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Targeted Delivery (targeted + delivery)
Selected AbstractsTargeted delivery of salicylic acid from acne treatment products into and through skin: role of solution and ingredient properties and relationships to irritationINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 4 2004L. Rhein Salicylic acid (SA) is a beta-hydroxy acid and has multifunctional uses in the treatment of various diseases in skin such as acne, psoriasis, and photoaging. One problem often cited as associated with salicylic acid is that it can be quite irritating at pH 3,4, where it exhibits the highest activity in the treatment of skin diseases. We have identified strategies to control the irritation potential of salicylic acid formulations and have focused on hydroalcoholic solutions used in acne wipes. One strategy is to control the penetration of SA into the skin. Penetration of the drug into various layers of skin, i.e. epidermis, dermis, and receptor fluid, was measured using a modified Franz in vitro diffusion method after various exposure times up to 24 h. A polyurethane polymer (polyolprepolymer-15) was found to be an effective agent in controlling delivery of SA. In a dose-dependent fashion it targeted delivery of more SA to the epidermis as compared to penetration through the skin into the receptor fluid. It also reduced the rapid rate of permeation of a large dose of SA through the skin in the first few hours of exposure. A second strategy that proved successful was incorporation of known mild nonionic surfactants like isoceteth-20. These surfactants cleanse the skin, yet due to their inherent mildness (because of their reduced critical micelle concentration and monomer concentration), keep the barrier intact. Also, they reduce the rate of salicylic acid penetration, presumably through micellar entrapment (either in solution or on the skin surface after the alcohol evaporates). Cumulative irritation studies showed that targeting delivery of SA to the epidermis and reducing the rapid early rate of penetration of large amounts of drug through the skin resulted in a reduced irritation potential. In vivo irritation studies also showed that the surfactant system is the most important factor controlling irritancy. SA delivery is secondary, as formulations with less SA content reduced the rate of delivery to the receptor and yet were some of the most irritating formulations tested, presumably due to the action of the specific anionic surfactant on the barrier. Alcohol content also did not appreciably affect irritation and SA delivery; formulations with considerably low alcohol content but containing anionic versus nonionic surfactant systems exhibited considerably higher irritancy. Thus the surfactant type was again the predominant factor in those studies, although arguably alcohol plays some role (solubilization of SA). Results showed that both polymers and mild surfactants work in concert to provide the optimal formulation benefits of targeted delivery and reduced irritation. Synergistic relationships among hydroalcoholic formulation components will be discussed along with the mechanisms likely involved in controlling delivery of SA to skin. [source] Targeted delivery of proteins by nanosized carriersJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 1 2008Roberto Solaro Abstract Proteic drug administration poses some additional issues as compared with conventional drugs because of protein high molecular weight and short half-life in plasma. It is well known that protein delivery canbe significantly improved by using targeted nanocarriers. Among the diverse investigated systems, this overview focuses onliposomes and nanoparticles. Indeed, because of their subcellular size, nanocarriers can cross the fenestration of the vascular epithelium and penetrate tissues. Moreover, nanosystems can be confined at the location of choice by conjugation to molecules that strongly bind the target cells. In spite of the significant progress made in the design and engineering of liposomes and nanoparticles tailored to the targeted delivery of proteins, these nanocarriers seldom succeed in delivering proteins directly inside the cell cytosol. Accordingly, some attention is also paid to virosomes and fusion proteins. These systems have a few advantages over conventional nanocarriers, particularly the ability to cross the cell membrane. They also share the main drawback of being highly immunogenic. