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At least 649 records · Page 36Linked to original sources
PubMed1998

Thermosensitive liposomal taxol formulation: heat-mediated targeted drug delivery in murine melanoma.

Taxol, an antitumour alkaloid which stabilizes microtubules, demonstrates marked activity against several tumours. However, due to its low aqueous solubility, Cremophor EL (polyoxyethylated castor oil) is used as the excipient in pharmaceutical drug preparations of taxol. This has toxic side effects, thereby limiting the clinical use of taxol in cancer therapy. The aim of this study was to design a novel taxol formulation using thermosensitive liposomes in order to eliminate the Cremophor EL vehicle and improve the antitumour activity of taxol by site-specific drug delivery. Temperature-sensitive liposomes encapsulating taxol were prepared using the natural lipids egg phosphatidylcholine and cholesterol in combination with ethanol. The liposomes have a phase transition temperature (Tm) of 43 degrees C. The in vivo efficacy of thermosensitive liposome encapsulated taxol was determined in B16F10 murine melanoma transplanted into C57BI/6 mice in combination with local hyperthermia. A significant reduction in tumour volume and an increase in survival time was observed in tumour-bearing mice treated with a combination of hyperthermia and thermosensitive liposome encapsulated taxol compared with animals treated with an equivalent dose of free taxol with or without hyperthermia. These results suggest that thermosensitive liposome encapsulated taxol in combination with hyperthermia may be useful in improving the therapeutic efficacy of taxol in the treatment of melanoma.

Animals↗
PubMed2006

Targeted drug delivery for refractory hemorrhagic Crohn disease.

Focal gastrointestinal inflammation and hemorrhage is a common problem associated with Crohn disease. The present report describes a case of chronic hemorrhage from an inflamed duodenum that was refractory to all endoscopic and systemic therapies, which was successfully treated with chemoembolization of the pancreaticoduodenal arcade with use of corticosteroids and gelatin sponge. The application of chemoembolization techniques need not be limited to treatment of malignancies.

Arteries↗
PubMed1997

Synthesis and evaluation of brain-targeted chemical delivery systems for the neurotrophomodulator 4-methylcatechol.

Since various 4-alkylcatechols stimulate nerve growth factor (NGF) biosynthesis both in-vitro and in-vivo, delivery of these agents to the brain may provide beneficial effect for the treatment of neurodegenerative diseases such as Alzheimer's. Several dihydropyridine-pyridinium salt type redox chemical delivery systems (CDS) of 4-methylcatechol (4-methylcatechol) were prepared as potential brain selective targetry forms for 4-methylcatechol. After preliminary evaluation by in-vitro stability studies in various buffer solutions and biological media, a selected CDS was further investigated in the rat to determine its in-vivo distribution. Selective and sustained delivery of the compound of interest to the rat brain was achieved. Furthermore, the NGF stimulatory activity in the rat brain after peripheral administration of the selected CDS was evaluated by measuring the levels of pre-pro-NGF mRNA in the rat hippocampus and frontal cortex, by dot blot hybridization and analysis. Results showed the peripheral administration of the CDS to achieve a 1.7-fold increase in NGF mRNA compared to control in the rat hippocampus, and an approximately 1.4-fold increase in the frontal cortex.

Animals↗
PubMed2002

Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway.

The membrane transferrin receptor-mediated endocytosis or internalization of the complex of transferrin bound iron and the transferrin receptor is the major route of cellular iron uptake. This efficient cellular uptake pathway has been exploited for the site-specific delivery not only of anticancer drugs and proteins, but also of therapeutic genes into proliferating malignant cells that overexpress the transferrin receptors. This is achieved either chemically by conjugation of transferrin with therapeutic drugs, proteins, or genetically by infusion of therapeutic peptides or proteins into the structure of transferrin. The resulting conjugates significantly improve the cytotoxicity and selectivity of the drugs. The coupling of DNA to transferrin via a polycation or liposome serves as a potential alternative to viral vector for gene therapy. Moreover, the OX26 monoclonal antibody against the rat transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain.

Animals↗
PubMed2003

Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics.

