A reactive oxygen species-responsive dendrimer with low cytotoxicity for efficient and targeted gene delivery

Nonviral vectors have been attracting more attention for several advantages in gene delivery and the development of nonviral gene ca rriers with high delivery efficiency and low cytotoxicity has long been a key project.Starburst polyamidoamine dendrimers are a class of synthetic polymers with unique structural and physical characteristics.However,when they are used as gene carrier,the gene transfection efficiency is not satisfactory.Herein,a novel thioketal-core polyamidoamine dendrimer(i.e.,ROS...     

Carrier-free, functionalized drug nanoparticles for targeted drug delivery

We demonstrate a new concept of carrier-free functionalized drug nanoparticles for targeted drug delivery. It exhibits significantly enhanced drug efficacy to folate receptor-positive cells with high selectivity and a high drug loading content up to more than 78%.     

Folate-decorated succinylchitosan nanoparticles conjugated with doxorubicin for targeted drug delivery

Amphiphilic biodegradable succinylchitosan nanoparticles modified with folic acid are described that act as an emulsifier to form nanoparticles. Their molecular structures and physicochemical as well as self‐assembly properties are characterized by means of FT‐IR, ¹H NMR, FESEM, DLS, and TEM. The nanoparticles are 60–80 nm in size and are not toxic in vitro. They are immobilized with the cytostatic drug doxorubicin. Specific transport of doxorubicin by the nanoparticles into the folate‐receptor‐overexpressing cancer cells and its biological activity as well as in vitro release are demonstrated. It is shown that under acidic condition more drug is released. The nanoparticles can thus not only specifically deliver doxorubicin to its target, but also release the drug depending on the pH.

     

The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform

Dendrimer-based anticancer nanotherapeutics containing approximately 5 folate molecules have shown in vitro and in vivo efficacy in cancer cell targeting. Multivalent interactions have been inferred from observed targeting efficacy, but have not been experimentally proven. This study provides quantitative and systematic evidence for multivalent interactions between these nanodevices and folate-binding protein (FBP). A series of the nanodevices were synthesized by conjugation with different amounts of folate. Dissociation constants (K(D)) between the nanodevices and FBP measured by SPR are dramatically enhanced through multivalency ( approximately 2,500- to 170,000-fold). Qualitative evidence is also provided for a multivalent targeting effect to KB cells using flow cytometry. These data support the hypothesis that multivalent enhancement of K(D), not an enhanced rate of endocytosis, is the key factor resulting in the improved biological targeting by these drug delivery platforms.     

A low-voltage electrokinetic nanochannel drug delivery system

Recent work has elucidated the potential of important new therapeutic paradigms, including metronomic delivery and chronotherapy, in which the precise timing and location of therapeutic administration has a significant impact on efficacy and toxicity. New drug delivery architectures are needed to not only release drug continuously at precise rates, but also synchronize their release with circadian cycles. We present an actively controlled nanofluidic membrane that exploits electrophoresis to control the magnitude, duration, and timing of drug release. The membrane, produced using high precision silicon fabrication techniques, has platinum electrodes integrated at the inlet and outlet that allow both amplification and reversal of analyte delivery with low applied voltage (at or below 2 VDC). Device operation was demonstrated with solutions of both fluorescein isothiocyanate conjugated bovine serum albumin and lysozyme using fluorescence spectroscopy, fluorescence microscopy, and a lysozyme specific bio-assay and has been characterized for long-term molecular release and release reversibility. Through a combination of theoretical and experimental analysis, the relative contributions of electrophoresis and electroosmosis have been investigated. The membrane's clinically relevant electrophoretic release rate at 2 VDC exceeds the passive release by nearly one order of magnitude, demonstrating the potential to realize the therapeutic paradigm goal.     

A new oral microsphere drug delivery system

A new oral proteinoid microsphere drug delivery system is discussed with respect to its unique dependence on pH. Extensive evidence indicate that this technique not only can be used to deliver the protein and polar macromolecular drugs which are currently administered via injection, but also can be used to administer antigens and vaccines. Future work has been proposed to study the physical interaction of specific drugs with specifically designed oligopeptides structures.     

Chitosan modified with terephthaloyl diazide as a drug delivery system

Russian Chemical Bulletin - pH- and thermo-sensitive hydrogels based on chitosan cross-linked with terephthaloyl diazide were synthesized. A new formulation of the polysaccharide modified with...     