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1,11, 2008 [source] Recent developments in carbohydrate-decorated targeted drug/gene deliveryMEDICINAL RESEARCH REVIEWS, Issue 2 2010Hailong Zhang Abstract Targeted delivery of a drug or gene to its site of action has clear therapeutic advantages by maximizing its therapeutic efficiency and minimizing its systemic toxicity. Generally, targeted drug or gene delivery is performed by loading a macromolecular carrier with an appropriate drug or gene, and by targeting the drug/gene carrier to specific cell or tissue with the help of specific targeting ligand. The emergence of glycobiology, glycotechnology, and glycomics and their continual adaptation by pharmaceutical scientists have opened exciting avenue of medicinal applications of carbohydrates. Among them, the biocompatibility and specific receptor recognition ability confer the ability of carbohydrates as potential targeting ligands for targeted drug and gene delivery applications. This review summarizes recent progress of carbohydrate-decorated targeted drug/gene delivery applications. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 2, 270,289, 2010 [source] An in,vitro Assay to Measure Targeted Drug Delivery to Bone MineralCHEMMEDCHEM, Issue 5 2010Wolfgang Jahnke Dr. Abstract Targeted delivery of drugs to their site of action is a promising strategy to decrease adverse effects and enhance efficacy, but successful applications of this strategy have been scarce. Human bone is a tissue with unique properties due to its high hydroxyapatite mineral content. However, with the exception of bisphosphonates, bone mineral has not been targeted in a successful clinical application of drugs that act on bone, such as anti-resorptive or bone anabolic agents. Herein we present an NMR-based in,vitro assay to measure binding affinities of small molecules to hydroxyapatite (HAP) or bone powder. Binding was shown to be specific and competitive, and the assay can be carried out in a direct binding format or in competition mode. A selection of clinically relevant bisphosphonates was ranked by their binding affinity for HAP. The binding affinity decreases in the order: pamidronate > alendronate > zoledronate > risedronate > ibandronate. The differences in binding affinities span a factor of 2.1 between pamidronate and ibandronate, consistent with previous studies. The rank order is very similar with bone powder, although the binding capacity of bone powder is smaller and binding kinetics are slower. A zoledronate derivative that lacks the central hydroxy group binds to HAP with 2.3-fold weaker affinity than zoledronate itself. Any small molecule can be analyzed for its binding to HAP or bone powder, and the binding of common bone-staining agents such as alizarin and its derivatives was confirmed in the new assay. This assay supports a strategy for targeted delivery of drugs to bone by attaching a bone-affinity tag to the active drug substance. [source] Broad T cell immunity to the LcrV virulence protein is induced by targeted delivery to DEC-205/CD205-positive mouse dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2008Yoonkyung Do Abstract There is a need for a more efficient vaccine against the bacterium Yersinia pestis, the agent of pneumonic plague. The F1-LcrV (F1-V) subunit vaccine in alhydrogel is known to induce humoral immunity. In this study, we utilized DC to investigate cellular immunity. We genetically engineered the LcrV virulence protein into the anti-DEC-205/CD205 mAb and thereby targeted the conjugated protein directly to mouse DEC-205+ DC in situ. We observed antigen-specific CD4+ T cell immunity measured by intracellular staining for IFN-, in three different mouse strains (C57BL/6, BALB/c, and C3H/HeJ), while we could not observe such T cell responses with F1-V vaccine in alhydrogel. Using a peptide library for LcrV protein, we identified two or more distinct CD4+ T cell mimetopes in each MHC haplotype, consistent with the induction of broad immunity. When compared to nontargeted standard protein vaccine, DC targeting greatly increased the efficiency for inducing IFN-,-producing T cells. The targeted LcrV protein induced antibody responses to a similar extent as the F1-V subunit vaccine, but Th1-dependent IgG2a and IgG2c isotypes were observed only after anti-DEC-205:LcrV mAb immunization. This study sets the stage for the analysis of functional roles of IFN-,-producing T cells in Y.,pestis infection. [source] Therapy-induced antitumor vaccination by targeting tumor necrosis factor-, to tumor vessels in combination with melphalanEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2007Lorenzo Mortara Abstract Treatment of tumor-bearing mice with mouse (m)TNF-,, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4+ T cells and consequent activation and maturation of CD8+ CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4+ and CD8+ T cells 6,days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-, and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4+CD25+ regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response. [source] Multifunctional Mesostructured