Drug delivery strategies using polysaccharidic gels

Hydrogels are hydrophilic polymeric networks, with chemical or physical crosslinks, that are capable of swell and can retain a large amount of water. Among the numerous types of macromolecules that can be used for hydrogel formation, polysaccharides show very attractive advantages in comparison to synthetic polymers. They are widely present in living organisms, are usually abundant and show a number of peculiar physicochemical properties; furthermore, these macromolecules are, in most cases, non-toxic, biocompatible and can be obtained from renewable sources. For these reasons, polysaccharides seem to be particularly suitable for different applications in the wide field of pharmaceutics. As examples of the studies that have been carried out on this topic, this review will focus on two polysaccharides, alginate and xyloglucan. Alginate has been, and still is, extensively investigated and has numerous industrial applications, whereas xyloglucan was chosen because, although it has been much less studied, it shows interesting properties that should find important practical uses in the near future. The possible advantages of physical gels over those that are chemically crosslinked are also discussed.     

Interpenetrating Polymer Networks polysaccharide hydrogels for drug delivery and tissue engineering

The ever increasing improvements of pharmaceutical formulations have been often obtained by means of the use of hydrogels. In particular, environmentally sensitive hydrogels have been investigated as “smart” delivery systems capable to release, at the appropriate time and site of action, entrapped drugs in response to specific physiological triggers. At the same time the progress in the tissue engineering research area was possible because of significant innovations in the field of hydrogels. In recent years multicomponent hydrogels, such as semi-Interpenetrating Polymer Networks (semi-IPNs) and Interpenetrating Polymer Networks (IPNs) have emerged as innovative biomaterials for drug delivery and as scaffolds for tissue engineering. These interpenetrated hydrogel networks, which can be obtained by either chemical or physical crosslinking, in most cases show physico-chemical properties that can remarkably differ from those of the macromolecular constituents. Among the synthetic and natural polymers that have been used for the preparation of semi-IPNs and IPNs, polysaccharides represent a class of macromolecules of particular interest because they are usually abundant, available from renewable sources and have a large variety of composition and properties that may allow appropriately tailored chemical modifications. Sometimes both macromolecular systems are based on polysaccharides but often also synthetic polymers are present together with polysaccharide chains.     

Marine polysaccharides: therapeutic efficacy and biomedical applications

The ocean contains numerous marine organisms, including algae, animals, and plants, from which diverse marine polysaccharides with useful physicochemical and biological properties can be extracted. In particular, fucoidan, carrageenan, alginate, and chitosan have been extensively investigated in pharmaceutical and biomedical fields owing to their desirable characteristics, such as biocompatibility, biodegradability, and bioactivity. Various therapeutic efficacies of marine polysaccharides have been elucidated, including the inhibition of cancer, inflammation, and viral infection. The therapeutic activities of these polysaccharides have been demonstrated in various settings, from in vitro laboratory-scale experiments to clinical trials. In addition, marine polysaccharides have been exploited for tissue engineering, the immobilization of biomolecules, and stent coating. Their ability to detect and respond to external stimuli, such as pH, temperature, and electric fields, has enabled their use in the design of novel drug delivery systems. Thus, along with the promising characteristics of marine polysaccharides, this review will comprehensively detail their various therapeutic, biomedical, and miscellaneous applications.     

Polysaccharide colloidal particles as delivery systems for macromolecules

Mucosal delivery of complex molecules such as peptides, proteins, oligonucleotides, and plasmids is one of the most intensively studied subjects. The use of colloidal carriers made of hydrophilic polysaccharides, i.e. chitosan, has arisen as a promising alternative for improving the transport of such macromolecules across biological surfaces. This article reviews the approaches which have aimed to associate macromolecules to chitosan in the form of colloidal structures and analyzes the evidence of their efficacy in improving the transport of the associated molecule through mucosae and epithelia. Chitosan has been shown to form colloidal particles and entrap macromolecules through a number of mechanisms, including ionic crosslinking, desolvation, or ionic complexation, though some of these systems have been realized only in conjunction with DNA molecules. An alternative involving the chemical modification of chitosan has also been useful for the association of macromolecules to self-assemblies and vesicles. To date, the in vivo efficacy of these chitosan-based colloidal carriers has been reported for two different applications: while DNA-chitosan hybrid nanospheres were found to be acceptable transfection carriers, ionically crosslinked chitosan nanoparticles appeared to be efficient vehicles for the transport of peptides across the nasal mucosa. The potential applications and future prospects of these new systems for mucosal delivery of macromolecules are highlighted at the end of the chapter.     

