due to its biocompatibility, high binding capacity to various drugs, and easy derivatization by covalent methods. Commercial products of albumin nanoparticles have emerged on the market after its recognition. Low and high density lipoproteins have recently been considered as valuable natural material for preparing hemocompatible small (app 20 nm) lipid-protein vesicles. For other proteins of plasma, however, there are a limited number of studies that explored their potential as nanocarrier formulation. Therefore, there is huge research potential for investigating the proteins like globulins, fibrinogen and transferrin as part of nanocarrier core. Conclusion: Plasma protein based nanoparticulate delivery systems, especially albumin based ones have opened up and also will continue to open new treatment strategy options for treating cancer, AIDS and other complex life threatening diseases with advances in nanotechnology and science.

Nanotherapeutics has the potential of providing limitless opportunities in the area of drug and gene delivery for treatment of cancer. Although the path toward commercialization of nanoparticulate oncology drugs is long and carries significant risks, there is still considerable excitement for utilizing nanoparticle technologies in cancer drug development. Recently, there has been a significant growth in the number of nanoparticle delivery systems, used in clinical trials. Several incorporations have been established between pharmaceutical and nanotechnology companies striving to understand, develop and utilize effective interactions between nanomaterials and biological systems for cancer treatment by means of colloidal delivery systems. Protein-based nanoparticles, with one already approved and several under-development products in the commercial market, are of the pioneers of the successful employment of nanoparticulate systems in improving the cancer treatment techniques. The main reason behind the widely tendency to the usage of protein-based systems is their possibility of functionalization, biocompatibility, nonimmunogenicity, and high loading capacity for both hydrophobic and hydrophilic therapeutics. The aim of this review is to provide a comprehensive overview on the most recent findings in the area of utilization of protein-based nanoparticles for delivery of anticancer agents, as well as interpretation of the challenges encountered in the field.

Background: Native lipoproteins as nanoparticulate drug delivery systems have gained considerable attention in recent years. This is due to their biocompatibility, being endogenous, no triggering the immunological responses, relatively long half-life in the circulation, simple diffusion from vascular to extravascular compartments due to their nanometric particle size, potentially targeting capability to cellular receptors, simple preparative processes in the reconstituted forms, easy functionalization and high capacity for drug loading. Clinical application of many therapeutic agents like anticancer drugs and genes is hampered due to their susceptibility to degradation and difficult delivery into cells. Several nanoparticle platforms for siRNA delivery have been developed to overcome the major limitations facing the therapeutic uses of bioactive therapeutic agents. Methods: This review covers a broad spectrum of lipoproteins as non-viral drug and gene delivery systems. These nanoparticles are developed for enhanced cellular uptake and specially targeted gene silencing in vitro and in vivo and their characteristics and opportunities for clinical applications of therapeutic agents are discussed in this article. Various types of lipoprotein nanovectors including: natural and modified lipoproteins used to deliver drugs, bioactive and genetic materials are introduced and the development of theranostics and combinational treatments are also discussed. Results: The unique physicochemical properties of lipoproteins as natural nanostructures in biological systems and their structural diversity, including chylomicrons, VLDL, LDL and HDL, has caused their utility as potent pharmaceutical carriers. Conclusion: According to the literatures, different lipoproteins especially the artificial lipoproteins, reconstituted and modified ones have potential to be used in targeted delivery of therapeutic agents to the tumors and effective delivery of the corresponding genetic and other bioactive components involving in diseases.