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At least 451 records · Page 25Linked to original sources
PubMed2002

Oral delayed-release system based on Zn-pectinate gel (ZPG) microparticles as an alternative carrier to calcium pectinate beads for colonic drug delivery.

A new oral timed-release system was developed for colon-targeted delivery of drugs. The system which consists of ketoprofen-loaded Zn-pectinate gel (ZPG) microparticles together with pectin/dextran mixtures in a tablet form, has been investigated, in vitro, using conditions chosen to simulate the pH and times likely to be encountered during transit to the colon. In order to find the suitable ZPG microparticles, the formulations were prepared by utilizing 2(3) factorial design and the effect of various formulation factors on the release and surface characteristics of the microparticles was studied. The results obtained implied that the release of ketoprofen from ZPG microparticles was greatly extended with the pectinate microparticles, which were prepared with 2.5 or 3% w/v pectin, 2.75% w/v Zn(CH3COO)2 and 2.5% w/v drug. Additionally, the analysis of variance results showed that the release of ketoprofen in simulated intestinal fluid (S.I.F., pH 7.4) was strongly affected by crosslinking agent concentration and initial drug amount, but not particularly affected by the amount of pectin added. The investigated drug concentration factor has significantly increased the drug entrapment efficiency (EE). The optimum colonic drug delivery ZPG/tablet system provided the expected delayed-release sigmoidal patterns with a lag-time of 4.125-4.85 h and t(50%) (the time for 50% of the drug to be released) at 7.45-8.70 h, depending on pectin/dextran ratio employed. The results also demonstrated that the untableted ZPG microparticles exhibited drug release profiles which were able to retard the release of ketoprofen in S.I.F. (pH 7.4) to be 5.28-37.82 times (depending on formulation parameters), lower than the conventional calcium pectinate beads. Therefore, this approach suggests that ZPG microparticles and their modified-release formulations are promising as useful controlled-release carriers for colon-targeted delivery of drugs.

Administration, Rectal↗
PubMed2006

An adenovirus vector with a chimeric fiber incorporating stabilized single chain antibody achieves targeted gene delivery.

Adenovirus (Ad) vectors are of utility for many therapeutic applications. Strategies have been developed to alter adenoviral tropism to achieve a cell-specific gene delivery capacity employing fiber modifications allowing genetic incorporation of targeting motifs. In this regard, single chain antibodies (scFv) represent potentially useful agents to achieve targeted gene transfer. However, the distinct biosynthetic pathways that scFv and Ad capsid proteins are normally routed through have thus far been problematic with respect to scFv incorporation into the Ad capsid. Utilization of stable scFv, which also maintain correct folding and thus functionality under intracellular reducing conditions, could overcome this restriction. We genetically incorporated a stable scFv into a de-knobbed, fibritin-foldon trimerized Ad fiber and demonstrated selective targeting to the cognate epitope expressed on the membrane surface of cells. We have shown that the scFv employed in this study retains functionality and that stabilizing the targeting molecule, per se, is critical to allow retention of antigen recognition in the adenovirus capsid-incorporated context.

Adenoviridae↗
PubMed2002

Self-assembly of a virus-mimicking nanostructure system for efficient tumor-targeted gene delivery.

Molecular therapy, including gene therapy, is a promising strategy for the treatment of human disease. However, delivery of molecular therapeutics efficiently and specifically to the target tissue remains a significant challenge. A human transferrin (Tf)-targeted cationic liposome-DNA complex, Tf-lipoplex, has shown high gene transfer efficiency and efficacy with human head and neck cancer in vitro and in vivo (Xu, L., Pirollo, K.F., Tang, W.H., Rait, A., and Chang, E.H. Hum. Gene Ther. 1999;10:2941-2952). Here we explore the structure, size, formation process, and structure-function relationships of Tf-lipoplex. We have observed Tf-lipoplex to have a highly compact structure, with a relatively uniform size of 50-90 nm. This nanostructure is novel in that it resembles a virus particle with a dense core enveloped by a membrane coated with Tf molecules spiking the surface. More importantly, compared with unliganded lipoplex, Tf-lipoplex shows enhanced stability, improved in vivo gene transfer efficiency, and long-term efficacy for systemic p53 gene therapy of human prostate cancer when used in combination with conventional radiotherapy. On the basis of our observations, we propose a multistep self-assembly process and Tf-facilitated DNA cocondensation model that may provide an explanation for the resultant small size and effectiveness of our nanostructural Tf-lipoplex system.