Polysaccharides in pharmacy: current applications and future concepts

Polysaccharides constitute a structurally diverse class of biological macromolecules with a wide range of physicochemical properties, which are the basis for the different applications in the broad field of pharmacy and medicine. Besides the classical applications of these biopolymers in industry and pharmaceutical practice, the relatively new field of the physiologically active polymers will be discussed. Some examples will be given for the so-called immune-modulating antitumor polysaccharides which have been shown to be prominent candidates for an adjuvant tumor therapy.     

Therapeutic applications of glycosaminoglycans

Complex polysaccharides, hyaluronic acid or hyaluronan (HA), keratan sulfate (KS), chondroitin sulfates (CSs) and heparin (Hep)/heparan sulfate (HS), are a class of ubiquitous molecules exhibiting a wide range of biological functions. They are widely distributed as glycosaminoglycans (GAGs) sidechains of proteoglycans (PGs) in the extracellular matrix and at cellular level. The recent emergence of improved enzymatic and analytical tools for the study of these complex sugars has produced a virtual explosion in the field of glycomics. In particular, the study of the GAG family of polysaccharides has shed considerable light on the way in which specific carbohydrate structures modulate cellular phenotypes. In addition to the well-known therapeutic applications of some of these macromolecules, such as HA and derivatives as structure modifying molecules and possessing gel-like properties able to provide functional support for tissues, Hep as an anticoagulant and antithrombotic drug and CS in the treatment of osteoarthritis (OA), this increased understanding of GAG structure-function relationship has led to the discovery of novel pharmaceuticals for the possible treatment of serious diseases, such as cancer. In this paper, the structure and the therapeutic applications of several complex natural polysaccharides, including HA, CS/DS, Hep and their derivatives, are presented and discussed also in the light of the many questions still left unanswered, such as improved preparation and GAG-based drugs with improved properties and new possible therapeutic applications.     

Steroidal conjugates and their pharmacological applications

Nature continues to be the main source of inspiration for synthetic chemists in their quest to make novel conjugates, which can have different physical, biological and medicinal properties. Nature makes these conjugates from mixed biosynthesis and some of these chimeras are found to exhibit unusual biological properties. During the past two decades design of such entities has been receiving increasing attention. Among the hybrid natural products, hybrids of steroid frameworks have attracted great attention due to the significant biological properties and numerous therapeutic effects of steroids. The developments made over the past few years in the isolation, design and synthesis of steroidal conjugates and their pharmacological applications are discussed in this review.     

Protein- and peptide-based electrospun nanofibers in medical biomaterials

Electrospun fibers are being studied and developed because they hold considerable promise for realizing some advantages of nanostructured materials. The fibers can be made of biocompatible and biodegradable polymers. Electrospinning has therefore attracted interest in biotechnology and medicine, and there has been rapid growth in this area in recent years. This review presents an introduction to polymer nanofiber electrospinning, focusing on the use of natural proteins and synthetic peptides. We summarize key physical properties of protein-based and peptide-based nanofiber mats, survey biomedical applications of these materials, identify key challenges, and outline future prospects for development of the technology for tissue engineering, drug delivery, wound healing, and biosensors.From the Clinical EditorThis review focuses on polymer nanofiber electrospinning using natural proteins and synthetic peptides. The authors describe key properties and applications of these materials, and outline future prospects for tissue engineering, drug delivery, wound healing, and biosensors based on these nanomats and nanofibers.     

