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At least 217 records · Page 12Linked to original sources
PubMed2004

Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice: the efficacy of parathyroid hormone-related protein and hepatocyte growth factor.

Treatment of acute renal failure (ARF) would be enhanced by identification of factors that accelerate renal recovery from injury. Parathyroid hormone-related protein (PTHrP) and hepatocyte growth factor (HGF) have been shown to stimulate proliferation in proximal nephron-derived cells. For studying the pathophysiologic roles and therapeutic potential of these two factors in ARF, transgenic mice overexpressing PTHrP or HGF in the proximal tubule under the direction of the gamma-glutamyl transpeptidase-I promoter were developed. These mice display (1) abundant expression of the respective transgenes in the kidney; (2) similar PTH type I receptor and HGF receptor (c-met) expression levels in the proximal tubule compared with control littermates; and (3) normal renal morphology, function, and tubule cell proliferation under basal conditions. However, in contrast to control mice, when acute ischemic renal injury was induced, renal function rapidly and dramatically recovered in HGF-overexpressing mice. In addition, 48 h after ischemia, HGF-overexpressing transgenic mice displayed a fourfold increase in tubule cell proliferation and a threefold decrease in apoptotic tubule cell death compared with control mice. In contrast, PTHrP-overexpressing mice responded to either ischemic or folic acid-induced renal damage similarly to control mice. These studies demonstrate that overexpression of PTHrP in the proximal nephron of mice does not seem to provide protection against acute renal injury. In marked contrast, HGF overexpression results in dramatic protection from ischemia-induced ARF, without inducing any apparent alteration in the physiology of the kidney under normal conditions. These studies suggest that HGF, when targeted specifically to the proximal tubule, may have therapeutic potential in providing protection against ischemia-induced renal failure.

Acute Kidney Injury↗
PubMed2005

Targeted delivery of a triplex-forming oligonucleotide to hepatic stellate cells.

Liver fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM), namely, fibrillar collagens in the hepatic stellate cells (HSCs). Earlier, we developed an antigene approach, using a type alpha1(I) collagen gene promoter specific triplex-forming oligonucleotide (TFO) to inhibit collagen gene expression. In this paper, to enhance overall delivery of TFOs to the liver and more specifically to HSCs, we synthesized mannose 6-phosphate-bovine serum albumin (M6P-BSA) by phosphorylating p-nitrophenyl-alpha-d-mannopyranoside, reducing its nitro group, and reacting it with thiophosgene to produce p-isothiocyanatophenyl-6-phospho-alpha-d-mannopyranoside (itcM6P) for conjugation with BSA. (33)P-TFO was conjugated with M6P-BSA via a disulfide bond, and the stability of the (M6P)(20)-BSA-TFO conjugate was determined. Following tail vein injection into rats, (M6P)(20)-BSA-(33)P-TFO rapidly cleared from the circulation and accumulated mainly in the liver. Almost 66% of the injected (M6P)(20)-BSA-(33)P-TFO accumulated in the liver at 30 min postinjection, which was significantly higher than that deposited after injection of (33)P-TFO. A large proportion of the injected (M6P)(20)-BSA-(33)P-TFO was taken up by the HSCs as evidenced by determination of radioactivity in the digested liver cells upon liver perfusion and separation on a Nycodenz gradient. Therefore, this TFO conjugate may be used for the treatment of liver fibrosis.

Animals↗
PubMed2003

Di/tri-peptide transporters as drug delivery targets: regulation of transport under physiological and patho-physiological conditions.