Animals↗
PubMed2002

In vitro and in vivo evaluations of dihydroquinoline- and dihydroisoquinoline-based targetor moieties for brain-specific chemical delivery systems.

Brain-targeted delivery of various drugs can be successfully achieved by chemical delivery systems (CDS) that contain a 1,4-dihydropyridine-based redox targetor moiety and undergo a sequential metabolism. However, the susceptibility of this moiety toward hydration in acidic media may limit the shelf-life of such compounds in aqueous formulation. Here, a systematic investigation of the chemical stability toward oxidation and hydration of ester and amide derivatives of 3-substituted 1,4-dihydropyridine, 1,4-dihydroquinoline, and 4-substituted 1,2-dihydroisoquinoline is reported, together with the in vitro stability and in vivo (rat) distribution of isoquinoline-based testosterone and hydrocortisone chemical delivery systems, which were selected as having the most suitable acid-resistant targetor moieties.

Animals↗
PubMed2006

Synthesis and characterization of chitosan-g-poly(ethylene glycol)-folate as a non-viral carrier for tumor-targeted gene delivery.

Poor water solubility and low transfection efficiency of chitosan are major drawbacks for its use as a gene delivery carrier. PEGylation can increase its solubility, and folate conjugation may improve gene transfection efficiency due to promoted uptake of folate receptor-bearing tumor cells. The aim of this study was to synthesize and characterize folate-poly(ethylene glycol)-grafted chitosan (FA-PEG-Chi) for targeted plasmid DNA delivery to tumor cells. Gel electrophoresis study showed strong DNA binding ability of modified chitosan. The pH(50) values, defined as the pH when the transmittance of a polymer solution at 600 nm has reached 50% of the original value, suggested that the water solubility of PEGylated chitosan had improved significantly. Regression analysis of pH(50) value as a function of substitution degree of PEG yielded an almost linear correlation for PEG-Chi and FA-PEG-Chi. The solubility of PEGylated chitosan decreased slightly by further conjugation of folic acid due to the relatively more hydrophobic nature of folic acid when compared to PEG. In addition, the chitosan-based DNA complexes did not induce remarkable cytotoxicity against HEK 293 cells. FA-PEG-Chi can be a promising gene carrier due to its solubility in physiological pH, efficiency in condensing DNA, low cytotoxicity and targeting ability.

Carrier Proteins↗
PubMed2002

Characterization of biodegradable drug delivery vehicles with the adhesive properties of leukocytes.

The site-specific expression of selectins (E- and P-selectin) on endothelial cells of blood vessels during inflammation provides an opportunity for the targeted delivery of anti-inflammatory drugs to inflammatory sites. Previous work in our laboratory has shown that artificial capsules with the adhesive properties of leukocytes can be made by attaching leukocyte adhesive ligands to polystyrene microspheres. In this work, we have adapted this technology to create a targeted delivery system using biodegradable, poly lactic-co-glycolic-acid (PLGA) microspheres. Biotinylated-Sialyl Lewis(x) (sLe(x)), a carbohydrate that serves as a ligand to selectins, was attached to the surface of avidin-linked PLGA microspheres. These carbohydrate-coated microspheres mimic the adhesive behavior of leukocytes on selectins in flow chambers, displaying slow rolling under flow. The rolling velocities displayed by sLe(x)-coated microspheres were similar to those displayed by leukocytes rolling on P- or E-selectin coated surfaces, and these rolling velocities, which relate to the residence time of the capsules, can be tuned by changing the density of carbohydrate residues on microsphere surfaces. We have also demonstrated that these microspheres will release model drugs on a time scale of several days. Therefore, we have made a targeted drug delivery vehicle that mimics the adhesive properties of leukocytes and is biodegradable.

Animals↗
PubMed1999

Targeted gene delivery to mammalian cells by filamentous bacteriophage.