Temperature-sensitive hydrogels

Thermo-sensitive polymers are appealing materials for several therapeutic applications, such as in regenerative medicine and in situ drug release. These macromolecules are characterized by the ability to undergo swelling/deswelling processes during temperature change-induced phase transitions. Swelling and shrinking temperatures depend on the specific physicochemical properties, namely salt concentration or pH, of the thermo-sensitive gels as well as the incubation environment. An understanding of the mechanisms underlying the gel-swelling equilibrium and kinetics is necessary for the selection of an appropriate gel in relation to the specific pharmaceutical application. Thermo-sensitive polymers used in medicine include polyacrylamides, polyvinyls, polyethers, polysaccharides, and polyphosphazenes. A few of them have been successfully used as 3-dimentional supports for cell cultivation, allowing for the production of scaffolds with excellent biologic properties for application in regenerative medicine. Stem cells that can undergo specific differentiation under the appropriate stimulation have also been cultivated. The ability of drug/polymer solutions to turn into gels at physiologic temperature has been exploited for local drug delivery. The prolonged in situ presence and slow drug release enhances the therapeutic performance of antibiotics used in urogenital pathologies, anti-inflammatory agents, and anticancer drugs. The reduced toxicity as well as lower fluctuations in peak-to-trough drug concentrations make these systems superior to traditional gels. Thermo-sensitive hydrogels have also been demonstrated to be interesting formulations for the delivery of biotechnological drugs. Proteins and oligonucleotides can be loaded under mild conditions, stabilized, and released at a controlled rate. Finally, thermo-reversible polymers have been investigated for protein conjugation to enhance the physicochemical, biologic, immunologic, and pharmacokinetic properties of biotechnological products.     

Absorption, pharmacokinetics and disposition properties of solid lipid nanoparticles (SLNs)

In recent years, many researchers have paid more and more attentions on the use of Nanotechnology. Solid lipid nanoparticles (SLNs) are emerged as a promising alternation herein to emulsions, liposomes, microparticles and polymeric nanoparticles for their advantages. As promising drug carrier systems, SLNs are valuable for nanomedicine and have been widely used as delivery systems mostly for drugs and macromolecules like proteins, oligonucleotides and DNA by various application routes, such as intravenous, oral, duodenalous, intramuscular, pulmonary, intranasal, ocular, rectal and intraperitoneal administrations. It has been shown that SLNs can increase bioavailability, alter pharmacokinetic parameters and tissue distribution of the drug loaded. In this review, we will primarily focus on the absorption, pharmacokinetics and disposition properties of SLNs for their possible applications in drug delivery.     

Cell-penetrating peptides

The established view in cellular biology dictates that the cellular internalization of hydrophilic macromolecules can only be achieved through the classical endocytosis pathway. However, in the past five years several peptides have been demonstrated to translocate across the plasma membrane of eukaryotic cells by a seemingly energy-independent pathway. These peptides have been used successfully for the intracellular delivery of macromolecules with molecular weights several times greater than their own. Cellular delivery using these cell-penetrating peptides offers several advantages over conventional techniques because it is efficient for a range of cell types, can be applied to cells en masse and has a potential therapeutic application.     

Recent trends in the use of polysaccharides for improved delivery of therapeutic agents: pharmacokinetic and pharmacodynamic perspectives

New and innovative methods of delivery of therapeutic agents using polysaccharides have been recently developed, which target site of action, increase the intensity and/or prolong pharmacologic action, and/or reduce toxicity of small molecule drugs, proteins, or enzymes. This review is focused on the role of dextran, pullulan, and mannan polysaccharides in such applications. While dextran and pullulan are glucose polymers with different glucosidic linkages, mannan is composed of mannose units. In terms of pharmacokinetics of the carriers themselves, molecular weight (MW), electric charge, various chemical modifications, and degree of polydispersity and/or branching would mostly determine their fate in vivo. Generally, large MW polysaccharides (MWs > or = 40 kD) have low clearance and relatively long plasma half life, resulting in accumulation in reticuloendothelial or tumor tissues. The tumor accumulation in most cases is a passive targeting due to "enhanced permeation and retention" of macromolecules by tumors. Additionally, drugs such as anticancer agents may be actively targeted to specific cells by polysaccharides to which appropriate ligands are attached. In terms of mode of use, polysaccharides have been utilized in a variety of innovative ways for improvement of drug delivery. Their most important application has been as carriers for preparation of macromolecular prodrugs that are normally inactive and need to release the active drug at the site(s) of interest. Also, they have been used for preparation of macromolecule-protein conjugates, which may retain the activity of the proteins, in order to increase the duration of effect and decrease the immunogenicity of proteins. Several other new applications, such as polysaccharide-anchored liposomal formulations, have also been gained attention recently and are briefly reviewed here. Finally, four recent examples of polysaccharide-based delivery systems involving specific drugs/imaging agents are reviewed in detail in terms of their development, pharmacokinetics, and pharmacodynamics. Collectively, these data suggest that macromolecular polysaccharides are promising agents for improving drug delivery.     

