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Advanced Drug Delivery Reviews (v.64, #9)
Approaches to drug delivery based on the principles of supramolecular chemistry
by Lyle Isaacs Theme Editor (pp. 763-763).
The strategic use of supramolecular p Ka shifts to enhance the bioavailability of drugs by Indrajit Ghosh; Werner M. Nau (pp. 764-783).
Macrocyclic hosts of the cyclodextrin, sulfonatocalixarene, and cucurbituril type can be employed as discrete supramolecular drug delivery systems, thereby complementing existing supramolecular drug formulation strategies based on polymers, hydrogels, liposomes, and related microheterogeneous systems. Cucurbiturils, in particular, stand out in that they do not only provide a hydrophobic cavity to encapsulate the drug in the form of a host–guest complex, but in that they possess cation-receptor properties, which favor the encapsulation of protonated drugs over their unprotonated forms, resulting in pronounced p Ka shifts up to 5 units. These p Ka shifts can be rationally exploited to activate prodrug molecules, to stabilize the active form of drug molecules, to enhance their solubility, and to increase their degree of ionization, factors which can jointly serve to enhance the bioavailability of drugs, particularly weakly basic ones. Additionally, macrocycles can serve to increase the chemical stability of drugs by protecting them against reactions with nucleophiles ( e.g., thiols) and electrophiles, by increasing their photostability, and by causing a higher thermal stability in the solid state. Detailed examples of the different effects of macrocyclic encapsulation of drugs and the associated p Ka shifts are provided and discussed. Other important considerations, namely a potential lowering of the bioactivity of drugs by macrocyclic complexation, interferences of the macrocycles with biocatalytic processes, the toxicity of the macrocyclic host molecules, and problems and opportunities related to a targeted release and the rate of release of the drug from the host–guest complexes are critically evaluated.Display Omitted
Keywords: Drug delivery; Drug stability; Formulation; Activation; Toxicity; Acid–base properties; Cucurbiturils; Cyclodextrins; Calixarenes; Macrocycles; Host–guest complexes
Synthetic membrane active amphiphiles by George W. Gokel; Saeedeh Negin (pp. 784-796).
During the past several decades, various synthetic organic compounds that form pores in bilayer membranes have been prepared and studied. These membrane active amphiphiles have also proved to be useful in affecting the transport of molecules into or through the bilayer. This article discusses the evolution of these compounds and exemplifies recent applications such as enhancement of antimicrobial activity.Display Omitted
Keywords: Amphiphiles; Antibiotics; Direct injection chemotherapy; Drug delivery; Hydraphiles; Synthetic ion transporters
Synthetic cell surface receptors for delivery of therapeutics and probes by David Hymel; Blake R. Peterson (pp. 797-810).
Receptor-mediated endocytosis is a highly efficient mechanism for cellular uptake of membrane-impermeant ligands. Cells use this process to acquire nutrients, initiate signal transduction, promote development, regulate neurotransmission, and maintain homeostasis. Natural receptors that participate in receptor-mediated endocytosis are structurally diverse, ranging from large transmembrane proteins to small glycolipids embedded in the outer leaflet of cellular plasma membranes. Despite their vast structural differences, these receptors share common features of binding to extracellular ligands, clustering in dynamic membrane regions that pinch off to yield intracellular vesicles, and accumulation of receptor-ligand complexes in membrane-sealed endosomes. Receptors typically dissociate from ligands in endosomes and cycle back to the cell surface, whereas internalized ligands are usually delivered into lysosomes, where they are degraded, but some can escape and penetrate into the cytosol. Here, we review efforts to develop synthetic cell surface receptors, defined as nonnatural compounds, exemplified by mimics of cholesterol, that insert into plasma membranes, bind extracellular ligands including therapeutics, probes, and endogenous proteins, and engage endocytic membrane trafficking pathways. By mimicking natural mechanisms of receptor-mediated endocytosis, synthetic cell surface receptors have the potential to function as prosthetic molecules capable of seamlessly augmenting the endocytic uptake machinery of living mammalian cells.Display Omitted
Keywords: Receptors; ligands; cholesterol; lipids; endocytosis; trafficking; recycling; delivery; endosomes; membranes; fluorescence; vancomycin
Virus-based nanocarriers for drug delivery by Yujie Ma; Roeland J.M. Nolte; Jeroen J.L.M. Cornelissen (pp. 811-825).
