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At least 541 records · Page 30Linked to original sources
PubMed1999

Targeted gene delivery into alpha9beta1-integrin-displaying cells by a synthetic peptide.

We have investigated the usefulness of two small synthetic peptides comprising either a linear or a cyclic PLAEIDGIEL domain and a DNA-binding moiety of 16 lysine residues to mediate gene transfer selectively into alpha9beta1-integrin-displaying cells. Such specific gene delivery could only be achieved with the peptide containing the cyclic PLAEIDGIEL domain. However, inclusion of the cationic liposome Lipofect-AMINE into the peptide/DNA complexes resulted for both peptides in efficient gene transfer with significant targeting specificity. Naturally, the integrin alpha9beta1 is present only in a few highly specialised tissues and abundant throughout the human airway epithelia in vivo. Targeting gene vectors to this integrin therefore appears a useful approach to gene therapy of lung diseases such as cystic fibrosis. As the integrin alpha9beta1 is associated with tissue differentiation during foetal development and may cause resurgence of the foetal phenotype in colon cancers, such vectors may also be applicable for prenatal and cancer gene therapy.

Cation Exchange Resins↗
PubMedDate not supplied

Preparation and in vitro analysis of microcapsule thalidomide formulation for targeted suppression of TNF-alpha.

Recent studies have implicated the cytokine tumor necrosis factor-alpha (TNF-alpha) in the inflammation associated with Crohn's disease (CD). Thalidomide has been shown to decrease this inflammation by the suppression of TNF-alpha secretion. However, side effects associated with thalidomide have precluded its widespread usage. In the present study we investigated the efficacy of a "targeted delivery approach" for thalidomide at the site of inflammation. We observed that alginate-poly-l-lysine-alginate (APA) polymer-based microcapsule formulations that encapsulate thalidomide could be designed. These capsules could be delivered at target sites where they almost entirely suppress TNF-alpha secretion in lipopolysaccharide activated RAW 264.7 macrophage cells in vitro. These findings indicate that targeted delivery of thalidomide using APA capsules could facilitate its usage in reducing the inflammation associated with chronic conditions such as Crohn's disease and ulcerative colitis.

Alginates↗
PubMed2000

Virosomes: evolution of the liposome as a targeted drug delivery system.

The drug delivery system (DDS) is attractive as a therapeutic method. Liposomes are of particular interest as a DDS because they can reduce drug toxicity, and offer promise as gene carriers. An evolution has occurred in the construction of liposomes in the effort to develop efficient vectors for in vivo use. To avoid uptake by the reticuloendothelial system (RES); Lipid components have been optimized. To enhance tissue targeting, liposome surface has been modified with antibodies or ligands recognized by specific cell types. To enhance the efficiency of gene delivery by the introduction of molecules directly into cells, virosomes have been developed by combining liposomes with fusiogenic viral envelope proteins. Liposomes are now being used in the treatment of intractable human diseases such as cancer and monogenic disorders. In the future, many medical procedures will be performed using liposomes.

Adenoviridae↗
PubMed2000

Specific cell targeting for delivery of toxins into small-cell lung cancer using a streptavidin fusion protein complex.

New modalities of treatment for small-cell lung cancer (SCLC) are needed, because the majority of patients continue to die of disseminated disease despite an initial response to conventional chemotherapy. Abnormal surface expression of the neural-cell adhesion molecule (NCAM) has been noted to be highly associated with SCLC. We examined the ability and efficiency of a streptavidin-Protein A (ST-PA) fusion protein complexed with an anti-NCAM monoclonal antibody (Mab) to transfer biotinylated beta-galactosidase into human SCLC cell lines NCI-H69, NCI-H526, and NCI-H446. When the surface molecule NCAM was targeted with this system, more than 99% of the targeted cells internalized and exhibited beta-galactosidase activity. In addition, we evaluated cytotoxic activity against SCLC lines NCI-H69 and NCI-H526 by efficient delivery of biotinylated glucose oxidase using the same ST-PA/anti-NCAM Mab complex. Cytotoxicity of the transduced cells (SCLC) was 10-fold and 100-fold greater, respectively, than the glucose oxidase control. This system could be widely applied for specific therapy of cancer cells by targeting unique surface molecules (antigens) using the corresponding Mab/ST-PA complex to transfer a variety of effector molecules; e.g., immunotoxic compounds, into target cells with a high degree of efficiency and specificity.

Animals↗
PubMed2003

Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes.

