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Advanced Drug Delivery Reviews (v.62, #1)
Chitosan-based formulations of drugs, imaging agents and biotherapeutics
by Maryam Amidi (Theme Editors); Wim E. Hennink Theme Editor (pp. 1-2).
Biodegradation, biodistribution and toxicity of chitosan by T. Kean; M. Thanou (pp. 3-11).
Chitosan is a natural polysaccharide that has attracted significant scientific interest during the last two decades. It is a potentially biologically compatible material that is chemically versatile (–NH2 groups and various Mw). These two basic properties have been used by drug delivery and tissue engineering scientists to create a plethora of formulations and scaffolds that show promise in healthcare. Despite the high number of published studies, chitosan is not approved by the FDA for any product in drug delivery, and as a consequence very few biotech companies are using this material. This review will aim to provide information on these biological properties that affect chitosan's safe use in drug delivery. The term “Chitosan” represents a large group of structurally different chemical entities that may show different biodistribution, biodegradation and toxicological profiles. Here we aim to review research in this area and critically discuss chitosan's potential to be used as a generally regarded as safe (GRAS) material.
Keywords: Chitosan; Biodegradation; Biodistribution; Toxicity; Delivery; In vitro; In vivo
Chitosan-based formulations for delivery of DNA and siRNA by Shirui Mao; Wei Sun; Thomas Kissel (pp. 12-27).
Among non-viral vectors, chitosan and chitosan derivatives have been developed in vitro and in vivo for DNA and siRNA delivery systems because of their cationic charge, biodegradability and biocompatibility, as well as their mucoadhesive and permeability-enhancing properties. However, the transfection efficiency of chitosan is too low for clinical application. Studies indicated that the transfection efficiency depends on a series of chitosan-based formulation parameters, such as the Mw of chitosan, its degree of deacetylation, the charge ratio of chitosan to DNA/siRNA (N/P ratio), the chitosan salt form used, the DNA/siRNA concentration, pH, serum, additives, preparation techniques of chitosan/nucleic acid particles and routes of administration. In this paper, chitosan-based formulations for the delivery of DNA and siRNA were reviewed to facilitate the process of chitosan vector development for clinical application. In addition to formulation optimization, chitosan structure modification or additive incorporation is an effective way to improve the stability of the polyplex in biological fluids, enhance targeted cell delivery and facilitate endo-lysosomal release of the complex. In summary, the transfection efficiency of chitosan-based delivery systems can be adjusted by changing formulation-related parameters.
Keywords: Chitosan; DNA; siRNA; Formulation; Gene delivery
Targeted delivery of low molecular drugs using chitosan and its derivatives by Jae Hyung Park; Gurusamy Saravanakumar; Kwangmeyung Kim; Ick Chan Kwon (pp. 28-41).
Chitosan has prompted the continuous impetus for the development of safe and effective drug delivery systems because of its unique physicochemical and biological characteristics. The primary hydroxyl and amine groups located on the backbone of chitosan allow for chemical modification to control its physical properties. When the hydrophobic moiety is conjugated to a chitosan molecule, the resulting amphiphile may form self-assembled nanoparticles that can encapsulate a quantity of drugs and deliver them to a specific site of action. Chemical attachment of the drug to the chitosan throughout the functional linker may produce useful prodrugs, exhibiting the appropriate biological activity at the target site. Mucoadhesive and absorption enhancement properties of chitosan increase the in vivo residence time of the dosage form in the gastrointestinal tract and improve the bioavailability of various drugs. The main objective of this review is to provide an insight into various target-specific carriers, based on chitosan and its derivatives, towards low molecular weight drug delivery. The first part of the review is concerned with the organ-specific delivery of low molecular drugs using chitosan and its derivatives. The subsequent section considers the recent developments of drug delivery carriers for cancer therapy with special focus on various targeting strategies.
Keywords: Chitosan; Low molecular drugs; Targeted delivery
Chitosan-based systems for molecular imaging by Prashant Agrawal; Gustav J. Strijkers; Klaas Nicolay (pp. 42-58).
