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At least 595 records · Page 33Linked to original sources
PubMed2000

A New Self-Assembling System for Targeted Gene Delivery We thank the BBSRC Chiroptical Service for CD studies, Brian McManus (Optokem Instruments, Nercyws, Flintshire) for assistance with the light-scattering studies, Dr. Clive Roberts (Molecular Profiles Ltd.) for AFM studies, Professor J.-H. Fuhrhop for many discussions, Dr. I. S. Blagbrough for related synthetic work, the EPSRC for support, and the Royal Society for a Leverhulme Trust Senior Research Fellowship (D.P.).

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Journal Article↗
PubMed2002

Targeted gene delivery to skin cells in vivo: a comparative study of liposomes and polymers as delivery vehicles.

Liposomes are microscopic lipid membrane vesicles that provide a current strategy for topical, dermal delivery of biologically active molecules. They have been successfully used for the delivery of various low and high molecular weight molecules into the skin, and as an alternative to virus-mediated delivery systems, have opened the field of dermal gene therapy. The present study was undertaken on 6-day-old rat pups to determine in vivo the efficacy of several liposome and nonliposome formulations, including phospholipid liposomes and their cationic or pegylated variants, nonionic liposomes and their cationic variant, PINC polymer (Protective, Interactive, Noncondensing polymers), and a propylene glycol:alcohol:water mixture (delivery vehicle for minoxidil) in delivering beta-galactosidase and luciferase reporter genes into skin cells. Based upon our observations of the expression of beta-galactosidase and luciferase reporter genes in skin cells, we report here that nonionic liposomes are the most efficient vehicle for transdermal delivery followed by nonionic/cationic and phospholipid (pegylated) liposomes. The propylene glycol:ethanol:water mixture and the PINC polymer were relatively inefficient in the delivery of beta-galactosidase or luciferase DNAs. This simple, noninvasive technique of using nonionic liposomes to deliver biomolecules provides an efficient delivery strategy for gene therapy and drug delivery to the dermal organ site.

Administration, Topical↗
PubMed1993

Suppression of plasma testosterone and prostate carcinoma size by a redox-based, brain-targeted estrogen delivery system in the rat.

Studies were undertaken to examine the effects of an estradiol-chemical delivery system (E2-CDS) or castration (CAST) on plasma testosterone (T) and growth of the Segaloff 11095 carcinoma. Fischer 344 rats were implanted subcutaneously with the Segaloff 11095 tumor and tumor growth was monitored thereafter. After optimal tumor growth, when the average tumor size was approximately 25 x 15 mm (length x width; 4-5 g wet weight), rats were randomized into (1) testis-intact controls; (2) CAST; (3) intact+E2-CDS groups (rats received weekly injection of the E2-CDS at 0.5 mg/kg). Animals were killed 7 or 14 days after the initiation of treatments. Blood and tissue samples were collected for subsequent analysis. Plasma T levels were suppressed by 98% and 97% through 14 days after CAST or E2-CDS treatment. CAST increased plasma gonadotropin (LH) concentrations, while E2-CDS reduced LH compared to intact control levels. E2-CDS treatment increased plasma E2 levels to 24 (one injection) or 75 pg/ml (two injections) at 7 or 14 days, respectively. E2-CDS, given once a week for 2 consecutive weeks, resulted in a decreased growth of the prostate tumor by 61%, while CAST reduced the weights of these tumors by only 20%. In response to E2-CDS (one or two injections), weights of the in situ ventral prostate and seminal vesicles were significantly reduced by 70% and 50%, respectively, in tumor-bearing rats. Similarly, CAST reduced the weights of these tissues by 80% (prostate) or 52% (seminal vesicle) at 7 or 14 days after treatment. Pituitary weight increased, while testes weight decreased by 20% with two injections of E2-CDS, compared with intact control rats. Collectively, these data indicate that E2-CDS is effective in reducing the growth rate of prostatic tumors in the rat.

Animals↗
PubMed1998

Targeted intraparenchymal delivery of human NGF by gene transfer to the primate basal forebrain for 3 months does not accelerate beta-amyloid plaque deposition.

