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Drug Targeting (drug + targeting)
Selected AbstractsCross-calibration of X-ray µCT and MRX for tissue analysisPROCEEDINGS IN APPLIED MATHEMATICS & MECHANICS, Issue 1 2009H. Rahn Ferrofluids are being considered as an aid for local cancer treatments, such as Magnetic Drug Targeting (MDT) and Magnetic Hyperthermia (MHT). Both methods make use of the strong influence of a magnetic field on the nanoparticles, with the aim of treating the cancer locally while reducing, or even eliminating, the side effects that usually occur during conventional cancer treatments. Microcomputed tomography analysis has been performed on tumour tissue after MDT and MHT in order to examine the distribution of the magnetic nanoparticles within the tissue. The majority of the measurements has been performed in a laboratory based on a polychromatic X-ray source. The strong energy dependence of the attenuation coefficient and the occurrence of the so called beam hardening artefacts make the quantitative evaluation of data acquired with polychromatic tomography equipment very difficult. In this paper we present a cross-calibration method for magnetorelaxometry and polychromatic X-ray tomography for biological tissue samples enriched with magnetic nanoparticles. (© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Evaluation of hepatotropic targeting properties of allogenic and xenogenic erythrocyte ghosts in normal and liver-injured ratsLIVER INTERNATIONAL, Issue 2 2008Olav A. Gressner Abstract Background/Aims: Haemoglobin-depleted erythrocyte ghosts have been recommended as vesicle carriers of drugs with hepatotropic properties. However, the influence of liver injury on ghost elimination and targeting has not been reported so far. Methods: Human and rat ghosts were prepared and loaded with model substances, and the basic parameters were characterized. Ghosts were injected intravenously into rats with acute, subacute and chronic liver injuries. Elimination from circulation, organ distribution and cellular targeting was measured. The uptake of ghosts by liver macrophages/Kupffer cells was determined in cell culture. Results: Ghosts are strong hepatotropic carriers with a recovery of 90% in normal liver. Kupffer cells are the almost exclusive target cell type. Hepatotropic properties remain in rats with chronic liver diseases, but are reduced by 60,70% in acute liver damage as a result of decline of phagocytosis of macrophages/Kupffer cells. Although the uptake of ghosts per gram liver tissue in chronic liver injury was also reduced by about 40%, the increase of liver mass and of macrophages/Kupffer cells compensated for the reduced phagocytotic activity. In subacute injury, the uptake per gram liver tissue was only moderately reduced. Conclusion: Drug targeting with ghosts might be feasible in chronic and subacute liver injuries, e.g. fibrogenesis and tumours, because the content of ingested ghosts is released by Kupffer cells into the micro-environment, providing the uptake by and pharmacological effects on adjacent cells. [source] Chronic inhibition of nitric-oxide synthase induces hypertension and erectile dysfunction in the rat that is not reversed by sildenafilBJU INTERNATIONAL, Issue 1 2010Serap Gur Study Type , Aetiology (case control) Level of Evidence 3b OBJECTIVE To evaluate the effect of N(G)-nitro- l -arginine methyl ester (L-NAME)-induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)-5 inhibitor, sildenafil, can reverse the effects of nitric oxide (NO) deficiency, as HT is a risk factor for erectile dysfunction (ED) and the NO synthase (NOS) inhibitor L-NAME induces NO-deficient HT. MATERIALS AND METHODS Thirty-six adult Sprague-Dawley male rats were divided into three groups, i.e. a control, L-NAME-HT (40 mg/rat/day in the drinking water for 4 weeks), and sildenafil-treated L-NAME-HT (1.5 mg/rat/day sildenafil, by oral gavage concomitantly with L-NAME). The erectile response expressed as a ratio of intracavernosal pressure (ICP)/mean arterial pressure (MAP), evaluated after electrical stimulation of the right cavernous nerve. The isometric tension of corpus cavernosum smooth muscle (CCSM) was measured in organ-bath experiments. NOS expression was determined immunohistochemically for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein. cGMP levels were evaluated by enzyme-linked immunosorbent assay. RESULTS The erectile response was diminished in the HT group. Nitrergic and endothelium-dependent relaxation was reduced, while the relaxation