Aptamer-based self-assembled supramolecular vesicles for pH-responsive targeted drug delivery

Supramolecular vesicles have received great attention in biomedical application due to their inherent features, including simple synthesis and tunable amphiphilicity of the building blocks. Despite tremendous research efforts, developing supramolecular vesicles with targeted recognition and controlled release remains a major challenge. Herein, we constructed a novel aptamer-based self-assembled supramolecular vesicle by host-guest complexation of pyrene, viologen lipid, and cucurbit[8]urils for pH-responsive and targeted drug delivery. The proposed supramolecular vesicles are easy to be assembled and offer simple drug loading. Based on confocal fluorescence microscopy and cytotoxicity experiments, the drug-loaded supramolecular vesicles were shown to possess highly efficient internalization and apparent cytotoxic effect on target cancer cells, but not control cells. Furthermore, through simple aptamer or drug substitution, supramolecular vesicles can be applied to a variety of target cell lines and drugs, making it widely applicable. Taking advantage of the easy preparation, good stability, rapid pH response, and cell targeting ability, the aptamer-based self-assembled supramolecular vesicles hold great promise in controlled-release biomedical applications and targeted cancer therapy.     

Polymers for targeted and/or sustained drug delivery

Recent advances in the use of polymers for passive targeting of drugs attached or incorporated into polymeric species (enhanced permeability and retention, EPR) as well as active targeting of drugs by ligands or antibodies of receptors overexpressed on the surface of the targeted cells, is discussed in the present review. Examples of sustained, slow release of a drug incorporated into a polymeric matrix are cited. Drugs used for passive modes of targeting have been described in the context of polymer‐drug conjugates, drugs in the polymer coated liposomes, and drugs inserted into polymeric micelles. Active targeting of the drugs and their internalization by receptors, on the surface of the targeted cells, was also discussed. Release of the drugs inside cells, after are broken the environmentally sensitive links attaching them to polymeric platforms was described. Examples illustrate targeting drug by local heat generated by ultrasound, or by photodynamic treatment. Delivery modes of drugs incorporated into other nanoparticles and the concept of prodrugs have been investigated. Copyright © 2008 John Wiley & Sons, Ltd.     

Lipid carrier systems for targeted drug and gene delivery

For effective chemotherapy, it is necessary to deliver therapeutic agents selectively to their target sites, since most drugs are associated with both beneficial effects and side effects. The use of lipid dispersion carrier systems, such as lipid emulsions and liposomes, as carriers of lipophilic drugs has attracted particular interest. A drug delivery system can be defined as a methodology for manipulating drug distribution in the body. Since drug distribution depends on the carrier, administration route, particle size of the carrier, lipid composition of the carrier, electric charge of the carrier and ligand density of the targeting carrier, these factors must be optimized. Recently, the lipid carrier system has also been applied to gene delivery systems for gene therapy. However, in both drug and gene medicine cases, a lack of cell-selectivity limits the wide application of this kind of drug and/or gene therapy. Therefore, lipid carrier systems for targeted drug and gene delivery must be developed for the rational therapy. In this review, we shall focus on the progress of research into lipid carrier systems for drug and gene delivery following systemic or local injection.     

Colon targeted drug delivery of branch-chained disulphide cross-linked polymers: design,synthesis, and characterisation studies

Drug delivery directly to the colon is a very useful approach for treating localised colonic diseases such as inflammatory bowel disease, ulcerative colitis, and Crohn’s disease. The use of disulphide cross-linked polymers in colon targeted drug delivery systems has received much attention because these polymers are redox sensitive, and the disulphide bonds are only cleaved by the low redox potential environment in the colon. The goal of this study was to synthesise tricarballylic acid-based trithiol monomers for polymerisation into branch-chained disulphide polymers. The monomer was synthesised via the amide coupling reaction between tricarballylic acid and (triphenylmethyl) thioethylamine using two synthesis steps. The disulphide cross-linked polymers which were synthesised using the air oxidation method were completely reduced after 1 h of reduction with different thiol concentrations detected for the different disulphide polymers. In simulated gastric and intestinal conditions, all polymers had low thiol concentrations compared to the thiol concentrations in the simulated colon condition with Bacteroides fragilis present. Degradation was more pronounced in polymers with loose polymeric networks, as biodegradability relies on the swelling ability of polymers in an aqueous environment. Polymer P15 which has the loosest polymeric networks showed highest degradation.     

A novel magnetic triple-responsive composite semi-IPN hydrogels for targeted and controlled drug delivery

In this work, Fe₃O₄/poly(3-acrylamidephenylboronic acid-co-(2-dimethylamino) ethyl methacrylate) (Fe₃O₄/P(AAPBA-co-DMAEMA)) hydrogels possessing magnetic and triple-responsive properties and semi-interpenetrated by β-cyclodextrin-epichlorohydrin (β-CD-EPI) were prepared via radical polymerization. The characteristics of the materials have been investigated by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM). The swelling measurements and the application of Fe₃O₄/P(AAPBA-co-DMAEMA)/(β-CD-EPI) hydrogels in controlled release of drug were also investigated. It was found that the magnetic hydrogels exhibit swelling behaviors affected by pH, temperature, glucose concentration and magnetic field, and have porous morphologies, superparamagnetism. Moreover, the hydrogels possess targeting and could control the release of quercetin by adjusting pH value, temperature, glucose concentration and magnetic field.     