Silica Microspheres from an Ultrasonic Aerosol Spray,ADVANCED FUNCTIONAL MATERIALS, Issue 19 2008Li Li Abstract Multifunctional mesostructured silica microspheres are prepared using ultrasonic aerosol spray in conjunction with solvent evaporation-induced assembly. Rare earth ion,phenanthroline complexes, magnetite particles, photoacid generators, and pH-sensitive dyes are chosen as luminescent, magnetic, and photosensitive components. The incorporation of these functional components into mesostructured silica microspheres can be readily realized by dispersing them in the precursor solution of the aerosol spray process. Luminescent microspheres that can emit at multiple wavelengths when excited at a single wavelength are produced by the addition of multiple rare earth complexes into the precursor solution. The addition of magnetite particles leads to the production of magnetic luminescent microspheres. Photoacid generators and pH-sensitive dyes are further employed to produce magnetic photosensitive microspheres that can release acid and change color upon UV light illumination. Such multifunctional microspheres could have exciting potential for many optical and biotechnological applications, such as multiplexed labeling, diagnosis, simultaneous imaging and therapy, cell capture and separation, targeted delivery, and optical data storage. [source] Selective occlusion of tumor blood vessels by targeted delivery of an antibody-photosensitizer conjugateINTERNATIONAL JOURNAL OF CANCER, Issue 7 2006Monica Fabbrini Abstract The irregular vasculature and high interstitial pressure of solid tumors hinder the delivery of cytotoxic agents to cancer cells. As a consequence, the doses of chemotherapy necessary to achieve complete tumor eradication are associated with unacceptably high toxicities. The selective thrombosis of tumor blood vessels has been postulated as an alternative avenue for combating cancer, depriving tumors of nutrients and oxygen and causing an avalanche of tumor cell deaths. The human antibody L19, specific to the EDB domain of fibronectin, a marker of angiogenesis, is capable of selective in vivo localization around tumor blood vessels and is thus a suitable agent for delivering toxic payloads to the tumor neovasculature. Here we show that a chemical conjugate of the L19 antibody with the photosensitizer bis(triethanolamine)Sn(IV) chlorin e6, after intravenous injection and irradiation with red light, caused an arrest of tumor growth in mice with subcutaneous tumors. By contrast, a photosensitizer conjugate obtained with an antibody of identical pharmacokinetic properties but irrelevant specificity did not exhibit a significant therapeutic effect. These results confirm that vascular targeting strategies, aimed at the selective occlusion/disruption of tumor blood vessels, have a significant anticancer therapeutic potential and encourage the use of antibody-photosensitizer conjugates for the therapy of superficial tumors and possibly other angiogenesis-related pathologies. © 2005 Wiley-Liss, Inc. [source] Targeted optical injection of gold nanoparticles into single mammalian cellsJOURNAL OF BIOPHOTONICS, Issue 12 2009Craig McDougall Abstract We present an all optical technique for the targeted delivery of single 100 nm diameter gold nanoparticles into a specified region of the interior of an individual mammalian cell through a combination of optical tweezing and optical injection. The internalisation of the nanoparticle is verified by confocal laser scanning microscopy and confocal laser scanning reflectance microscopy. This represents the first time that nano sized particles have been tweezed and optically injected into mammalian cells using only light, and provides a novel methodology for internalising nanosphere based biosensors within specific intracellular regions of a mammalian cell. (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Targeted delivery of proteins by nanosized carriersJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 1 2008Roberto Solaro Abstract Proteic drug administration poses some additional issues as compared with conventional drugs because of protein high molecular weight and short half-life in plasma. It is well known that protein delivery canbe significantly improved by using targeted nanocarriers. Among the diverse investigated systems, this overview focuses onliposomes and nanoparticles. Indeed, because of their subcellular size, nanocarriers can cross the fenestration of the vascular epithelium and penetrate tissues. Moreover, nanosystems can be confined at the location of choice by conjugation to molecules that strongly bind the target cells. In spite of the significant progress made in the design and engineering of liposomes and nanoparticles tailored to the targeted delivery of proteins, these nanocarriers seldom succeed in delivering proteins directly inside the cell cytosol. Accordingly, some attention is also paid to virosomes and fusion proteins. These systems have a few advantages over conventional nanocarriers, particularly the ability to cross the cell membrane. They also share the main drawback of being highly immunogenic. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1,11, 2008 [source] Cell-mediated Delivery and Targeted Erosion of Vascular Endothelial Growth Factor-Crosslinked HydrogelsMACROMOLECULAR RAPID COMMUNICATIONS, Issue 14 2010Sung Hye Kim Abstract We have previously reported a novel polymeric delivery vehicle that is assembled via interaction between heparin and the vascular endothelial growth factor (VEGF). Here, the cell-responsiveness of this hydrogel,including the delivery of VEGF in response to VEGFR-2 overexpressing PAE/KDR cells (porcine aortic endothelial cells (PAE) equipped with the transcript for the kinase insert domain receptor (KDR)), consequent erosion of the hydrogel matrix, and cellular response,are highlighted. The release of VEGF and hydrogel erosion reached 100% only in the presence of PAE/KDR. The [PEG-LMWH/VEGF] hydrogel (PEG,=,poly(ethylene glycol), LMWH,=,low molecular weight heparin) correspondingly prompted increases in VEGFR-2 phosphorylation and proliferation of PAE/KDR cells. This study proves that growth factor-crosslinked hydrogels can liberate VEGF in response to specific receptors, causing gel erosion and desired cell responses. The promise of these approaches in therapeutic applications, including targeted delivery, is suggested. [source] Carbohydrate recognition by boronolectins, small molecules, and lectinsMEDICINAL RESEARCH REVIEWS, Issue 2 2010Shan Jin Abstract Carbohydrates are known to mediate a large number of biological and pathological events. Small and macromolecules capable of carbohydrate recognition have great potentials as research tools, diagnostics, vectors for targeted delivery of therapeutic and imaging agents, and therapeutic agents. However, this potential is far from being realized. One key issue is the difficulty in the development of "binders" capable of specific recognition of carbohydrates of biological relevance. This review discusses systematically the general approaches that are available in developing carbohydrate sensors and "binders/receptors," and their applications. The focus is on discoveries during the last 5 years. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 2, 171,257, 2010 [source] Nanotechnology advances in controlled drug delivery systemsPHYSICA STATUS SOLIDI (C) - CURRENT TOPICS IN SOLID STATE PHYSICS, Issue 12 2008C. Kiparissides Abstract Nanotechnology advances in drug delivery deal with the development of synthetic nanometer sized targeted delivery systems for therapeutic agents of increased complexity, and biologically active drug products. Therapeutic systems in this class are up to a million times larger than classical drugs like aspirin. Being larger there is more scope for diversity and complexity, which makes their protection much more challenging and their delivery more difficult. Their increased complexity however, gives these systems the unique power to tackle more challenging diseases. Targeted delivery systems can have multiple functions, a key one being their ability to recognize specific molecules which can be located either on the membrane of target cells, or in specific compartments within the cell. A challenging objective of targeted drug delivery is the development of innovative multidisciplinary approaches for the design, synthesis and functionalization of novel nanocarriers for targeted delivery of protein/peptide (P/P) drugs via oral, pulmonary and nasal administration routes as well as the fabrication of "smart" miniaturized drug delivery devices able to release a variety of drugs on demand. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Ibuprofen and Lipoic Acid Diamides as Potential Codrugs with Neuroprotective ActivityARCHIV DER PHARMAZIE, Issue 3 2010Piera Sozio Abstract Current evidences support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, our attention was focused on ibuprofen (IBU) used in clinical trails to prevent Alzheimer's disease, and (R)-,-lipoic acid (LA) considered as a potential neuroprotective agent in AD therapy. In particular, we investigated a series of lipophilic molecular combinations obtained by joining (R)-,-lipoic acid and ibuprofen via an amide bond. These new entities might allow targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation seem related to Alzheimer's disease. Our study included the synthesis of conjugates 1,3 and the evaluation of their physicochemical and in-vitro antioxidant properties. The new compounds are extremely stable in aqueous