Nerve growth factor therapy has been proposed as a potential means of preventing degeneration of basal forebrain cholinergic neurons in Alzheimer's disease and thereby improving cognition. However, NGF has been reported to upregulate expression of the beta-amyloid precursor protein, which in turn could accelerate deposition of "mature" beta-amyloid in the brain. To address this possibility, the brains of 16 adult and aged rhesus monkeys were examined for beta-amyloid plaque deposition in the presence or absence of NGF treatment. Six aged monkeys received intraparenchymal grafts into the cholinergic basal forebrain of autologous cells genetically modified to secrete NGF, six aged monkeys received intraparenchymal grafts of autologous control cells expressing the reporter gene beta-galactosidase, and four adult nonoperated monkeys served as additional controls. All brains were examined for expression of mature beta-amyloid using an antibody recognizing amino acids 1-40 of the beta-amyloid peptide. Amyloid plaques were systematically quantified in representative sections of the temporal, frontal, cingulate, insular, and parietal cortices and in the amygdala and hippocampus. Results disclosed that aging resulted in an increase in amyloid plaque formation: no plaques at all were detected in nonaged monkeys, whereas a mean of 20 +/- 13 plaques per section were present in control-aged monkeys. Aged subjects with intraparenchymal NGF-secreting grafts for 3 months contained a mean of 29 +/- 14 plaques per section, an amount that did not differ significantly from control-aged monkeys (P = 0.66). Thus, 3 months of intraparenchymal NGF delivery did not significantly increase beta-amyloid deposition.

Aging↗
PubMed2005

Evaluation of transferrin-polyethylenimine conjugate for targeted gene delivery.

With the aim to improve the specificity and to reduce the cytotoxicity of polyethylenimine (PEI), we have synthesized the conjugates of the branched PEI (25 kDa) with transferrin. The transferrin-PEI (TP) conjugates with five compositions were synthesized using periodate oxidation method and confirmed by FT-IR spectroscopy and gel permeation chromatography. The free amine contents of TP conjugates, which were able to condense and deliver DNA, increased as the amount of PEI increased. TP/DNA polyplexes were characterized by measuring gel electrophoresis, ethidium bromide fluorescence quenching, particle size and zeta potential of complexes. Complete complexation of the polyplexes was observed above the N/P ratio of 5 in TP/ DNA, and above 3 in PEI/DNA, respectively. The zeta potential of the complexes decreased as the amount of transferrin in TP conjugates increased. Transfection efficiency of TP conjugates was evaluated in HeLa cell and Jurkat cell systems. Among the five compositions of TP conjugates, TP-2 system mediated a higher beta-galactosidase gene expression than PEI system in Jurkat cell which was known to express elevated numbers of transferrin receptors. From the results of the cell viability based on MTT assay, TP conjugates showed lower cytotoxicity compared with the PEI system. We expect that the TP conjugate can be used efficiently as a nonviral gene delivery vector.

Cell Survival↗
PubMed2005

Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles: in vitro and in vivo studies.

PURPOSE: To develop safe and effective systemically administered nonviral gene therapy vectors for solid tumors, DNA-containing poly(ethylene glycol)-modified (PEGylated) gelatin nanoparticles were fabricated and evaluated in vitro and in vivo. METHODS: Reporter plasmid DNA encoding for beta-galactosidase (pCMV-beta) was encapsulated in gelatin and PEGylated gelatin nanoparticles using a water-ethanol solvent displacement method under controlled pH and temperature. Lewis lung carcinoma (LLC) cells in culture were transfected with the pCMV-beta in the control and nanoparticle formulations. Periodically, the expression of beta-galactosidase in the cells was measured quantitatively using an enzymatic assay for the conversion of o-nitrophenyl-beta-D: -galactopyranoside (ONPG) to o-nitrophenol (ONP). Qualitative expression of beta-galactosidase in LLC cells was observed by staining with 5-bromo-4-chloro-3-indolyl-beta-D: -galactopyranoside (X-gal). Additionally, the plasmid DNA-encapsulated gelatin and PEGylated gelatin nanoparticles were administered intravenously (i.v.) and intratumorally (i.t.) to LLC-bearing female C57BL/6J mice. At various time points postadministration, the animals were sacrificed and transgene expression in the tumor and liver was determined quantitatively by the ONPG to ONP enzymatic conversion assay and qualitatively by X-gal staining. RESULTS: Almost 100% of the pCMV-beta was encapsulated in gelatin and PEGylated gelatin nanoparticles (mean diameter 200 nm) at 0.5% (w/w) concentration. PEGylated gelatin nanoparticles efficiently transfected the LLC cells and the beta-galactosidase expression, as measured by the ONPG to ONP enzymatic conversion assay at 420 nm absorbance, increased starting from 12 h until 96 h post-transfection. The efficient expression of LLC cells was also evident by the X-gal staining method that shows blue color formation. The in vivo studies showed significant expression of beta-galactosidase in the tumor following administration of DNA-containing PEGylated gelatin nanoparticles to LLC-bearing mice by both i.v. and i.t. routes. Following i.v. administration of pCMV-beta in PEGylated gelatin nanoparticles, for instance, the absorbance at 420 nm per gram of tumor increased from 0.60 after 12 h to 0.85 after 96 h of transfection. After i.t. administration, the absorbance values increased from 0.90 after 12 h to almost 1.4 after 96 h. CONCLUSIONS: The in vitro and in vivo results of this study clearly show that a long-circulating, biocompatible and biodegradable, DNA-encapsulating nanoparticulate system would be highly desirable for systemic delivery of genetic constructs to solid tumors.