We report that prokaryotic viruses can be re-engineered to infect eukaryotic cells resulting in expression of a reporter gene inserted into the bacteriophage genome. Phage capable of binding mammalian cells expressing the growth factor receptor ErbB2 and undergoing receptor-mediated endocytosis were isolated by selection of a phage antibody library on breast tumor cells and recovery of infectious phage from within the cell. As determined by immunofluorescence, F5 phage were efficiently endocytosed into 100 % of ErbB2 expressing SKBR3 cells. To achieve reporter gene expression, F5 phage were engineered to package the green fluorescent protein (GFP) reporter gene driven by the CMV promoter. These phage when applied to cells underwent ErbB2-mediated endocytosis leading to GFP expression. GFP expression occurred only in cells overexpressing ErbB2, was dose-dependent reaching, 4 % of cells after 60 hours and was detected with phage titers as low as 2.0 x 10(7) cfu/ml (500 phage/cell). The results demonstrate that bacterial viruses displaying the appropriate antibody can bind to mammalian receptors and utilize the endocytic pathway to infect eukaryotic cells, resulting in expression of a reporter gene inserted into the viral genome. This represents a novel method to discover targeting molecules capable of delivering a gene intracellularly into the correct trafficking pathway for gene expression by directly screening phage antibodies. This should significantly facilitate the identification of appropriate targets and targeting molecules for gene therapy or other applications where delivery into the cytosol is required. This approach can be adapted to directly select, rather than screen, phage antibodies for targeted gene expression. The results also demonstrate the potential of phage antibodies as an in vitro or in vivo targeted gene delivery vehicle.

Bacteriophages↗
PubMed2002

Targeted drug delivery by thermally responsive polymers.

This review article summarizes recent results on the development of macromolecular carriers for thermal targeting of therapeutics to solid tumors. This approach employs thermally responsive polymers in conjunction with targeted heating of the tumor. The two thermally responsive polymers that are discussed in this article, poly(N-isopropylacrylamide-co-acrylamide) (poly(NIPAAm)) and an artificial elastin-like polypeptide (ELP), were designed to exhibit a soluble-insoluble lower critical solution transition in response to increased temperature slightly above 37 degrees C. In vivo fluorescent videomicroscopy and radiolabel distribution studies of ELP delivery to human tumors implanted in nude mice demonstrated that hyperthermic targeting of the thermally responsive ELP for 1 h provides a approximately two-fold increase in tumor localization compared to the same polypeptide without hyperthermia. Similar results were also obtained for poly(NIPAAm) though the extent of accumulation was somewhat lesser than observed for the ELP. The endocytotic uptake of a thermally responsive ELP was also observed to be significantly enhanced by the thermally triggered phase transition of the polypeptide in cell culture for three different tumor cell lines. Preliminary cytotoxicity studies of an ELP-doxorubicin conjugate indicate that the ELP-doxorubicin conjugate has near equivalent cytotoxicity as free doxorubicin in a cell culture assay.

Acrylic Resins↗
PubMed2006

Selective delivery of therapeutic agents for the diagnosis and treatment of cancer.

Research activity aimed towards achieving specific and targeted delivery of cancer therapeutics has expanded tremendously in the last decade, resulting in new ways of directing drugs to tumours, as well as new types of drugs. The available strategies exploit differences in the nature of normal and cancer cells and their microenvironment. The discovery and validation of cancer-associated markers, as well as corresponding ligands, is pivotal for developing selective delivery technology for cancer. Although most current clinical trials are either monoclonal antibody- or gene-based, methodological advances in combinatorial libraries of peptides, single chain variable fragments and small organic molecules are expected to change this scenario in the near future. Nanotechnology platforms today allow systematic and modular combinations of therapeutic agents and tumour-binding moieties that may generate novel, personalised agents for selective delivery in cancer. This paper discusses recent developments and future prospects of targeted delivery technologies in the management of cancer.

Animals↗
PubMed2004

A human biotin acceptor domain allows site-specific conjugation of an enzyme to an antibody-avidin fusion protein for targeted drug delivery.