To assess O2 delivery to tissue by a new surface-modified, polyethylene glycol-conjugated human hemoglobin [MP4; Po2 at 50% saturation of hemoglobin (P50); 5.4 mmHg], we studied microcirculatory hemodynamics and O2 release in golden Syrian hamsters hemodiluted with MP4 or polymerized bovine hemoglobin (PolyBvHb; P50 54.2 mmHg). Comparisons were made with the animals' hemodiluted blood with a non-O2 carrying plasma expander with similar solution properties (Dextran-70). Systemic hemodynamics (arterial blood pressure and heart rate) and acid-base parameters were not correlated with microhemodynamics (arteriolar and venular diameter, red blood cell velocity, and flow). Microscopic measurements of Po2 and the O2 equilibrium curves permitted analysis of O2 release in precapillary and capillary vessels by red blood cells and plasma hemoglobin separately. No significant differences between the groups of animals with respect to arteriolar diameter, flow, or flow velocity were observed, but the functional capillary density was significantly higher in the MP4-treated animals (67%) compared with PolyBvHb-treated animals (37%; P < 0.05) or dextran-treated animals (53%). In the PolyBvHb-treated animals, predominant O2 release (both red blood cells and plasma hemoglobin) occurred in precapillary vessels, whereas in MP4 animals most of the O2 was released from both red blood cells and plasma hemoglobin in capillaries. Base excess correlated directly with capillary O2 release but not systemic O2 content or total O2 release. Higher O2 extraction of both red blood cell and plasma hemoglobin in capillaries represents a new mechanism of action of cell-free hemoglobin. High O2 affinity appears to be an important property for cell-free hemoglobin solutions.

Acid-Base Equilibrium↗
PubMed2006

Magnetic nanoparticles: inner ear targeted molecule delivery and middle ear implant.

Superparamagnetic iron oxide nanoparticles (SNP) composed of magnetite (Fe(3)O(4)) were studied preliminarily as vehicles for therapeutic molecule delivery to the inner ear and as a middle ear implant capable of producing biomechanically relevant forces for auditory function. Magnetite SNP were synthesized, then encapsulated in either silica or poly (D,L,-Lactide-co-glycolide) or obtained commercially with coatings of oleic acid or dextran. Permanent magnetic fields generated forces sufficient to pull them across tissue in several round window membrane models (in vitrocell culture, in vivo rat and guinea pig, and human temporal bone) or to embed them in middle ear epithelia. Biocompatibility was investigated by light and electron microscopy, cell culture kinetics, and hair cell survival in organotypic cell culture and no measurable toxicity was found. A sinusoidal magnetic field applied to guinea pigs with SNP implanted in the middle ear resulted in displacements of the middle ear comparable to 90 dB SPL.

Animals↗
PubMed2004

Targeted cell delivery into infarcted rat hearts by retrograde intracoronary infusion: distribution, dynamics, and influence on cardiac function.

BACKGROUND: Intracoronary infusion for cell transplantation has potential advantages in disseminating cells globally into the myocardium with less injury over direct intramuscular injection. Arterial route, however, has a risk of coronary embolism and a limitation in cell delivery into ischemic or infarcted areas. We assessed the efficiency of retrograde intracoronary cell implantation into infarcted hearts using a novel rat model. METHODS AND RESULTS: After left coronary artery ligation in rat, a catheter was inserted into the left cardiac vein, which drains the left ventricular free wall. Through this, 1x10(6) skeletal muscle precursor cells expressing nuclear beta-galactosidase were infused retrogradely into the vein. In situ staining demonstrated that beta-galactosidase-expressing donor cells had disseminated throughout the left ventricular free wall, including both infarcted and surrounding border areas, at 10 minutes after infusion. At 28 days, in contrast, positively stained multinuclear myotubes were found in border zones, whereas no positive cells were seen in infarcted areas. Measurement of beta-galactosidase enzyme activity estimated that 29.8+/-6.9% of total infused cells were retained within the myocardium at 10 minutes and that this number decreased to 23.7+/-8.1% at 3 days but rapidly increased thereafter, reaching a plateau at 90.2+/-17.1% by 14 days. Echocardiography and Langendorff perfusion demonstrated that cell implantation improved cardiac function and dimensions by 28 days, compared with both sham-treated and phosphate-buffered saline-infused infarcted hearts, and this was associated with decreased collagen deposition. CONCLUSIONS: Retrograde intracoronary cell transplantation could provide an effective cell delivery into infarcted hearts and could be a useful strategy for treating myocardial infarction.

Animals↗
PubMed2004

The use of microbubbles to target drug delivery.