buffer solutions (pH = 1.3 and 7.4), and in rat and human plasma they showed a slow bioconversion to ibuprofen and (R)-,-lipoic acid. Codrugs 1,3 displayed in vitro free radical scavenging activity and were hydrolyzed more rapidly in brain tissue than in rat serum indicating that these new entities might allow targeted delivery of the parent drugs to neurons. The immunohistochemical analysis of A, (1-40) protein showed that A,-injected cerebral cortices treated with ibuprofen or compound 1 showed few plaques within capillary vessels and, in particular, A, (1-40) protein was less expressed in codrug- 1 -treated than in ibuprofen-treated cerebral cortex. [source] Genetic engineering of a lysosomal enzyme fusion protein for targeted delivery across the human blood-brain barrierBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2008Ruben J. Boado Abstract Mucopolysaccharidosis Type I, Hurler's Syndrome, is a lysosomal storage disorder that affects the brain. The missing enzyme, ,- L -iduronidase (IDUA), does not cross the blood-brain barrier (BBB). To enable BBB transport of the enzyme, human IDUA was fused to the carboxyl terminus of the heavy chain of a chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb crosses the BBB on the endogenous insulin receptor, and acts as a molecular Trojan horse to ferry into brain the IDUA. Transfection of COS cells resulted in high levels of IDUA enzyme activity both in the medium and in the intracellular space. The size of the fusion heavy chain, as measured with Western blotting and antibodies to either human IDUA or human IgG, was increased about 80 kDa, relative to the size of the heavy chain of the parent HIRMAb. The IDUA enzyme specific activity of the affinity purified HIRMAb-IDUA fusion protein was 363,±,37 U/µg protein, which is comparable to specific activity of recombinant IDUA. The accumulation of glycosoaminoglycans in Hurler fibroblasts was decreased 70% by treatment with the HIRMAb-IDUA fusion protein. Confocal microscopy showed targeting of the fusion protein to the lysosome. The HIRMAb-IDUA fusion protein bound with high affinity to the HIR, and was rapidly transported into the brain of the adult Rhesus monkey following intravenous administration. The HIRMAb-IDUA fusion protein is a new treatment for Hurler's syndrome, which has been specifically engineered to cross the human BBB. Biotechnol. Bioeng. 2008;99: 475,484. © 2007 Wiley Periodicals, Inc. [source] An in,vitro Assay to Measure Targeted Drug Delivery to Bone MineralCHEMMEDCHEM, Issue 5 2010Wolfgang Jahnke Dr. Abstract Targeted delivery of drugs to their site of action is a promising strategy to decrease adverse effects and enhance efficacy, but successful applications of this strategy have been scarce. Human bone is a tissue with unique properties due to its high hydroxyapatite mineral content. However, with the exception of bisphosphonates, bone mineral has not been targeted in a successful clinical application of drugs that act on bone, such as anti-resorptive or bone anabolic agents. Herein we present an NMR-based in,vitro assay to measure binding affinities of small molecules to hydroxyapatite (HAP) or bone powder. Binding was shown to be specific and competitive, and the assay can be carried out in a direct binding format or in competition mode. A selection of clinically relevant bisphosphonates was ranked by their binding affinity for HAP. The binding affinity decreases in the order: pamidronate > alendronate > zoledronate > risedronate > ibandronate. The differences in binding affinities span a factor of 2.1 between pamidronate and ibandronate, consistent with previous studies. The rank order is very similar with bone powder, although the binding capacity of bone powder is smaller and binding kinetics are slower. A zoledronate derivative that lacks the central hydroxy group binds to HAP with 2.3-fold weaker affinity than zoledronate itself. Any small molecule can be analyzed for its binding to HAP or bone powder, and the binding of common bone-staining agents such as alizarin and its derivatives was confirmed in the new assay. This assay supports a strategy for targeted delivery of drugs to bone by attaching a bone-affinity tag to the active drug substance. [source] HER-2-Targeted Nanoparticle,Affibody Bioconjugates for Cancer TherapyCHEMMEDCHEM, Issue 12 2008Frank Alexis Dr. Affibodies are a class of polypeptide ligand that are potential candidates for tissue-specific targeting of drug-encapsulated controlled release polymeric nanoparticles (NPs). We developed drug delivery vehicles composed of polymeric NPs surface modified with affibody ligands that bind the extracellular domain of the human epidermal growth factor receptor,2 (HER-2) for targeted delivery to cells that overexpress the HER-2 antigen. [source] | ||||||||||||||||