We have previously constructed an antibody-avidin (Av) fusion protein, anti-transferrin receptor (TfR) IgG3-Av, which can deliver biotinylated molecules to cells expressing the TfR. We now describe the use of the fusion protein for antibody-directed enzyme prodrug therapy (ADEPT). The 67 amino acid carboxyl-terminal domain (P67) of human propionyl-CoA carboxylase alpha subunit can be metabolically biotinylated at a fixed lysine residue. We genetically fused P67 to the carboxyl terminus of the yeast enzyme FCU1, a derivative of cytosine deaminase that can convert the non-toxic prodrug 5-fluorocytosine to the cytotoxic agent 5-fluorouracil. When produced in Escherichia coli cells overexpressing a biotin protein ligase, the FCU1-P67 fusion protein was efficiently mono-biotinylated. In the presence of 5-fluorocytosine, the biotinylated fusion protein conjugated to anti-rat TfR IgG3-Av efficiently killed rat Y3-Ag1.2.3 myeloma cells in vitro, while the same protein conjugated to an irrelevant (anti-dansyl) antibody fused to Av showed no cytotoxic effect. Efficient tumor cell killing was also observed when E. coli purine nucleoside phosphorylase was similarly targeted to the tumor cells in the presence of the prodrug 2-fluoro-2'-deoxyadenosine. These results suggest that when combined with P67-based biotinylation, anti-TfR IgG3-Av could serve as a universal delivery vector for targeted chemotherapy of cancer.

Animals↗
PubMed1997

Strategies to accomplish targeted gene delivery to muscle cells employing tropism-modified adenoviral vectors.

We are developing strategies to modify the tropism of adenoviral vectors to accomplish targeted transduction of muscle cells for DMD gene therapy. In one approach, we have introduced targeting ligands into the adenovirus fibre, which mediates the binding of the virus Ad5 to the primary cellular receptor. In order to incorporate these fibre-ligand fusions into recombinant adenoviral vectors, we have employed a method based upon homologous DNA recombination between a fibre-deleted, propagation-defective rescue plasmid and a shuttle plasmid encoding a variant fibre. To date, we have generated an adenoviral vector containing chimeric fibres composed of the tail and shaft domains of adenovirus serotype 5 and the knob domain of serotype 3. This modification altered the receptor recognition profile of the virus containing the fibre chimera. In an alternative approach to the generation of a targeted adenoviral vector, we conjugated folate to the neutralising Fab fragment of an anti-fibre monoclonal antibody. This Fab-folate conjugate was shown to redirect adenoviral infection of target cells via the folate receptor at a high efficiency. These studies suggest that it will be possible to achieve our goal of deriving targeted adenoviral vectors for muscle cell-specific gene delivery in vivo.

Adenoviridae↗
PubMed2005

Targeted drug delivery crossing cytoplasmic membranes of intended cells via ligand-grafted sterically stabilized liposomes.

In this study, we tested whether sterically stabilized liposomes (SSL) with surface ligands specific for the mu opioid receptor (MOR) can actively target MOR-expressing cells. Dermorphin, a selective MOR agonist, was conjugated to DSPE-PEG(3400) to obtain DSPE-PEG(3400)-dermorphin. Dermorphin-grafted SSL (dermorphin-SSL) was prepared by thin-film rehydration-extrusion and post-insertion method. DSPE-PEG(3400)-dermorphin and dermorphin-SSL retained the affinity to MOR as determined by receptor binding assay using [(3)H]DAMGO, whereas plain SSL without surface ligands showed no binding to the receptor. Cellular uptake of cholesteryl BODIPY encapsulated dermorphin-SSL was studied by microplate spectrofluorometry as well as fluorescent and confocal microscopy. Significant fluorescence signal was observed inside CHO-hMOR cells after the treatment with dermorphin-SSL, indicative of MOR-mediated endocytosis. In contrast, no uptake of dermorphin-SSL was found in naive CHO cells or CHO-hDOR cells that lack MOR. Taken together, these results demonstrate that dermorphin-SSL delivery system is capable of targeting intracellular components of MOR-expressing cells. Such a system may be applied to carry pharmaceutical agents to achieve region-specific delivery of analgesics and/or to attenuate side effects associated with opioids.