Is the oral route possible for peptide and protein drug delivery?

Oral delivery of peptides and proteins remains an attractive alternative to parenteral delivery and has challenged various attempts at delivery development. Incorporation of new tools into the delivery systems that can raise membrane permeability of macromolecules is essential to attain high oral bioavailability that is acceptable in clinical applications. In developing oral protein delivery systems with high bioavailability, three practical approaches might be most helpful: (1) modification of the physicochemical properties of macromolecules; (2) addition of novel function to macromolecules; or (3) use of improved delivery carriers. Clearly, it is essential that these approaches maintain the biological activity of the proteins.     

Protein release from alginate matrices

There are a variety of both natural and synthetic polymeric systems that have been investigated for the controlled release of proteins. Many of the procedures employed to incorporate proteins into a polymeric matrix can be harsh and often cause denaturation of the active agent. Alginate, a naturally occurring biopolymer extracted from brown algae (kelp), has several unique properties that have enabled it to be used as a matrix for the entrapment and/or delivery of a variety of biological agents. Alginate polymers are a family of linear unbranched polysaccharides which contain varying amounts of 1,4'-linked beta-D-mannuronic acid and alpha-L-guluronic acid residues. The residues may vary widely in composition and sequence and are arranged in a pattern of blocks along the chain. Alginate can be ionically crosslinked by the addition of divalent cations in aqueous solution. The relatively mild gelation process has enabled not only proteins, but cells and DNA to be incorporated into alginate matrices with retention of full biological activity. Furthermore, by selection of the type of alginate and coating agent, the pore size, degradation rate, and ultimately release kinetics can be controlled. Gels of different morphologies can be prepared including large block matrices, large beads (>1 mm in diameter) and microbeads (<0.2 mm in diameter). In situ gelling systems have also been made by the application of alginate to the cornea, or on the surfaces of wounds. Alginate is a bioadhesive polymer which can be advantageous for the site specific delivery to mucosal tissues. All of these properties, in addition to the nonimmunogenicity of alginate, have led to an increased use of this polymer as a protein delivery system. This review will discuss the chemistry of alginate, its gelation mechanisms, and the physical properties of alginate gels. Emphasis will be placed on applications in which biomolecules have been incorporated into and released from alginate systems.     

荧光标记多糖及其体内药动学应用进展

多糖研究和应用越来越普及,多糖荧光标记技术也在不断发展。由于多糖自身分子结构的特点,目前尚无标准的多糖体内吸收代谢的检测方法,使多糖在生物医药领域的应用受到限制。体外荧光标记技术已广泛用于多糖体内药动学研究。本文总结了目前用于多糖标记的各种荧光素,及其在多糖口服、静脉注射和腹腔注射给药的体内药动学研究中的应用。并进一步结合荧光标记多糖在体内药动学研究中的优势,阐述多糖口服吸收机制,增加多糖口服吸收的策略,影响多糖药动学的因素,以及多糖体内降解机制等,旨在为多糖体内药动学研究提供参考。     

Supercritical fluid technology: a promising approach in pharmaceutical research

Supercritical fluids possess the unique properties of behaving like liquids and gases, above their critical point. Supercritical fluid technology has recently emerged as a green and novel technique for various processes such as solubility enhancement of poorly soluble drugs, plasticization of polymers, surface modification, nanosizing and nanocrystal modification, and chromatographic extraction. Research interest in this area has been fuelled because of the numerous advantages that the technology offers over the conventional methods. This work aims to review the merits, demerits, and various processes such as rapid expansion of supercritical solutions (RESS), particles from gas saturated solutions (PGSS), gas antisolvent process (GAS), supercritical antisolvent process (SAS) and polymerization induced phase separation (PIPS), that have enabled this technology to considerably raise the interest of researchers over the past two decades. An insight has been given into the numerous applications of this technology in pharmaceutical industry and the future challenges which must be appropriately dealt with to make it effective on a commercial scale.     