OBJECTIVE: To increase the therapeutic activity of glucocorticoids in experimental arthritis by encapsulation in long-circulating polyethylene glycol liposomes, which have shown the ability to preferentially accumulate in inflamed joints after intravenous administration. METHODS: Rats with adjuvant-induced arthritis (AIA) were treated intravenously with liposomal and free prednisolone phosphate (PLP) a few days after the first signs of disease. The effect on paw inflammation scores during the weeks after treatment was evaluated. Liposome biodistribution and joint localization were investigated by labeling the preparation with radioactive (111)In-oxine. By studying PLP encapsulated in other types of liposomes, which show a distinctive tissue distribution pattern and reduced accumulation in inflamed joints, the importance of targeted delivery to inflamed joints for achieving an increased therapeutic effect was illustrated. RESULTS: Liposomal PLP proved to be highly effective in the rat AIA model. A single injection of 10 mg/kg resulted in complete remission of the inflammatory response for almost a week. In contrast, the same dose of unencapsulated PLP did not reduce inflammation, and only a slight effect was observed after repeated daily injections. Evidence was found that preferential glucocorticoid delivery to the inflamed joint was the key factor explaining the observed strong therapeutic benefit obtained with the liposomal preparation, while other possible mechanisms, such as splenic accumulation or prolonged release of prednisolone in the circulation, were excluded. CONCLUSION: Targeted delivery using long-circulating liposomes is a promising, novel means to successfully intervene in arthritis with glucocorticoid therapy.

Animals↗
PubMed2006

Recombinant polymer-protein fusion: a promising approach towards efficient and targeted gene delivery.

BACKGROUND: Synthetic vectors such as polymers have the potential to reduce the safety problems associated with viral vectors; however, their low transfection efficiency limits their clinical utility. To study the critical steps involved in an efficient transgene expression, there is a need for creative approaches that allow a systematic correlation between gene carrier structure and properties necessary for successful gene transfer. Using recombinant techniques a prototype vector comprised of tandem repeating units fused to a targeting moiety was biosynthesized to mediate gene transfer in mammalian cell lines. The carrier was designed to have the structure of (KHKHKHKHKK)6-FGF2 where lysine (K) residues would allow complexation with plasmid DNA, basic fibroblast growth factor (FGF2) to target cells over-expressing FGF2 receptors (FGFR), and histidine (H) residues to facilitate escape from the endosomal compartments. METHODS: The gene carrier was biosynthesized in E. coli, purified using a Ni-NTA column, characterized, complexed with pDNA, and the complexes were used to transfect NIH 3T3, T-47D and COS-1 mammalian cell types known to express FGFR. RESULTS: Results demonstrate the successful cloning and expression of the gene carrier with over 95% purity. The molecular weight of the gene carrier was determined by MALDI-TOF to be 27 402. Amino acid content analysis and Western blot confirmed the expression of the gene carrier in E. coli. The vector was able to condense pDNA, induce cell proliferation in NIH 3T3 fibroblasts, and mediate transgene expression in NIH 3T3, T-47D and COS-1 mammalian cell types. CONCLUSION: Genetic engineering techniques show promise for systematic investigation of structure-activity relationships of non-viral gene delivery vectors.

Amino Acid Sequence↗
PubMed2000

Targeted intracellular delivery of photosensitizers to enhance photodynamic efficiency.

Photodynamic therapy (PDT) is a novel treatment, used mainly for anticancer therapy, that depends on the retention of photosensitizers (PS) in tumour cells and irradiation of the tumour with appropriate wavelength light. Photosensitizers are molecules such as porphyrins and chlorins that, on photoactivation, effect strongly localized oxidative damage within target cells. The PS used for PDT localize in various cytoplasmic membranous structures, but are not found in the most vulnerable intracellular sites for reactive oxygen species, such as the cell nucleus. The experimental approaches discussed in the present paper indicate that it is possible to design highly efficient molecular constructs, PS carriers, with specific modules conferring cell-specific targeting, internalization, escape from intracellular vesicles and targeting to the most vulnerable intracellular compartments, such as the nucleus. Nuclear targeting of these PS-carrying constructs results in enhanced photodynamic activity, maximally about 2500-fold that of free PS. Future work is intended to optimize this approach to the point at which tumour cells can be killed rapidly and efficiently, while minimizing normal cell and tissue damage.

Amino Acid Sequence↗
PubMed2005

The facile preparation of primary and secondary amines via an improved Fukuyama-Mitsunobu procedure. Application to the synthesis of a lung-targeted gene delivery agent.

An efficient modification of the Fukuyama-Mitsunobu procedure has been developed whereby primary or secondary amines can be synthesized from alkyl alcohols and the corresponding nosyl-protected/activated amine. Most importantly, the use of the DTBAD and diphenylpyridinylphosphine, as Mitsunobu reagents, generates reaction by-products that can be easily removed, providing a remarkably clean product mixture. This improved technique was implemented in the synthesis of a complex lipopeptide designed to target alpha9beta1-integrin proteins predominant on upper airway epithelial cells.

Amines↗
PubMed2005

Targeted gene delivery by intravenous injection of retroviral vectors.