Two human di/tri-peptide transporters, hPepT1 and hPepT2 have been identified and functionally characterized. In the small intestine hPepT1 is exclusively expressed, whereas both PepT1 and PepT2 are expressed in the proximal tubule. The transport via di/tri-peptide transporters is proton-dependent, and the transporters thus belong to the Proton-dependent Oligopeptide Transporter (POT)-family. The transporters are not drug targets per se, however due to their uniquely broad substrate specificity; they have proved to be relevant drug targets at the level of drug transport. Drug molecules such as oral active beta-lactam antibiotics, bestatin, prodrugs of aciclovir and ganciclovir have oral bioavailabilities, which largely are a result of their interaction with PepT1. In the last few years an increasing number of studies concerned with regulation of di/tri-peptide transporter capacity have appeared. Studies on receptor-mediated regulation has shown that both PepT1 and PepT2 is down-regulated by long-term exposure to epidermal growth factor (EGF) due to a decreased gene transcription. PepT1-mediated transport is up-regulated by certain substrates and in response to fasting and starvation at the level of increased gene transcription. PepT1-mediated transport is up-regulated by short-term exposure to receptor agonists such as EGF, insulin, leptin, and clonidine, and down-regulated by VIP. Overall, the regulation of di/tri-peptide transport may be contributed to 1) changes in apical proton-motive force 2) recruitment of di/tri-peptide transporters from vesicular storages 3) changes in gene transcription/mRNA stability. The aim of the present review is to discuss physiological, patho-physiological and drug-induced regulation of di/tri-peptide transporter mediated transport.

Animals↗
PubMed2004

In vivo monitoring of tissue pharmacokinetics of liposome/drug using MRI: illustration of targeted delivery.

The purpose of this study was to determine if MnSO(4)/doxorubicin (DOX) loaded liposomes could be used for in vivo monitoring of liposome concentration distribution and drug release using MRI. In vitro results show that T(1) shortening correlates with MnSO(4) concentration. Using a temperature-sensitive liposome formulation, it was found that MnSO(4) release significantly shortened T(1). This feature, therefore, suggests that content release can also be measured with these MnSO(4)-loaded liposomes. The feasibility of monitoring this drug delivery and release-imaging agent was shown in a murine tumor model. Upon tumor heating, nonthermally sensitive liposomes selectively but heterogeneously accumulated in the tumor region. The thermally sensitive liposomes showed a clear pattern of accumulation at the periphery of the tumor, concordant with the release temperature of this formulation (39-40 degrees C). This liposome contrast agent has potential for use with hyperthermia by providing individualized monitoring of tissue drug concentration distribution during or after treatment. This would allow for: 1) modification of treatment variables to improve the uniformity of drug delivery, and 2) provide a means to select patients most likely to benefit from this liposomal drug treatment. Additionally, the drug-loading method used for this liposome is applicable to a wide range of drugs, thereby broadening its applicability. The method is also applicable to other liposomal formulations with triggered release mechanisms.

Animals↗
PubMed1992

Targeted delivery of antisense oligonucleotides by molecular conjugates.

Antisense oligonucleotides efficiently inhibit gene expression in vitro; however, the successful therapeutic application of this technology in vivo will require the development of improved delivery systems. In this report we describe a technique that efficiently delivers antisense oligonucleotides into cells using molecular conjugates. This technique, which was initially developed for the delivery of eukaryotic genes, is based on the construction of DNA-protein complexes that are recognized by the liver-specific asialoglycoprotein receptor. Binding of poly(L-lysine)-asialoorosomucoid (AsOR) protein conjugates with phosphorothioate antisense oligonucleotides to chloramphenicol acetyltransferase (CAT) led to the formation of 50- to 150-nm toroids. Exposure of the antisense molecular complexes (3 microM oligonucleotide) to NIH 3T3 cells genetically modified to express both the AsOR receptor and CAT, inhibited CAT expression by 54%, which was completely blocked by excess AsOR. Equivalent inhibition of CAT activity with purified oligonucleotide alone was observed at a 30 microM concentration. Furthermore, examination of the cells using indirect immunofluorescence for the presence of CAT protein showed 28% of cells exposed to the molecular conjugates lacked any detectable CAT enzyme. Cells exposed to oligonucleotide alone showed a highly variable staining pattern, and only a few of the cells were completely void of CAT protein. Together these data demonstrate that molecular conjugates provide a highly specific and efficient system for the delivery of antisense oligonucleotides.

