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Edoardo Scarpa Agnieszka A Janeczek Alethia Hailes Maria C de Andrés Antonio De Grazia Richard OC Oreffo Tracey A Newman Nicholas D Evans 《Nanomedicine : nanotechnology, biology, and medicine》2018,14(4):1267-1277
Spatiotemporal control of drug delivery is important for a number of medical applications and may be achieved using polymersome nanoparticles (PMs). Wnt signalling is a molecular pathway activated in various physiological processes, including bone repair, that requires precise control of activation. Here, we hypothesise that PMs can be stably loaded with a small molecule Wnt agonist, 6-bromoindirubin-3′-oxime (BIO), and activate Wnt signalling promoting the osteogenic differentiation in human primary bone marrow stromal cells (BMSCs). We showed that BIO-PMs induced a 40% increase in Wnt signaling activation in reporter cell lines without cytotoxicity induced by free BIO. BMSCs incubated with BIO-PMs showed a significant up-regulation of the Wnt target gene AXIN2 (14?±?4 fold increase, P?<?0.001) and a prolonged activation of the osteogenic gene RUNX2. We conclude that BIO-PMs could represent an innovative approach for the controlled activation of Wnt signaling for promoting bone regeneration after fracture. 相似文献
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《Drug discovery today》2022,27(2):538-546
Successful small-molecule drug design requires a molecular target with inherent therapeutic potential and a molecule with the right properties to unlock its potential. Present-day drug design strategies have evolved to leave little room for improvement in drug-like properties. As a result, inadequate safety or efficacy associated with molecular targets now constitutes the primary cause of attrition in preclinical development through Phase II. This finding has led to a deeper focus on target selection. In this current reality, design tactics that enable rapid identification of risk-balanced clinical candidates, translation of clinical experience into meaningful differentiation strategies, and expansion of the druggable proteome represent significant levers by which drug designers can accelerate the discovery of the next generation of medicines. 相似文献
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RNA interference (RNAi) is induced by 21-25 nucleotide, double-stranded small interfering RNA (siRNA), which is incorporated into the RNAi-induced silencing complex (RISC) and is a guide for cleavage of the complementary target mRNA in the cytoplasm. There are many obstacles to in vivo delivery of siRNAs, such as degradation by enzymes in blood, interaction with blood components and non-specific uptake by the cells, which govern biodistribution in the body. In order to achieve the knockdown by siRNAs in vivo, many delivery systems of siRNAs based on physical and pharmaceutical approaches have been proposed. In addition, the immune responses of siRNA must be taken into account when considering the application of siRNAs to in vivo therapy. This review focuses on recent reports about delivery systems and immune responses of siRNAs. 相似文献
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《Expert opinion on drug delivery》2013,10(1):145-157
Over the past decade, significant research has been done in the area of polymer-mediated gene delivery. Synthesis of new polymers and modifications to existing polymers has resulted in polyplexes with improved invitro and invivo transfection efficiencies. Targeting has been an important aspect of this research, and various strategies for obtaining selective and enhanced gene delivery to the target site have been evaluated. This review covers the different aspects involved in polyplex targeting. Development of targeted polyplexes involves a careful consideration of the target site, the targeting ligand and the physicochemical properties of the polyplex itself. The need to redirect the polyplexes by using the ‘shield and target’ approach by reducing nonspecific interactions with negatively charged components, while conferring specificity by incorporating targeting ligands, is discussed. Basic chemistry involved in modifying polymers is covered and examples of targeting strategies used for tissue-specific gene delivery are discussed. Targeting is also discussed in the broader context of developing safe and effective polymeric vectors for invivo gene delivery. Maximum benefit of targeting can be obtained when it is used as part of a multi-functional complex containing elements designed to improve gene delivery and reduce overall toxicity of the polyplex.Keywords: gene delivery, polymers, targeted delivery 相似文献
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Over the past decade, significant research has been done in the area of polymer-mediated gene delivery. Synthesis of new polymers and modifications to existing polymers has resulted in polyplexes with improved in vitro and in vivo transfection efficiencies. Targeting has been an important aspect of this research, and various strategies for obtaining selective and enhanced gene delivery to the target site have been evaluated. This review covers the different aspects involved in polyplex targeting. Development of targeted polyplexes involves a careful consideration of the target site, the targeting ligand and the physicochemical properties of the polyplex itself. The need to redirect the polyplexes by using the 'shield and target' approach by reducing nonspecific interactions with negatively charged components, while conferring specificity by incorporating targeting ligands, is discussed. Basic chemistry involved in modifying polymers is covered and examples of targeting strategies used for tissue-specific gene delivery are discussed. Targeting is also discussed in the broader context of developing safe and effective polymeric vectors for in vivo gene delivery. Maximum benefit of targeting can be obtained when it is used as part of a multi-functional complex containing elements designed to improve gene delivery and reduce overall toxicity of the polyplex. 相似文献