Ultrasound-mediated microbubbles destruction has been proposed as an innovative method for noninvasive delivering of drugs and genes to different tissues. Microbubbles are used to carry a drug or gene until a specific area of interest is reached, and then ultrasound is used to burst the microbubbles, causing site-specific delivery of the bioactive materials. Furthermore, the ability of albumin-coated microbubbles to adhere to vascular regions with glycocalix damage or endothelial dysfunction is another possible mechanism to deliver drugs even in the absence of ultrasound. This review focuses on the characteristics of microbubbles that give them therapeutic properties and some important aspects of ultrasound parameters that are known to influence microbubble-mediated drug delivery. In addition, current studies involving this novel therapeutical application of microbubbles will be discussed.

Drug Delivery Systems↗
PubMed2002

Targeted brain delivery of 17 beta-estradiol via nasally administered water soluble prodrugs.

The utility of the nasal route for the systemic delivery of 17beta-estradiol was studied using watersoluble prodrugs of 17beta-estradiol. This delivery method was examined to determine if it will result in preferential delivery to the brain. Several alkyl prodrugs of 17beta-estradiol were prepared and their physicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, and rat brain homogenate were determined by high-performance liquid chromatography. In vivo nasal experiments were carried out on rats. Levels of 17beta-estradiol in plasma and cerebral spinal fluid (CSF) were determined with radioimunoassay using a gamma counter. The study revealed that the aqueous solubilities of the prodrugs were several orders of magnitude greater than 17beta-estradiol with relatively fast in vitro conversion in rat plasma. Absorption was fast following nasal delivery of the prodrugs with high bioavailability. CSF 17beta-estradiol concentration was higher following nasal delivery of the prodrugs compared to an equivalent intravenous dose. It was determined that water-soluble prodrugs of 17beta-estradiol can be administered nasally. These prodrugs are capable of producing high levels of estradiol in the CSF and as a result may have a significant value in the treatment of Alzheimer's disease.

Administration, Intranasal↗
PubMed1990

Possible application of polyamine graft copolymer to targeting drug delivery.

Polystyrene microspheres were coated with polyamine graft copolymer and mixed with rat lymphocyte suspension. In the mixture of T and B cells, the microspheres formed large aggregates, while they were fairly well dispersed in the T cell suspension. This result was understood to be the result of preferential adsorption of B cells to the microspheres, indicating it would be possible to deliver drugs to B cells alone with these copolymer-coated microspheres.

Animals↗
PubMed2005

Pharmacokinetic/pharmacodynamic evaluation of inhalation drugs: application to targeted pulmonary delivery systems.

Inhaled therapy with either glucocorticoids and/or beta(2)-adrenergic drugs remains the mainstay of asthma treatment. In the last few years, a number of new products have been introduced into the market with the goal of improving efficacy and safety. This review article summarises the pharmacokinetic and pharmacodynamic properties of inhaled drugs for topical delivery necessary to achieve this goal. Pharmacokinetic properties include a high pulmonary deposition, low oral bioavailability, optimised pulmonary residence time and a very high systemic clearance. Optimisation of pharmacodynamic properties, such as receptor selectivity, may also yield drugs with improved pulmonary selectivity. As existing drugs also provide high efficacy and safety profiles, future developments will represent only slight improvements and quantum leap improvements are unlikely to occur.

Administration, Inhalation↗
PubMed2004

Caveolae--an alternative endocytotic pathway for targeted drug delivery.

Caveolae are bottleshape-like invaginations of the plasma membrane. After internalization they are involved in endocytosis, transcytosis, potocytosis, and pinocytosis. Our recently expanded knowledge has made clear that various molecules and macromolecular complexes enter the cells after docking on caveolar receptors, before subsequent internalization of the caveolae. The internalization is initiated by the ligand receptor interaction. Folate, cholesterol, serum lipoproteins, and liposomes are among the most common examples. It is important to point out that, in contrast to the classic clathrin-dependent endocytosis, the caveolar internalization pathway seems to avoid the lysosomes. Internalized caveolae fuse with caveosomes, and the caveosomes deliver their contents into other subcellular (non-lysosomal) compartments. The bypass of the acidic and harmful milieu might be a major advantage for drug delivery via the caveolar pathway. Not all cell types have caveolae. Cells, where the Caveolin I protein is not expressed, do not develop caveolar invaginations. However, these cells have caveolar-equivalent plasma membrane domains, so-called "lipid rafts." Lipid rafts are assembled from the same lipid constituents and proteins as caveolae, but they are flat. Specific ligands may also dock on appropriate receptors of the raft domain. As a complication, certain types of ligand-covered raft receptors can migrate to clathrin-coated pits and get internalized via clathrin-coated vesicles. Nevertheless, suitable ligands or antibodies developed against proteins of the caveolar/raft domains may selectively direct the attached drug carrier to the less harmful caveolar/raft pathway. Thus, understanding of caveolar transport may help in the rational design of more effective drug carriers.