3T3 Cells↗
PubMed1999

["Targeted delivery" in the gastrointestinal tract].

Drug delivery to the intestine has become attractive to researchers with the main interest in the delivery of peptide drugs to the large intestine and the treatment of colonic diseases. There are currently 4 strategies that are pursued to reach colon specificity: 1. by relying on the pH difference between the small and the large intestine; 2. by exploiting the enzymatic activity of the colonic microflora; 3. by relying on the relatively constant small intestinal transit time and 4. by taking advantage of the increase of the luminal pressure in the colon due to strong peristaltic waves. Drug delivery to the small intestine may be achieved by pH-controlled and time-controlled drug release mechanisms. Diffusion-controlled systems allow drug delivery over the entire gastrointestinal tract.

Administration, Oral↗
PubMed2006

Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 3. Therapeutic efficacy and safety studies in ovarian cancer xenograft model.

PURPOSE: The objective of this study was to evaluate the anti-tumor efficacy and lack of systemic toxicity of paclitaxel when administered in pH-sensitive poly(ethylene oxide) (PEO)-modified poly(beta-amino ester) (PbAE) nanoparticles in mice bearing human ovarian adenocarcinoma (SKOV-3) xenograft. METHODS: Paclitaxel-encapsulated PEO-modified PbAE (PEO-PbAE) nanoparticles were prepared by the solvent displacement method. PEO-modified poly(epsilon-caprolactone) (PCL) (PEO-PCL) nanoparticles were used as a non pH-responsive control formulation. Efficacy studies were conducted in SKOV-3 tumor-bearing athymic (Nu/Nu) mice at an equivalent paclitaxel dose of 20 mg/kg with the control and nanoparticle formulations. Safety of the drug when administered in the control and nanoparticle formulation was determined from blood cell counts and changes in body weight of the animals. RESULTS: The formulated paclitaxel-containing PEO-PbAE and PEO-PCL nanoparticles had a particle size in the range of 100-200 nm and a surface charge of + 39.0 and - 30.8 mV, respectively. After intravenous administration of paclitaxel in these formulations, the tumor growth was inhibited significantly. Both of the formulated nanoparticles tested have shown improved therapeutic efficacy as compared to the paclitaxel aqueous solution. Additionally, significantly lower toxicity profile of paclitaxel was observed with PEO-modified nanoparticles as compared to the aqueous solution formulation CONCLUSION: PEO-modified PbAE nanoparticles are a unique pH-sensitive drug delivery system that elicits enhanced efficacy and safety profile in solid tumor therapy.

Animals↗
PubMed1993

Targeted delivery of hygromycin B using reconstituted Sendai viral envelopes lacking hemagglutinin-neuraminidase.

Hygromycin B was encapsulated in reconstituted Sendai viral envelopes containing only the fusion (F) protein (F-virosomes). Incubation of loaded F-virosomes with cultured HepG2 cells resulted in fusion mediated delivery of hygromycin B to the cell cytoplasm, as was inferred from inhibition of DNA synthesis. Binding of the F-virosomes to HepG2 cells was mediated by the interaction of terminal beta-galactose residues of fusion protein with asialoglycoprotein receptor on HepG2 cells, subsequently leading to fusion between the two membranes. The cytotoxic effect of hygromycin B enclosed in F-virosomes was comparable with that of F,HN-virosomes containing both hemagglutinin-neuraminidase (HN) and F protein and F,HNred-virosomes containing HN whose disulfide bonds were irreversibly reduced (HNred). Hygromycin B loaded fusogenic liposomes were prepared by coreconstituting the viral envelope containing only fusion protein with exogenous lipids. These fusogenic liposomes were found to be more active than F-virosomes at the same fusion protein concentrations.