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The objective of this work was to modulate transdermal drug delivery by iontophoresis though skin microchannels created by microneedles. Calcein and human growth hormone were used as a model small and large molecule, respectively. In vitro permeation studies were performed on porcine ear skin under three different settings: (a) modulated iontophoresis alone, (b) pretreatment with microneedles and (c) combination of microneedles pretreatment and modulated iontophoresis. For modulated iontophoresis, 0.5 mA/cm(2) current was applied for 1h each at 2nd and 6th hour of the study. Methylene blue staining, calcein imaging and pore permeability index suggested maltose microneedles created uniform microchannels in skin. Application of iontophoresis provided two peaks in flux of 1.04 μg/(cm(2)h) at 4th hour and 2.09 μg/(cm(2)h) at 8th hour of study for calcein. These peaks in flux were significant higher when skin was pretreated with microneedles (p<0.05). Similarly, for human growth hormone, modulation in transdermal flux was achieved with combination of microneedles and iontophoresis. This combination also provided significant increase in cumulative amount of calcein and human growth hormone delivered as compared to microneedles or iontophoresis alone (p<0.05). Therefore, iontophoresis can be used to modulate drug delivery across skin microchannels created by microneedles. 相似文献
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Proprietary Rel-Ease (Praecis Pharmaceuticals) drug delivery technology uses biocompatible polymers as carriers to incorporate a drug into a polymer matrix through opposite charge interaction or complexation. The resulting low solubility complexes can be used to prepare sustained release depot injections or potentially sustained release formulations for oral administration. As a regulatory approved and commercialised drug delivery technology, Rel-Ease is used in abarelix for injectable suspension, a monthly depot injection for the treatment of patients with advanced prostate cancer. The technology offers high drug loading and minimal-to-no initial burst effect in vivo. It uses aqueous processes and is compatible for complexation with many peptide and protein therapeutics; its mechanism can also be applied to many small-molecule therapeutics and offers conventional and alternative methods for sustained release delivery via an oral route. 相似文献
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Targeted delivery to the nucleus 总被引:2,自引:0,他引:2
Macromolecules and supramolecular complexes are frequently required to enter and exit the nucleus during normal cell function, but access is restricted and exchange to and from the nucleus is tightly controlled. We describe the mechanisms which regulate nuclear import of endogenous molecules and indicate how viruses exploit these mechanisms during their life cycle. Opportunities exist to make use of natural pathways for delivery of therapeutic entities, in particular to develop safe and effective methods for gene therapy, although past attempts to design non-viral nuclear delivery systems have met with limited success. To increase the likelihood of success scientists will need an appreciation of the mechanisms by which viruses deliver their genomes to the nucleus, and will need a commitment to control the architecture of non-viral delivery systems at the molecular level. Effective delivery systems will require several attributes to facilitate endosomal escape, microtubular transport and uptake through the nuclear pore complex. The published literature provides a strong foundation for design of nuclear targeting systems. The challenge faced by delivery scientists is to assemble a system which is as effective as, for example, the adenovirus but which lacks its immunogenicity. This article reviews the relevant literature and indicates key areas for future research. 相似文献
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《Expert opinion on drug delivery》2013,10(5):531-541
Liver fibrosis and its end stage disease cirrhosis are a major cause of mortality and morbidity around the world. There is no effective pharmaceutical intervention for liver fibrosis at present. Many drugs that show potent antifibrotic activities in vitro often show only minor effects in vivo because of insufficient concentrations of drugs accumulating around the target cell and their adverse effects as a result of affecting other non-target cells. Hepatic stellate cells (HSC) play a critical role in the fibrogenesis of liver, so they are the target cells of antifibrotic therapy. Several kinds of targeted delivery system that could target the receptors expressed on HSC have been designed, and have shown an attractive targeted potential in vivo. After being carried by these delivery systems, many agents showed a powerful antifibrotic effect in animal models of liver fibrosis. These targeted delivery systems provide a new pathway for the therapy of liver fibrosis. The characteristics of theses targeted carriers are reviewed in this paper. 相似文献
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Selective gene inhibition by antisense oligodeoxynucleotide (AS-ODN) or by small interference RNA (siRNA) therapeutics promises the treatment of diseases that cannot be cured by conventional drugs. However, antisense therapy is hindered due to poor stability in physiological fluids and limited intracellular uptake. To address these problems, a ligand targeted and sterically stabilized nanoparticle formulation has been developed in our lab. Human lung cancer cells often overexpress the sigma receptor and, thus, can be targeted with a specific ligand such as anisamide. AS-ODN or siRNA against human survivin was mixed with a carrier DNA, calf thymus DNA, before complexing with protamine, a highly positively charged peptide. The resulting particles were coated with cationic liposomes consisting of DOTAP and cholesterol (1:1, molar ratio) to obtain LPD (liposome-polycation-DNA) nanoparticles. Ligand targeting and steric stabilization were then introduced by incubating preformed LPD nanoparticles with DSPE-PEG-anisamide, a PEGylated ligand lipid developed earlier in our lab, by the postinsertion method. Nontargeted nanoparticles coated with DSPE-PEG were also prepared as a control. Antisense activities of nanoparticles were determined by survivin mRNA down-regulation, survivin protein down-regulation, ability to trigger apoptosis in tumor cells, tumor cell growth inhibition, and chemosensitization of the treated tumor cells to anticancer drugs. We found that tumor cell delivery and antisense activity of PEGylated nanoparticles were sequence dependent and rely on the presence of anisamide ligand. The uptake of oligonucleotide in targeted, PEGylated nanoparticles could be competed by excess free ligand. Our results suggest that the ligand targeted and sterically stabilized nanoparticles can provide a selective delivery of AS-ODN and siRNA into lung cancer cells for therapy. 相似文献
