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Advanced Drug Delivery Reviews (v.58, #15)
Toxin entry and trafficking in mammalian cells by Peter Watson; Robert A. Spooner (pp. 1581-1596).
There is a vast number of bacterial and plant toxins that affect cytosolic targets in mammalian cells, and whether the purpose of the toxin is to act as a defence mechanism against predators, or to cause deliberate cell death in order to form an environment more suitable for bacterial growth, each of these toxins must cross a lipid membrane barrier in order to exert their effect. This review looks at the methods employed by bacterial and plant toxins in order to reach their target. We examine the trafficking methods involved in toxin transport throughout the cell, highlighting the proteins necessary for the toxins movement, and noting how many of the toxins hijack the cells own trafficking and protein processing machinery in order to reach their goals. Studying the trafficking of toxins has led to a greater understanding of retrograde transport, a process which has key relevance to the correct intracellular delivery of pharmacological agents.
Keywords: Abbreviations; BFA; Brefeldin A; CTx; cholera toxin; DRM; detergent-resistant membrane microdomains; DTx; diphtheria toxin; EF-2; elongation factor 2; ER; endoplasmic reticulum; ERAD; ER-associated protein degradation; MβCD; methyl-beta-cyclodextrin; PDI; protein disulphide isomerase; PEx; Pseudomonas; exotoxin A; RIP; ribosome inactivating protein; STx; Shiga toxin and the closely related Shiga-like toxin; TGN; trans-Golgi networkToxin; Endocytosis; Retrograde transport; Ribosome inactivating protein; ER-associated degradation
Polymer genomics: An insight into pharmacology and toxicology of nanomedicines by Alexander V. Kabanov (pp. 1597-1621).
Synthetic polymers and nanomaterials display selective phenotypic effects in cells and in the body signal transduction mechanisms involved in inflammation, differentiation, proliferation, and apoptosis. When physically mixed or covalently conjugated with cytotoxic agents, bacterial DNA or antigens, polymers can drastically alter specific genetically controlled responses to these agents. These effects, in part, result from cooperative interactions of polymers and nanomaterials with plasma cell membranes and trafficking of polymers and nanomaterials to intracellular organelles. Cells and whole organism responses to these materials can be phenotype or genotype dependent. In selected cases, polymer agents can bypass limitations to biological responses imposed by the genotype, for example, phenotypic correction of immune response by polyelectrolytes. Overall, these effects are relatively benign as they do not result in cytotoxicity or major toxicities in the body. Collectively, however, these studies support the need for assessing pharmacogenomic effects of polymer materials to maximize clinical outcomes and understand the pharmacological and toxicological effects of polymer formulations of biological agents, i.e. polymer genomics.
Keywords: Artificial vaccines; DNA microarray; Drug resistance; Signal transduction; Phenotype
Display technologies: Application for the discovery of drug and gene delivery agents by Anna Sergeeva; Mikhail G. Kolonin; Jeffrey J. Molldrem; Renata Pasqualini; Wadih Arap (pp. 1622-1654).
Recognition of molecular diversity of cell surface proteomes in disease is essential for the development of targeted therapies. Progress in targeted therapeutics requires establishing effective approaches for high-throughput identification of agents specific for clinically relevant cell surface markers. Over the past decade, a number of platform strategies have been developed to screen polypeptide libraries for ligands targeting receptors selectively expressed in the context of various cell surface proteomes. Streamlined procedures for identification of ligand-receptor pairs that could serve as targets in disease diagnosis, profiling, imaging and therapy have relied on the display technologies, in which polypeptides with desired binding profiles can be serially selected, in a process called biopanning, based on their physical linkage with the encoding nucleic acid. These technologies include virus/phage display, cell display, ribosomal display, mRNA display and covalent DNA display (CDT), with phage display being by far the most utilized. The scope of this review is the recent advancements in the display technologies with a particular emphasis on molecular mapping of cell surface proteomes with peptide phage display. Prospective applications of targeted compounds derived from display libraries in the discovery of targeted drugs and gene therapy vectors are discussed.