Animals↗
PubMed2004

Novel paramagnetic contrast agents for molecular imaging and targeted drug delivery.

Molecular biology and genomic sciences are revealing the early biological signatures for many diseases. In response, the Molecular Imaging community is rapidly developing contrast agents to visualize the nascent pathological changes and to concomitantly deliver treatment directly to the site of disease. The evaluation, development and use of these new agents require a complementary understanding of contrast chemistry and imaging techniques. The fundamental issues surrounding magnetic contrast agent development, rational drug delivery, MR molecular imaging, and their interdependence are elucidated.

Animals↗
PubMed1996

Targeted drug delivery to the respiratory tract: solute permeability of air-interface cultured rabbit tracheal epithelial cell monolayers.

The permeability characteristics of air-interfaced rabbit tracheal epithelial cell monolayers to model macromolecules and low molecular weight solutes were evaluated. The model macromolecules were fluorescein isothiocyanate (FITC)-labeled dextrans of varying molecular sizes (4,000 to 70,000 daltons). The model low molecular weight solutes were beta-adrenergic compounds of similar sizes with widely different log octanol/pH 7.4 buffer partition coefficients (log P). FITC-dextrans were assayed spectrofluorimetrically and beta-adrenergic compounds were assayed by reverse phase HPLC with UV detection. The apparent permeability coefficients (Papp) for FITC alone to FITC-dextran 70,000 in the tracheal epithelial barrier were in the range of 11.2 to 0.3 x 10(8) cm/sec. A molecular cut-off at about 20,000 daltons, consistent with a single equivalent pore population of about 5 nm in radius, was found. A sigmoidal relationship best described the influence of drug lipophilicity on the Papp of beta-adrenergic compounds, where the log P at the half maximal Papp was 2.08. Thus, the air-interfaced rabbit tracheal epithelial cell culture model has been successfully applied to elucidate the permeability of tracheal epithelial barrier to model macromolecules and small solutes. It appears that the tracheal epithelial cell monolayers absorb drugs in a similar manner as do native excised tracheal and other epithelia.

Adrenergic beta-Agonists↗
PubMed2002

Gene therapy for meningioma: improved gene delivery with targeted adenoviruses.

OBJECT: Due to their surgical inaccessibility or aggressive behavior, some meningiomas cannot be cured with current treatment strategies. Gene therapy is an emerging strategy for the treatment of brain tumors, which the authors investigated to determine whether adenoviruses could be used for gene transfer in meningioma cells. METHODS: The presence of the high-affinity Coxsackievirus and adenovirus receptor (CAR) for adenovirus type 5, as well as endothelial growth factor receptor (EGFR) and alpha, integrins (ITGAVs), were analyzed in primary tumors by using immunohistochemical studies and in primary meningioma cell cultures by using fluorescence-activated cell sorting. Targeting of adenoviruses to EGFR was achieved using bispecific antibodies, whereas targeting of adenoviruses to the ITGAVs was accomplished by insertion of an RGD (arginine-glycine-aspartic acid) motif in the adenovirus fiber H1 loop. Gene transfer efficiency of untargeted and targeted vectors was compared in primary cell cultures and in spheroids derived from patients' resected tumor material. The presence of CARs was observed in all tumors and in all but one of the derived primary meningioma cells. The higher expression of EGFRs and ITGAVs indicated that these receptors could be used as alternative targets to redirect the adenoviruses. Redirection of adenoviruses to the EGFRs or integrins enhanced gene transfer threefold (range two-sevenfold) for EGFRs in primary meningioma cells and ninefold (range three-23-fold) for integrins (p = 0.002, analysis of variance). The effect of adenovirus targeting was confirmed in spheroids composed of primary meningioma cells. CONCLUSIONS: Gene transfer with adenoviruses targeted to tumor-specific receptors is very effective in primary meningioma cells and spheroids. These vectors are promising agents for gene therapy of meningiomas.

Adenoviridae↗