Animals↗
PubMed1988

A redox system for brain targeted estrogen delivery causes chronic body weight decrease in rats.

The effects of 2 redox based carriers for brain directed delivery of estradiol (CDS-E2) and ethinyl estradiol (CDS-EE) on body weight were examined in rats. A single dose of CDS-E2 (3 mg/kg) decreased weight gain in castrate rats for at least 24 days. The dose response of weight gain and LH suppression were compared 12 days and 12 to 25 after CDS-E2 and CDS-EE, respectively, in ovariectomized (OVX) rats. Weight decrease was detected at a lower dose and was significant for longer after drug treatment than LH decrease. Both compounds were more potent than equimolar estradiol or estradiol valerate in reducing weight gain. Intact rats also showed decreased weight gain but were less sensitive to CDS-E2 compared to OVX rats. The effects appeared to be estrogen specific as carrier-linked testosterone had no effect on weight. The mechanisms of sustained and potent drug effects on weight are being explored.

Animals↗
PubMedDate not supplied

Control of geohelminths by delivery of targeted chemotherapy through schools.

This study describes the age-targeted chemotherapeutic control of geohelminthiasis in the total population (n = 11,500) of the island of Montserrat, West Indies. The intervention programme involved the treatment with single dose albendazole of all children aged 2-15 years (approximately 2500) in 4 sequential cycles at intervals of 4 months. Infection status was monitored by an initial coprological survey of an age-stratified sample (11.5%) of the population, and by surveys of smaller samples (4-5%) after 2 and 4 cycles of treatment (7 and 15 months respectively). The programme delivered treatment to greater than 90% of the target population in each cycle, and reduced the prevalence and intensity of Ascaris lumbricoides and Trichuris trichiura infection in the target age-class. A decline in infection was also observed in the 16-25 year age-class, even though less than 4% of adults received treatment. The study demonstrates that chemotherapy targeted only at children can be implemented within an existing health infrastructure, and can achieve an overall reduction in the prevalence and intensity of geohelminth infection.

Adolescent↗
PubMed2006

Differential effects between intravenous and targeted renal delivery of fenoldopam on renal function and blood pressure in patients undergoing cardiac catheterization.

A randomized, controlled clinical trial demonstrated that intravenous (IV) fenoldopam did not prevent further deterioration in renal function after contrast administration in patients with chronic renal insufficiency. This lack of effect may have been a consequence of the inability to administer an effective renal dose of IV fenoldopam. This study sought to determine whether compared with IV administration, selective intrarenal (IR) fenoldopam would increase local concentration, leading to a higher glomerular filtration rate (GFR), and, because of first-pass renal elimination, result in lower systemic drug levels and less decrease in systemic blood pressure (BP). A randomized, controlled, open-label, partial crossover design trial was conducted in which 33 patients who underwent coronary angiography were randomized in a 1:2 ratio to control or fenoldopam (initially IV, then crossed over to IR through a bifurcated renal infusion catheter). Compared with IV fenoldopam, IR administration was associated with a significantly higher GFR (73.7 +/- 3.1 vs 62.6 +/- 2.5 ml/min, p = 0.0007) and renal plasma flow (537.2 +/- 34.0 vs 494.0 +/- 35.5 ml/min, p <0.01), lower fenoldopam plasma levels (3.3 +/- 0.3 vs 4.8 +/- 0.3 ng/ml, p <0.0001), and greater nadir systolic BP (125.5 +/- 3.6 vs 117.4 +/- 2.8 mm Hg, p <0.0001). Two hours after drug discontinuation after contrast administration, GFRs in the patients who received IR fenoldopam remained higher than in controls (+15.0 ml/min [+25%] vs -8.0 ml/min [-14.0%], p <0.05). In conclusion, this pilot trial demonstrates that the IR infusion of fenoldopam is safe and practical, producing greater renal effect and less reduction of BP than IV infusion. It would be appropriate to restudy this renal vasodilator for the prevention of contrast nephropathy, using selective IR delivery.

Aged↗