Keywords: Combinatorial peptide libraries; Vascular cell surface proteomics; Targetomics; Targeted therapies; Display scaffold; Phage display; Viral display; Bacterial display; Yeast display; Cell display; Ribosome display; mRNA display; Covalent DNA display
Thermo- and pH-responsive polymers in drug delivery by Dirk Schmaljohann (pp. 1655-1670).
Stimuli-responsive polymers show a sharp change in properties upon a small or modest change in environmental condition, e.g. temperature, light, salt concentration or pH. This behaviour can be utilised for the preparation of so-called ‘smart’ drug delivery systems, which mimic biological response behaviour to a certain extent. The possible environmental conditions to use for this purpose are limited due to the biomedical setting of drug delivery as application. Different organs, tissues and cellular compartments may have large differences in pH, which makes the pH a suitable stimulus. Therefore the majority of examples, discussed in this paper, deal with pH-responsive drug delivery system. Thermo-responsive polymer is also covered to a large extent, as well as double-responsive system. The physico-chemical behaviour underlying the phase transition will be discussed in brief. Then selected examples of applications are described.
Keywords: Stimuli-responsive; Smart polymers; LCST; Polyacids; Poly(amine)s; Phase transition; Nanomedicines; Micelle
Synthetic approaches to uniform polymers by Monzur Ali; Steve Brocchini (pp. 1671-1687).
Uniform polymers are characterised by a narrow molecular weight distribution (MWD). Uniformity is also defined by chemical structure in respect of (1) monomer orientation, sequence and stereo-regularity, (2) polymer shape and morphology and (3) chemical functionality. The function of natural polymers such as polypeptides and polynucleotides is related to their conformational structure (e.g. folded tertiary structure). This is only possible because of their high degree of uniformity. While completely uniform synthetic polymers are rare, polymers with broad structure and MWD are widely used in medicine and the biomedical sciences. They are integral components in final dosage forms, drug delivery systems (DDS) and in implantable devices. Increasingly uniform polymers are being used to develop more complex medicines (e.g. delivery of biopharmaceuticals, enhanced formulations or DDS's for existing actives). In addition to the function imparted by any new polymer it will be required to meet stringent specifications in terms of cost containment, scalability, biocompatibility and performance. Synthetic polymers with therapeutic activity are also being developed to exploit their polyvalent properties, which is not possible with low molecular weight molecules. There is need to utilise uniform polymers for applications where the polymer may interact with the systemic circulation, tissues or cellular environment. There are also potential applications (e.g. stimuli responsive coatings) where uniform polymers may be used for their more defined property profile. While it is not yet practical to prepare synthetic polymers to the same high degree of uniformity as proteins, nature also effectively utilises many polymers with lower degrees of uniformity (e.g. polysaccharides, poly(amino acids), polyhydroxyalkanoates). In recent years it has become possible to prepare with practical experimental protocols sufficient quantities of polymers that display many aspects of uniformity. This review describes practical strategies for polymer synthesis focusing on addition processes that have been developed that allow narrow MWD polymers to be prepared. Also described are some examples where aspects of polymer uniformity in terms of molecular weight and/or chemical constitution are exploited for their unique properties.
Freeze-drying of nanoparticles: Formulation, process and storage considerations by Wassim Abdelwahed; Ghania Degobert; Serge Stainmesse; Hatem Fessi (pp. 1688-1713).
Freeze-drying has been considered as a good technique to improve the long-term stability of colloidal nanoparticles. The poor stability in an aqueous medium of these systems forms a real barrier against the clinical use of nanoparticles. This article reviews the state of the art of freeze-drying nanoparticles. It discusses the most important parameters that influence the success of freeze-drying of these fragile systems, and provides an overview of nanoparticles freeze-drying process and formulation strategies with a focus on the impact of formulation and process on particle stability.
Keywords: Nanoparticles; Freeze-drying; Stability; Freezing; Cryoprotectant; Glass transition; Physical and chemical characterization; Formulation