Development of nanosafety forecasting system from the viewpoint of nanomaterial-protein interaction

With recent developments in nanotechnology, nanomaterials have been successfully employed in various industrial applications such as medicine and cosmetics. Nanomaterials demonstrate useful properties such as electronic reactivity and tissue permeability that are absent in micromaterials. Thus, it is anticipated that nanomaterials will be developed as innovative materials in medicine and the cosmetics industry. However, these innovative properties may be accompanied by unknown biological responses that could not have been detected by conventional toxicity assays. To promote industrial development and to establish an affluent society that enjoys only the benefits of nanomaterials, we urgently need to gather information on the properties and biological effects of nanomaterials, and to establish appropriate standard safety evaluation methods. We are therefore analyzing the association of nanomaterial interactions with macromolecules (proteins, DNA etc.) and biodistribution using nanosilicas (nSP) as a standard nanomaterial. The results of this study are useful for extrapolation to other nanomaterials and to establish practicable strategies for the development of prediction methods for nanomaterials.     

Photochemical internalization: a new tool for drug delivery

The utilisation of macromolecules in the therapy of cancer and other diseases is becoming increasingly important. Recent advances in molecular biology and biotechnology have made it possible to improve targeting and design of cytotoxic agents, DNA complexes and other macromolecules for clinical applications. In many cases the targets of macromolecular therapeutics are intracellular. However, degradation of macromolecules in endocytic vesicles after uptake by endocytosis is a major intracellular barrier for the therapeutic application of macromolecules having intracellular targets of action. Photochemical internalisation (PCI) is a novel technology for the release of endocytosed macromolecules into the cytosol. The technology is based on the activation by light of photosensitizers located in endocytic vesicles to induce the release of macromolecules from the endocytic vesicles. Thereby, endocytosed molecules can be released to reach their target of action before being degraded in lysosomes. PCI has been shown to stimulate intracellular delivery of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), DNA delivered as gene-encoding plasmids or by means of adenovirus or adeno-associated virus, peptide nucleic acids (PNAs) and chemotherapeutic agents such as bleomycin and in some cases doxorubicin. PCI of PNA may be of particular importance due to the low therapeutic efficacy of PNA in the absence of an efficient delivery technology and the 10-100-fold increased efficacy in combination with PCI. The efficacy and specificity of PCI of macromolecular therapeutics has been improved by combining the macromolecules with targeting moieties, such as the epidermal growth factor. In general, PCI can induce efficient light-directed delivery of macromolecules into the cytosol, indicating that it may have a variety of useful applications for site-specific drug delivery as for example in gene therapy, vaccination and cancer treatment.     

Advances in oral macromolecular drug delivery

Introduction: Various macromolecules including polypeptides, proteins, genes and polysaccharides have been drawing attention for their therapeutic potential. The passage through intestinal epithelium is the major barrier for the oral delivery of macromolecules, by either paracellular or transcellular pathways. However, most macromolecules are poorly absorbed in oral route due to their high molecular weight and low stability in the gastrointestinal (GI) tract. Nonetheless, advancing in oral macromolecular drug delivery will be significant in expanding the clinical use of therapeutic macromolecules.

Areas covered: Technologies using chemical conjugation, absorption enhancers and nano-/micro-particulate systems have been developed to improve oral bioavailability of macromolecules, and some of them are in the process of clinical trials. In this review, they are discussed in the context of their progression states, hurdles and modes of action.

Expert opinion: According to the better understanding of receptor or transporter structure and transport mechanisms in the GI tract, the progress ineffective oral delivery systems for therapeutic macromolecules is anticipated over the next decades. In addition, the advent of numerous particulate systems will also speed up the development of novel drug delivery technologies. This offers an optimistic perspective on the potential clinical usage of oral macromolecular drugs.