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《Expert opinion on drug delivery》2013,10(1):57-65
Functionalised carbon nanotubes (f-CNTs) are emerging as new tools in the field of nanobiotechnology and nanomedicine. This is because they can be easily manipulated and modified by encapsulation with biopolymers or by covalent linking of solubilising groups to the external walls and tips. The possibility of incorporating f-CNTs into biological systems has opened the way to the exploration of their potential applications in biology and medicinal chemistry. Within the different fields of applications (i.e., biosensors, composite materials, molecular electronics), one use of CNTs is as new carrier systems for the delivery of therapeutic molecules. Research discussed in this review is focused on recent advances in the development of CNT technology for the delivery of drugs, antigens and genes. 相似文献
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The present study systematically studied the intravenous injectable formulation of liposomes loaded with levofloxacin, an amphipathic antibiotic. The aim of the present study was to design passive targeting liposomes, which might improve the antibacterial activity by accumulating in lung and reduce side effects such as neurotoxicity and hematotoxicity associated with direct injection of the drug. Levofloxacin-loaded liposomes were prepared by the ammonium sulfate gradients method. The formulated liposomes were found to be relatively uniform in size (7.424 ± 0.689 μm) with a positive zeta potential (+13.11 ± 1.08 mV). The entrapment efficiency of levofloxacin-loaded liposomes ranged from 82.19% to 86.23%. The administered liposomes were composed of soybean phosphatides, cholesterol, levofloxacin, and sulfate which existed in inner liposomes. In vitro drug release was monitored for up to 3 days, and the release behavior was in accordance with the Weibull equation. The levofloxacin-loaded liposomes exhibited a longer elimination half-life (t1/2β) in vivo compared with the levofloxacin solution after intravenous injection to New Zealand rabbits. The encapsulation of levofloxacin in liposomes also changed its biodistribution in mice after intravenous injection in caudal vein. Liposomal levofloxacin performed significant lung targeting efficiency with area under the concentration–time curve, targeting efficacy (Te), and The intake rate (Re) of lung, all showing obvious increase. In addition, liposomal formulations presented accumulative activity in spleen and liver. Conversely, the biodistribution of liposomal formulation in non-RES sites, such as kidney, brain, heart, and plasma, decreased with descending peak concentration ration (Ce) compared to levofloxacin injection, which potentially resulted in the reduction of the side effects of free drug. These results indicated that the levofloxacin-loaded liposomes were promising passive targeting to lung for pulmonary infection treatment. 相似文献
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Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems. Targeted nanoparticle delivery to the lungs is an emerging area of interest. This article reviews research performed over the last decades on the application of nanoparticles administered via different routes of administration for treatment or diagnostic purposes. Nanotoxicological aspects of pulmonary delivery are also discussed. 相似文献
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The safest and most effective way of targeting drugs to the entire brain is via delivery systems directed at endogenous receptor-mediated uptake mechanisms present at the cerebral capillaries. Such systems have been shown to be effective in animal models including primates, but no clinical trials have been performed so far. This review focuses on the well-characterised transferrin and insulin receptor-targeted systems, as well as on the more recently described systems that use the low-density lipoprotein-related protein 1 receptor, the low-density lipoprotein-related protein 2 receptor (also known as megalin and glycoprotein 330) or the diphtheria toxin receptor (which is the membrane-bound precursor of heparin-binding epidermal growth factor-like growth factor). The possibilities and limitations of these systems are compared and their future for human application is discussed. 相似文献
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Carbon nanotubes for the delivery of therapeutic molecules 总被引:1,自引:0,他引:1
Bianco A 《Expert opinion on drug delivery》2004,1(1):57-65
Functionalised carbon nanotubes (f-CNTs) are emerging as new tools in the field of nanobiotechnology and nanomedicine. This is because they can be easily manipulated and modified by encapsulation with biopolymers or by covalent linking of solubilising groups to the external walls and tips. The possibility of incorporating f-CNTs into biological systems has opened the way to the exploration of their potential applications in biology and medicinal chemistry. Within the different fields of applications (i.e., biosensors, composite materials, molecular electronics), one use of CNTs is as new carrier systems for the delivery of therapeutic molecules. Research discussed in this review is focused on recent advances in the development of CNT technology for the delivery of drugs, antigens and genes. 相似文献