Carcinoma, Hepatocellular↗
PubMed1996

The potential of Lactobacillus as a carrier for oral immunization: development and preliminary characterization of vector systems for targeted delivery of antigens.

Oral administration of lactobacilli evokes mucosal and systemic immune responses against epitopes associated with these organisms (Gerritse et al., 1990, 1991). The adjuvant function of different Lactobacillus species was investigated under the conditions of intraperitoneal (i.p.) injection or oral administration. After i.p. injection of trinitrophenylated chicken gamma-globulin, high DTH responses were observed with Lactobacillus casei and Lactobacillus plantarum, but low responses with Lactobacillus fermentum and Lactobacillus delbrueckii subsp. bulgaricus. In different experimental model systems L. casei and L. plantarum consistently showed significant adjuvanticity. A series of expression and expression-secretion vectors containing the strong constitutive promoter of the L. casei L-ldh gene or the regulatable promoter of the Lactobacillus amylovorus amy gene (Pouwels and Leer, 1995) was used for the intracellular, extracellular and surface-bound expression of an influenza virus antigenic determinant fused to Escherichia coli beta-glucuronidase. Intracellular expression of the fusion protein amounted to 1-2% of total soluble protein. Lactobacilli synthesizing the fusion protein intracellularly evoked an oral immune response after subcutaneous priming.

Administration, Oral↗
PubMed1993

Targeted delivery of toxins and enzymes by antibodies and growth factors.

Significant progress has been made in our understanding of some of the important physiological and pharmacological barriers that limit immunoconjugate efficacy. Recent successes obtained employing immunotoxins in the treatment of leukemia and lymphoma in mouse models are suggesting ways of improving clinical strategies to treat these diseases in humans.

Animals↗
PubMed2005

Targeted delivery, safety, and efficacy of oral enteric-coated formulations of budesonide.

Budesonide is a potent corticosteroid with a high first-pass metabolism rate. Two commercially available enteric-coated pH-dependent release formulations (Entocort EC and Budenofalk) deliver budesonide to the ileum and proximal colon, regions most commonly affected in Crohn's disease. The drug's effectiveness in this disease has been proven in multiple, placebo-controlled trials, where it has been shown to be superior to mesalamine and placebo, and equivalent to prednisolone for the control of mild to moderately active right-sided Crohn's disease. This beneficial therapeutic effect comes with less adrenal suppression and a small improvement in the clinical adverse effect profile, as compared to prednisolone. However, budesonide provides no benefit over conventional therapy for left-sided colonic disease, and it is less effective for treatment of more severe disease activity and more distal colonic disease. Continuous budesonide does not prolong remission and is, therefore, best used in an intermittent fashion to treat acute exacerbations.

Administration, Oral↗
PubMed2004

Targeted delivery of heparin and LMWH using a fibrin antibody prevents restenosis.

This study investigates a stent-less local delivery system for anti-restenotic agents utilizing antibodies to cross-linked fibrin (XLF). Heparin and low molecular weight heparin (LMWH) were conjugated to an antibody to cross-linked fibrin D-dimer (1D2). Rabbit right carotid arteries were injured with a balloon catheter, then the animals were given a bolus injection of 40 microg/kg 1D2-heparin (26-70 microg/kg heparin) or 1D2-LMWH (29-80 microg/kg LMWH) conjugates or controls of saline (0.5 ml/kg), heparin (150 U/kg), LMWH (2 mg), or 1D2 (40 microg/kg), with or without a heparin bolus and sacrificed after 2 weeks (8 groups, n = 6/group). The injured artery of rabbits given 1D2-heparin or 1D2-LMWH conjugates had reduced neointimal development, with decreased luminal narrowing and positive remodelling compared with animals given control drugs. Animals given 1D2-heparin conjugate (with a heparin bolus) had three to five times more endothelial cells than the rabbits given saline or unconjugated heparin, while rabbits given 1D2-LMWH conjugate had up to 59% fewer neointimal cells than those given unconjugated drugs. There was little difference in extracellular matrix organization or composition. Thus cross-linked fibrin-antibodies can site-deliver anti-restenotic agents to injured areas of the artery wall where they influence wall remodelling and endothelial and neointimal cell number, reducing neointimal formation without systemic complications. Local delivery of anti-restenotic agents should minimise systemic effects, bleeding complications and potentially the cost of treatment due to a single, lower dose.