response to sodium nitroprusside and contractile response to phenylephrine were not altered in CCSM from L-NAME-treated rats. HT rats showed decreased expression of nNOS, whereas eNOS and iNOS protein expression was increased. Sildenafil partly restored endothelial and molecular changes in CCSM from HT rats, but did not reverse the decreased erectile response, even as cGMP levels returned to normal levels. CONCLUSIONS Sildenafil treatment did not correct the ED in L-NAME-treated HT rats. Under sustained high blood pressure, up-regulation of PDE5 expression failed to reverse the depletion of neuronal NO and/or impaired nNOS activity. However, endothelium-dependent relaxation was restored. Drug targeting of neuronal dysfunction might delay the onset of ED in HT. [source] Sphingosine-1-phosphate and FTY720 as anti-atherosclerotic lipid compoundsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2007M. Tölle Abstract All stages of atherosclerosis have been identified as a chronic vascular inflammatory disease. In the last few years there is increasing evidence that endogenous lysophospholipids such as sphingosine-1-phosphate (S1P) have potent anti-inflammatory properties. The S1P analogue FTY720 that has been developed as a potent, orally active, immunosuppressant in the field of transplantation and autoimmune disease has interesting effects on inflammatory processes in the arterial vessel wall. S1P targets five specific S1P receptors (S1P1,5), which are ubiquitously expressed. S1P1,3 receptor expression is identified in arterial vessels. S1P and FTY720 show potent silencing effects on some vascular proinflammatory mechanisms in endothelial and vascular smooth muscle cells. In addition, the interaction of monocytes with the vessel wall is inhibited. As shown recently, FTY720 can effectively reduce the progression of atherosclerosis in apolipoprotein E-deficient mice having a high-cholesterol diet. It is not entirely clear which S1P receptor subtype is mainly involved in this process. However, it is currently speculated that the S1P3 and probably the S1P1 is involved in the anti-atherosclerotic effects of FTY720. This review summarizes the current knowledge about S1P- and FTY720-effects on mechanisms of vascular inflammatory disease. In addition S1P receptor subtypes are identified which might be interesting for molecular drug targeting. [source] Synthesis of Magnetic, Up-Conversion Luminescent, and Mesoporous Core,Shell-Structured Nanocomposites as Drug CarriersADVANCED FUNCTIONAL MATERIALS, Issue 7 2010Shili Gai Abstract The synthesis (by a facile two-step sol,gel process), characterization, and application in controlled drug release is reported for monodisperse core,shell-structured Fe3O4@nSiO2@mSiO2@NaYF4: Yb3+, Er3+/Tm3+ nanocomposites with mesoporous, up-conversion luminescent, and magnetic properties. The nanocomposites show typical ordered mesoporous characteristics and a monodisperse spherical morphology with narrow size distribution (around 80,nm). In addition, they exhibit high magnetization (38.0,emu g,1, thus it is possible for drug targeting under a foreign magnetic field) and unique up-conversion emission (green for Yb3+/Er3+ and blue for Yb3+/Tm3+) under 980,nm laser excitation even after loading with drug molecules. Drug release tests suggest that the multifunctional nanocomposites have a controlled drug release property. Interestingly, the up-conversion emission intensity of the multifunctional carrier increases with the released amount of model drug, thus allowing the release process to be monitored and tracked by the change of photoluminescence intensity. This composite can act as a multifunctional drug carrier system, which can realize the targeting and monitoring of drugs simultaneously. [source] Synthesis of oligotuftsin-based branched oligopeptide conjugates for chemotactic drug targetingJOURNAL OF PEPTIDE SCIENCE, Issue 5 2006Gábor Mezö Abstract The synthesis and chemotactic properties of a new class of branched oligopeptide-based conjugates are described. Tetratuftsin derivatives containing chemotactic formyl tripeptides (For-MLF, For-NleLF or For-MMM) in branches were prepared by stepwise solid-phase peptide synthesis. The influence of the composition and ionic charge of the carrier-branched oligopeptide on the chemotactic behaviour of the conjugate was studied in Tetrahymena pyriformis. Conjugates with methotrexate (Mtx) as a drug component was also prepared. For this, a GFLGC spacer, cleavable by cathepsin B, was used. The spacer with N -terminal methotrexate was coupled to the chloroacetylated chemotactic carrier molecule by thioether bond formation. The chemotactic activity and cytotoxity of Mtx conjugates were also studied. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [source] Colloidal soft matter as drug delivery systemJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2009Giulia Bonacucina Abstract Growing interest is being dedicated to soft matter because of its potential in delivering any type of drugs. Since hydrophilic, lipophilic, small and big molecules can be loaded into these colloidal systems and administered through the parenteral or nonparenteral route, soft matter systems have been used to solve many biomedical and pharmaceutical problems. In fact, they make possible to overcome difficulties in the formulation and delivery of poorly water-soluble drug molecules, settle some stability issues typical of biological drug molecules, design parenteral sustained release forms and provide functionalized soft particles that are very effective in drug targeting. This review deals with the important role that colloids play in the drug delivery and targeting, with particular attention to the more currently used systems such as microemulsions, organogels, liposomes, micelles, and dendrimers. Though significant progress has been made in drug targeting, some challenges still remain. Further efforts will be required to better understand the characteristics of targets and to discover new ones. In-depth knowledge of the physico-chemical structure and properties of the systems used for targeting is fundamental for understanding the mechanism of interaction with the biological substrate and the consequent drug release. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1,42, 2009 [source] Amphotericin B formulations and drug targetingJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2008J.J. Torrado Abstract Amphotericin B is a low-soluble polyene antibiotic which is able to self-aggregate. The aggregation state can modify its activity and pharmacokinetical characteristics. In spite of its high toxicity it is still widely employed for the treatment of systemic fungal infections and parasitic disease and different formulations are marketed. Some of these formulations, such as liposomal formulations, can be considered as classical examples of drug targeting. The pharmacokinetics, toxicity and activity are clearly dependent on the type of amphotericin B formulation. New drug delivery systems such as liposomes, nanospheres and microspheres can result in higher concentrations of AMB in the liver and spleen, but lower concentrations in kidney and lungs, so decreasing its toxicity. Moreover, the administration of these drug delivery systems can enhance the drug accessibility to organs and tissues (e.g., bone marrow) otherwise inaccessible to the free drug. During the last few years, new AMB formulations (AmBisome®, Abelcet®, and Amphotec®) with an improved efficacy/toxicity ratio have been marketed. This review compares the different formulations of amphotericin B in terms of pharmacokinetics, toxicity and activity and discusses the possible drug targeting effect of some of these new formulations. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2405,2425, 2008 [source] In-vitro evaluation of khaya and albizia gums as compression coatings for drug targeting to the colonJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2005Oluwatoyin A. Odeku Khaya and albizia gums were evaluated as compression coatings for target drug delivery to the colon using indometacin (a water insoluble drug) and paracetamol (a water soluble drug) as model drugs. The core tablets were compression-coated with 300 and 400mg of 100% khaya gum, 100% albizia gum and a mixture of khaya and albizia gum (1:1). Drug release studies were carried out in 0.1M HCI (pH 1.2) for 2h, Sorensen's buffer (pH 7.4) for 3 h and then in phosphate-buffered saline (pH 6.8) or in simulated colonic fluid for the rest of the experiment to mimic the physiological conditions from the mouth to colon. The results indicated that khaya and albizia gums were capable of protecting the core tablet in the physiological environment of the stomach and small intestine, with albizia gum showing greater ability than khaya gum. The release from tablets coated with the mixture of khaya and albizia gums was midway between the two individual gums, indicating that there was no interaction between the gums. Studies carried out using rat caecal matter in phosphate-buffered saline at pH 6.8 (simulated colonic