New nanocarrier platforms based on natural biological building blocks offer great promises in revolutionalizing medicine. The usage of specific protein cage structures: virus-like particles (VLPs) for drug packaging and targetted delivery is summarized here. Versatile chemical and genetic modifications on the outer surfaces and inner cavities of VLPs facilitate the preparation of new materials that could meet the biocompatibility, solubility and high uptake efficiency requirements for drug delivery. A full evaluation on the toxicity, bio-distribution and immunology of these materials are envisaged to boost their application potentials.Display Omitted
Keywords: Virus; Virus-like particle (VLP); Drug delivery; Bioconjugation; Supramolecular chemistry; Targeting
Triazine dendrimers as drug delivery systems: From synthesis to therapy by Jongdoo Lim; Eric E. Simanek (pp. 826-835).
The use of triazine dendrimers as drug delivery systems benefits from their synthetic versatility and well-defined structure. Triazine dendrimers can be designed and readily synthesized to display orthogonally functional surfaces that facilitate post-synthetic manipulation such as attachment of drug, PEGylation, and/or the installation of ligands or reporting groups. The synthesis is scalable, and large generations can be accessed. To date, triazine dendrimers have been probed for a variety of medicinal applications including drug delivery with an emphasis on cancer, nonviral DNA and RNA delivery systems, in sensing applications, and as bioactive materials. Specifically, triazine adducts with paclitaxel, camptothecin, brefeldin A, and desferrioxamine have been prepared and assessed. Paclitaxel constructs show promising activity in vivo. The use of these materials in fluorescence-based glucose sensors is being pursued. Glycosylated triazine dendrimers interfere with signal transduction in the Toll-4 receptor pathway.Display Omitted
Keywords: Triazine dendrimer; Drug delivery; Chemotherapy; Paclitaxel; RNAi; DNA; Pharmacokinetics; Camptothecin; Iron-overload; Septic shock; Glucose sensing
Polymer nanogels: A versatile nanoscopic drug delivery platform by Reuben T. Chacko; Judy Ventura; Jiaming Zhuang; S. Thayumanavan (pp. 836-851).
In this review we put the spotlight on crosslinked polymer nanogels, a promising platform that has the characteristics of an “ideal” drug delivery vehicle. Some of the key aspects of drug delivery vehicle design like stability, response to biologically relevant stimuli, passive targeting, active targeting, toxicity and ease of synthesis are discussed. We discuss several delivery systems in this light and highlight some examples of systems, which satisfy some or all of these design requirements. In particular, we point to the advantages that crosslinked polymeric systems bring to drug delivery. We review some of the synthetic methods of nanogel synthesis and conclude with the diverse applications in drug delivery where nanogels have been fruitfully employed.Display Omitted
Keywords: Nanomaterial; Ligand display; Encapsulation stability; Stimuli responsive
Approaches for the preparation of non-linear amphiphilic polymers and their applications to drug delivery by Yi Wang; Scott M. Grayson (pp. 852-865).
Amphiphilic polymers are particularly useful for drug delivery because of their ability to self-assemble into discrete aggregates. While this behavior has been studied in depth for simple linear block copolymer amphiphiles, recent advances in synthetic methodologies have provided efficient routes to amphiphilic polymers with more complex architecture, including dendrimers, hyperbranched polymers, star polymers, and cyclic polymers. These architectures can impart unique advantages, such as increased stability, on their micellar aggregates. Herein the different strategies for preparing these complex amphiphiles are described, and the application of their assemblies towards drug delivery are summarized.Display Omitted
Keywords: Drug delivery; Self-assembly; Dendrimers; Hyperbranched polymers; Star polymers; Cyclic polymers; Amphiphiles
Stimuli-responsive polymeric nanocarriers for the controlled transport of active compounds: Concepts and applications by Emanuel Fleige; Mohiuddin A. Quadir; Rainer Haag (pp. 866-884).
The use of polymeric nanocarriers to transport active compounds like small-molecular drugs, peptides, or genes found an increased attention throughout the different fields of natural sciences. Not only that these nanocarriers enhance the properties of already existing drugs in terms of solubility, bioavailability, and prolonged circulation times, furthermore they can be tailor-made in such a manner that they selectively release their cargo at the desired site of action. For the triggered release, these so-called smart drug delivery systems are designed to react on certain stimuli like pH, temperature, redox potential, enzymes, light, and ultrasound. Some of these stimuli are naturally occurring in vivo, for example the difference in pH in different cellular compartments while others are caused by the disease, which is to be treated, like differences in pH and temperature in some tumor tissues. Other external applied stimuli, like light and ultrasound, allow the temporal and spatial control of the release, since they are not triggered by any biological event. This review gives a brief overview about some types of stimuli-responsive nanocarriers with the main focus on organic polymer-based systems. Furthermore, the different stimuli and the design of corresponding responsive nanocarriers will be discussed with the help of selected examples from the literature.Display Omitted
Keywords: Nanomedicine; Drug delivery; Gene delivery; Triggered release; pH; Temperature; Redox; Enzyme; Light; Dual-responsive