Theranostic hyaluronic acid prodrug micelles with aggregation-induced emission characteristics for targeted drug delivery

Theranostic hyaluronic acid (HA) prodrug micelles with pH-responsive drug release and aggregation-induced emission (AIE) properties were prepared by chemical graft of biomimetic phosphorylcholine (PC), anticancer drug doxorubicin (DOX) and AIE fluorogen tetraphenylene (TPE) to the HA backbone. DOX was conjugated to the HA backbone by a hydrazone bond which can be hydrolyzed under acidic environment and result in pH-triggered smart release of DOX. The TPE units with typical AIE characteristics were applied for real time drug tracking in cancer cells. The HA-based prodrugs could self-assemble into micelles in aqueous solution as confirmed by the dynamic light scattering (DLS) and transmission electron microscopy (TEM). The intracellular distribution of HA prodrug micelles could be clearly observed by fluorescence microscopy based on the strong fluorescence of TPE. Moreover, after treated with the micelles, stronger fluorescence of TPE in CD44 overexpressed MDA-MB-231 cancer cells was observed, compared to the CD44 negative cell line, NIH3T3 cells, suggesting efficient cell uptake of HA prodrug micelles by receptor-mediated endocytosis. The cell viability results indicated that the prodrug micelles could inhibit the proliferation of the cancer cells effectively. Such pH-triggered theranostic drug delivery system with AIE features can provide a new platform for targeted and image-guided cancer therapy.     

Liposaccharide-based nanoparticulate drug delivery system

A series of anionic liposaccharide derivatives were synthesized in order to develop a system, which would have the capacity to act as an absorption enhancer and to improve oral bioavailability of drugs. The addition of a liposaccharide to a drug enhances drug stability against enzymatic degradation, while the lipophilicity can be controlled by variation of the lipid side chain. All liposaccharide derivatives were purified and fully characterized by nuclear magnetic resonance and high-resolution mass spectrometry. The thermodynamic profiles, critical aggregation concentrations and size of the synthesized liposaccharides were determined by isothermal titration microcalorimetry, transmission electron microscopy and dynamic light scattering. These liposaccharides formed nanoparticles with sizes below 100 nm.     

Gold nanoparticles as a versatile platform for optimizing physicochemical parameters for targeted drug delivery

The development of targeted vehicles for systemic drug delivery relies on optimizing both the cell-targeting ligand and the physicochemical characteristics of the nanoparticle carrier. A versatile platform based on modification of gold nanoparticles with thiolated polymers is presented in which design parameters can be varied independently and systematically. Nanoparticle formulations of varying particle size, surface charge, surface hydrophilicity, and galactose ligand density were prepared by conjugation of PEG-thiol and galactose-PEG-thiol to gold colloids. This platform was applied to screen for nanoparticle formulations that demonstrate hepatocyte-targeted delivery in vivo. Nanoparticle size and the presence of galactose ligands were found to significantly impact the targeting efficiency. Thus, this platform can be readily applied to determine design parameters for targeted drug delivery systems.Modified gold nanoparticles are a suitable model for nanoparticle-based gene carriers.     

Numerical study of a drug release profile in the transdermal drug delivery system

Drug release by diffusion from an unstressed thin polymer film with a dissolved crystallizable component was simulated using a kinetic Monte Carlo model. This model was used previously to study Ostwald ripening in a high crystallizable component regime and was shown to correctly simulate solvation, diffusion, and precipitation. In this study, the same model with modifications was applied to the drug transportation and release in the low concentration regime of interest to the transdermal drug delivery system (TDS) community. We demonstrate the model's utility by simulating diffusion, crystal precipitation, growth and shrinkage during storage, and drug release from the thin TDS to a surface under different conditions. The simulation results provide a first approximation for the drug release profile occurring from TDS to skin. It has been reported that growth of drug crystals in TDS occurs mainly in the middle third of the polymer layer at relatively higher temperatures. The results from the simulations showed that the release rate and concentration profile of a TDS depend on the dissolution process of the crystal. At low storage temperature, the drug precipitates to form small evenly distributed crystals throughout the thickness of the TDS patch. The release rate of these small, evenly distributed crystals most closely matched that of a completely dissolved drug.     

Catechol polymers for pH-responsive, targeted drug delivery to cancer cells

A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug-polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug-polymer conjugates. The pH-sensitive catechol-boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.     

Recent advances in targeted stimuli-responsive nano-based drug delivery systems combating atherosclerosis

Atherosclerosis(AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, the development of carriers precisely delivering the therapeutic agents to the target sites is the primary goal, which could minimize the potential adverse effects and be more effective in treating lesions. Due to the precise location, real-time monitoring, AS microenvironment respons...