fluid) showed that the gums were susceptible to degradation by the colonic bacterial enzymes, leading to release of the drug. The results demonstrate that khaya gum and albizia gum have potential for drug targeting to the colon. [source] Networks for recognition of biomolecules: molecular imprinting and micropatterning poly(ethylene glycol)- Containing films,POLYMERS FOR ADVANCED TECHNOLOGIES, Issue 10-12 2002Mark E. Byrne Abstract Engineering the molecular design of biomaterials by controlling recognition and specificity is the first step in coordinating and duplicating complex biological and physiological processes. Studies of protein binding domains reveal molecular architectures with specific chemical moieties that provide a framework for selective recognition of target biomolecules in aqueous environment. By matching functionality and positioning of chemical residues, we have been successful in designing biomimetic polymer networks that specifically bind biomolecules in aqueous environments. Our work addresses the preparation, behavior, and dynamics of the three-dimensional structure of biomimetic polymers for selective recognition via non-covalent complexation. In particular, the synthesis and characterization of recognitive gels for the macromolecular recognition of D -glucose is highlighted. Novel copolymer networks containing poly(ethylene glycol) (PEG) and functional monomers such as acrylic acid, 2-hydroxyethyl methacrylate, and acrylamide were synthesized in dimethyl sulfoxide (polar, aprotic solvent) and water (polar, protic solvent) via UV-free radical polymerization. Polymers were characterized by single and competitive equilibrium and kinetic binding studies, single and competitive fluorescent and confocal microscopy studies, dynamic network swelling studies, and ATR-FTIR. Results qualitatively and quantitatively demonstrate effective glucose-binding polymers in aqueous solvent. Owing to the presence of template, the imprinting process resulted in a more macroporous structure as exhibited by dynamic swelling experiments and confocal microscopy. Polymerization kinetic studies suggest that the template molecule has more than a dilution effect on the polymerization, and the effect of the template is related strongly to the rate of propagation. In addition, PEG containing networks were micropatterned to fabricate microstructures, which would be the basis for micro-diagnostic and tissue engineering devices. Utilizing photolithography techniques, polymer micropatterns of a variety of shapes and dimensions have been created on polymer and silicon substrates using UV free-radical polymerizations with strict spatial control. Micropatterns were characterized using optical microscopy, SEM, and profilometry. The processes and analytical techniques presented are applicable to other stimuli-sensitive and recognitive networks for biomolecules, in which hydrogen bonding, hydrophobic, or ionic contributions will direct recognition. Further developments are expected to have direct impact on applications such as analyte controlled and modulated drug and protein delivery, drug and biological elimination, drug targeting, tissue engineering, and micro- or nano-devices. This work is supported by NSF Grant DGE-99-72770. Copyright © 2003 John Wiley & Sons, Ltd. [source] Prodrug Strategies in Anticancer ChemotherapyCHEMMEDCHEM, Issue 1 2008Felix Kratz Dr. Abstract The majority of clinically approved anticancer drugs are characterized by a narrow therapeutic window that results mainly from a high systemic toxicity of the drugs in combination with an evident lack of tumor selectivity. Besides the development of suitable galenic formulations such as liposomes or micelles, several promising prodrug approaches have been followed in the last decades with the aim of improving chemotherapy. In this review we elucidate the two main concepts that underlie the design of most anticancer prodrugs: drug targeting and controlled release of the drug at the tumor site. Consequently, active and passive targeting using tumor-specific ligands or macromolecular carriers are discussed as well as release strategies that are based on tumor-specific characteristics such as low pH or the expression of tumor-associated enzymes. Furthermore, other strategies such as ADEPT (antibody-directed enzyme prodrug therapy) and the design of self-eliminating structures are introduced. Chemical realization of prodrug approaches is illustrated by drug candidates that have or may have clinical importance. [source] | ||||||||||||||||