Molecular imaging enables the non-invasive assessment of biological and biochemical processes in living subjects. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development. Molecular imaging allows a repetitive and non-invasive study of the same living subject using identical or alternative biological imaging assays at different time points, thus harnessing the statistical power of longitudinal studies, and reducing the number of animals required and cost. Chitosan is a hydrophilic and non-antigenic biopolymer and has a low toxicity toward mammalian cells. Hence, it has great potential as a biomaterial because of its excellent biocompatibility. Conjugated to additional materials, chitosan composites result in a new class of biomaterials that possess mechanical, physicochemical and functional properties, which have potential for use in advanced biomedical imaging applications. The present review will discuss the strengths, limitations and challenges of molecular imaging as well as applications of chitosan nanoparticles in the field of molecular imaging.
Keywords: Chitosan; Molecular imaging; Imaging techniques; Imaging agents; MRI; CT; Ultrasound; Optical imaging
Chitosan-based delivery systems for protein therapeutics and antigens by Maryam Amidi; Enrico Mastrobattista; Wim Jiskoot; Wim E. Hennink (pp. 59-82).
Therapeutic peptides/proteins and protein-based antigens are chemically and structurally labile compounds, which are almost exclusively administered by parenteral injections. Recently, non-invasive mucosal routes have attracted interest for administration of these biotherapeutics. Chitosan-based delivery systems enhance the absorption and/or cellular uptake of peptides/proteins across mucosal sites and have immunoadjuvant properties. Chitosan is a mucoadhesive polysaccharide capable of opening the tight junctions between epithelial cells and it has functional groups for chemical modifications, which has resulted in a large variety of chitosan derivatives with tunable properties for the aimed applications. This review provides an overview of chitosan-based polymers for preparation of both therapeutic peptides/protein and antigen formulations. The physicochemical properties of these carrier systems as well as their applications in protein and antigen delivery through parenteral and mucosal (particularly nasal and pulmonary) administrations are summarized and discussed.
Keywords: Chitosan; Trimethylated chitosan (TMC); Protein/peptides delivery; Mucosal delivery; Targeting; Vaccination; Micro- and nanoparticles
Chitosan-based hydrogels for controlled, localized drug delivery by Narayan Bhattarai; Jonathan Gunn; Miqin Zhang (pp. 83-99).
Hydrogels are high-water content materials prepared from cross-linked polymers that are able to provide sustained, local delivery of a variety of therapeutic agents. Use of the natural polymer, chitosan, as the scaffold material in hydrogels has been highly pursued thanks to the polymer's biocompatibility, low toxicity, and biodegradability. The advanced development of chitosan hydrogels has led to new drug delivery systems that release their payloads under varying environmental stimuli. In addition, thermosensitive hydrogel variants have been developed to form a chitosan hydrogel in situ, precluding the need for surgical implantation. The development of these intelligent drug delivery devices requires a foundation in the chemical and physical characteristics of chitosan-based hydrogels, as well as the therapeutics to be delivered. In this review, we investigate the newest developments in chitosan hydrogel preparation and define the design parameters in the development of physically and chemically cross-linked hydrogels.
Keywords: Chitosan; Hydrogel; Cross-linking; Controlled release; Stimuli-responsive; Injectable
Chitosan-based nanostructures: A delivery platform for ocular therapeutics by Maria de la Fuente; Ravina Manuela Raviña; Patrizia Paolicelli; Alejandro Sanchez; Begoña Seijo; Maria Jose Alonso (pp. 100-117).
Nanoscience and nanotechnology has caused important breakthroughs in different therapeutic areas. In particular, the application of nanotechnology in ophthalmology has led to the development of novel strategies for the treatment of ocular disorders. Indeed, the association of an active molecule to a nanocarrier allows the molecule to intimately interact with specific ocular structures, to overcome ocular barriers and to prolong its residence in the target tissue. Over the last decade, our group has designed and developed a delivery platform based on the polysaccharide chitosan, which suits the requirements of the topical ocular route. These nanosystems have been specifically adapted for the delivery of hydrophilic and lipophilic drugs and also polynucleotides onto the eye surface. The results collected up until now suggest the potential of this delivery platform and the subsequent need of a full preclinical evaluation in order to satisfy the specific regulatory demands of this mode of administration.
Keywords: Chitosan; Ocular; Ophthalmics; Drug delivery; Gene delivery; Hyaluronan; Nanocapsules; Nanoparticles; Nanostructures; Emulsions