Animals↗
PubMed2001

Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature.

Radiation can be used to guide drugs to specific sites such as neoplasms or aberrant blood vessels. When blood vessels are treated with ionizing radiation, they respond by expressing a number of cell adhesion molecules and receptors that participate in homeostasis. Examples of radiation-induced molecules in blood vessels include ICAM-1, E-selectin, P-selectin and the beta(3) integrin. We have observed that the endothelium and blood components respond to oxidative stress in a similar, if not identical manner in all tumor models. Although we have identified several other radiation-induced molecules within tumor blood vessels, the beta(3) target for drug delivery achieves the greatest site-specific peptide binding within irradiated tumor blood vessels. We have focused on peptides and antibodies that bind to integrin beta(3). beta(3)-binding proteins have been conjugated to fluorochromes and radionuclides to study the site specificity and microscopic distribution. We have found immunofluorescent and immunohistochemical staining of beta(3) within the lumen of blood vessels immediately following irradiation. To determine whether it is feasible to guide drug delivery to irradiated tumors, we studied ligands to alpha(2b)beta(3) (fibrinogen). Peptides within fibrinogen that bind to alpha(2b)beta(3) includes the dodecapeptide, HHLGGAKQAGDV and the RGD peptide. We utilized 131I conjugation to these ligands to study the biodistribution in tumor bearing mice. Our clinical trial consists of the RGD peptidomimetic, biapcitide, labeled with 99mTc. This study shows that it is feasible to guide drugs to human neoplasms by use of radiation-guided peptides. These studies have shown that peptides that bind to these integrins bind to tumors following exposure to ionizing radiation.

Amino Acid Sequence↗
PubMed1997

Lipoproteins: their potential as endogenous target oriented novel drug delivery system.

Targeting of drugs to specific cellular sites is a major area of interest now a day. Various carrier systems, viz, liposomes, resealed erythrocytes, niosomes, immunomodulated nanospheres, etc. have been reported. A newer class of carrier system based on endogenous origin has been identified as lipoproteins. The present review discusses the classification, biological fate and targeting potentials of such system when the drug is encapsulated. Furthermore their is a brief discussion about the approaches utilised for their more specific targeting (acyloglycoprotein receptor etc.). Some of the observed drawbacks of such systems could be combated with the use of synthetically prepared lipoproteins named as SMBV (supramolecular biovectors) have also been discussed. Various biomedical potential of these lipoproteins in the delivery of drug to neoplastic cell lines, viral and parasitic infections in liver have also been highlighted.

Cell Line↗
PubMed2005

Asialoglycoprotein receptor targeted gene delivery using galactosylated polyethylenimine-graft-poly(ethylene glycol): in vitro and in vivo studies.

The asialoglycoprotein receptor (ASGP-R) on the hepatocyte membrane is a specific targeting marker for gene and drug delivery. Polyethylenimine (PEI) is a polycationic nonviral vector that is used for gene transfer. We have synthesized galactosylated polyethylenimine-graft-poly(ethylene glycol) (GPP) for performing gene delivery to the hepatocytes. The present study reports on the in vitro and in vivo data that was achieved in hepatoma bearing transgenic mice. The cytotoxicity was decreased with the increasing PEG content. The particle size of the complex was increased with the increasing PEG at an N/P ratio of 3.0, while the zeta potentials were decreased. The (99m)Tc labeled complexes were transfected into HepG2 and HeLa cells, while the GFP reporter genes were mainly expressed in the HepG2 cells. The in vivo data was achieved in ALB/c-Ha-ras transgenic mice. (99m)Tc labeled GPP(50)/DNA was injected into the mice via the tail vein, and the gamma images were acquired at 5, 15 and 30 min. The (99m)Tc labeled complexes were mainly localized in the heart and liver, and they were excreted through the kidneys. The GFP gene was mainly expressed in the proliferating cells at the tumor periphery. This result was confirmed by PCNA staining. The GPP(50)/DNA complexes were bound to ASGP-R of the proliferating hepatocytes in vitro and in vivo. The present results demonstrate the feasibility of nonviral gene transfer using galactosylated PEI-PEG in vivo.

Animals↗