Animals↗
PubMed2006

Targeted delivery system for juxtacrine signaling growth factor based on rhBMP-2-mediated carrier-protein conjugation.

We propose a model of artificial juxtacrine signaling for the controlled release of recombinant human bone morphogenetic protein-2 (rhBMP-2) suitable for guided bone regeneration. A porous three-dimensional scaffold of poly-(lactide-co-glycolide) was fabricated by means of gel molding and particulate leaching. Collagen immobilization onto the scaffold surface was produced by performing photo-induced graft polymerization of acrylic acid, and rhBMP-2 was tethered to the collagenous surface by covalent conjugation. On pharmacokinetic analysis, in vitro enzyme-linked immunosorbent and alkaline phosphatase assays revealed sustained, slow release of rhBMP-2 over 28 days, with a cumulative release of one third of the initial load diffusing out of the scaffold. Conjugation of rhBMP-2 inhibited the free lateral diffusion and internalization of the activated complex of rhBMP-2 and the bone morphogenetic protein receptor. Osteoprogenitor cells were used as bone precursors to determine the expression of biosignaling growth factor in regulating cell proliferation and differentiation. To identify the phenotype of cells seeded on the rhBMP-2-conjugated scaffold, cellular activity was evaluated with scanning electron microscopy and with viability, histological, and immunohistochemical testing. The rhBMP-2-conjugated scaffold prolonged stimulation of intracellular signal proteins in cells. Enhancement of cell growth and differentiation was considered a consequence of juxtacrine signaling transduction. Animal studies of rhBMP-2-containing filling implants showed evidence of resorption and de novo bone formation. The present study revealed the potential of biomimetic constructs with co-immobilized adhesion and growth factors to induce osteoinduction and osteogenesis. Such constructs may be useful as synthetic bone-graft materials in orthopaedic tissue engineering.

Alkaline Phosphatase↗
PubMed2004

A survival motor neuron:tetanus toxin fragment C fusion protein for the targeted delivery of SMN protein to neurons.

Spinal muscular atrophy (SMA) is a degenerative disorder of spinal motor neurons caused by homozygous mutations in the survival motor neuron (SMN1) gene. Because increased tissue levels of human SMN protein (hSMN) in transgenic mice reduce the motor neuron loss caused by murine SMN knockout, we engineered a recombinant SMN fusion protein to deliver exogenous hSMN to the cytosolic compartment of motor neurons. The fusion protein, SDT, is comprised of hSMN linked to the catalytic and transmembrane domains of diphtheria toxin (DTx) followed by fragment C of tetanus toxin (TTC). Following overexpression in Escherichia coli, SDT possessed a subunit molecular weight of approximately 130 kDa as revealed by both SDS-PAGE and immunoblot analyses with anti-SMN, anti-DTx, and anti-TTC antibodies. Like wild-type SMN, purified SDT showed specific binding in vitro to an RG peptide derived from Ewing's sarcoma protein. The fusion protein also bound to cultured primary neurons in amounts similar to those achieved by TTC. Unlike the case with TTC, however, immunolabeling of SDT-treated neurons with anti-TTC and anti-SMN antibodies showed staining restricted to the cell surface. Results from cytotoxicity studies in which the DTx catalytic domain of SDT was used as a reporter protein for internalization and membrane translocation activity suggest that the SMN moiety of the fusion protein is interfering with one or both of these processes. While these studies indicate that SDT may not be useful for SMA therapy, the use of the TTC:DTx fusion construct to deliver other passenger proteins to the neuronal cytosol should not be ruled out.

Animals↗