Specifically and effectively directing a therapeutic gene to its intended site of action is a critical issue for translation of basic genomics to clinical gene therapy. Delivering gene therapy vectors to specific cells or tissues through intravenous injection is the most desirable method for this purpose. In 2001, we reported successful targeted gene transduction in vitro utilizing both oncoretroviral and lentiviral vectors pseudotyped with a chimeric Sindbis virus envelope (ZZ SINDBIS). However, these pseudotypes mediated nonspecific gene transduction to liver and spleen in vivo. To address this problem we generated the modified ZZ SINDBIS (termed m168) with significantly less nonspecific infectivity. To investigate the ability of m168 pseudotyped lentiviral vector to mediate targeted gene transduction in vivo, we utilized a metastatic tumor model by using mouse melanoma cells engineered to express human P-glycoprotein. We administered the m 168 pseudotyped vector conjugated with anti-P-glycoprotein antibody into the mice intravenously to target metastatic melanoma. The m168 pseudotyped vector selectively infected metastatic melanoma cells demonstrating successful targeted gene transduction in vivo. Targeting technology based upon m168 can be further modified for application not only to cancer but also potentially to genetic, neurologic, infectious and immune diseases, thereby expanding the future application of gene therapy.

Animals↗
PubMed2006

A human mAb specific to oncofetal fibronectin selectively targets chronic skin inflammation in vivo.

The antibody-based targeted delivery of bioactive agents to sites of angiogenesis is an attractive therapeutic strategy for cancer treatment, but is largely unexplored for chronic inflammatory diseases. In this article, we show that the extra domain B (EDB) domain of fibronectin, a marker of angiogenesis, is expressed in psoriatic lesions, and that the anti-EDB human antibody L19 can selectively localize to chronically inflamed skin in vivo. The L19-based delivery of the cytokines IL10 and IL12 did not improve or worsen inflammation in a mouse model of chronic skin inflammation, which overexpressed vascular endothelial growth factor under the control of the keratin-14 promoter. By contrast, the L19-based targeted delivery of the proinflammatory cytokine IL2 or of the photosensitizer Sn(IV) chlorin e6 resulted in an increased swelling and reddening of inflamed skin. These results indicate that antibodies specific to components of the modified extracellular matrix can selectively accumulate at chronically inflamed sites in vivo. This observation now stimulates the search for bioactive molecules which can be fused to antibodies and which may confer a therapeutic benefit as a result of their preferential accumulation in psoriatic lesions and other sites of inflammation.

Animals↗
PubMed2006

Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis.

Mycobacterium tuberculosis is an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 microg/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.

Animals↗
PubMed1995

Three-dimensional visualisation of the large bowel: a potential tool for assessing targeted drug delivery and colonic pathology.

A study has been undertaken to assess the feasibility of three-dimensional imaging of the dispersion of a non-absorbable tracer released into the colon of normal subjects. Six healthy volunteers were selected who were participating in a scintigraphic study designed to assess the spreading of 1 MBq indium-111 Amberlite resin delivered from a delayed capsule system targeted to release in the ascending colon. In each case subjects were imaged using a rotating gamma camera over a data collection period of approximately 20 min. Three-dimensional volume rendered images demonstrated good visualisation of the dispersion of the tracer throughout the ascending, transverse and descending colon and provided good anatomical visualisation of the shape of the colon, not previously apparent from the planar views. The present study demonstrates for the first time, the successful three-dimensional imaging of a radiolabelled tracer dispersed throughout the colon and opens up the prospects for more detailed study of quantification of the volume and distribution of tracers contained within the colon.

Adult↗
PubMed2006

Targeted brain delivery of AZT via transferrin anchored pegylated albumin nanoparticles.

Hydrophilic drugs/peptides have poor cross Blood-brain permeability. Various drug delivery systems with diverse surfacial characteristics have been reported for effective translocation of drugs across Blood-brain barrier. In present investigation, the potential of engineered albumin nanoparticles was evaluated for brain specific delivery after intravenous administration. Long circulatory PEGylated albumin nanoparticles encapsulating water-soluble antiviral drug azidothymidine (AZT) were prepared by ultra-emulsification method using chemical cross-linking by glutaraldehyde. Surface of the PEGylated nanoparticles was modified by anchoring transferrin as a ligand for brain targeting. Nanoparticles were characterized for their size, polydispersity, surfacial charge, drug loading and in vitro drug release. Fluorescence studies revealed the enhanced uptake of transferrin-anchored nanoparticles in the brain tissues when compared with unmodified nanoparticles. In vivo evaluation was carried out on albino rats to evaluate tissue distribution of engineered nanoparticles after intravenous administration. A significant ((*)P < 0.01) enhancement of brain localization of AZT was observed for transferrin anchored pegylated albumin nanopariticles (Tf-PEG-NPs). Hence, the specific role of transferrin ligand on nanoparticles for brain targeting was confirmed.

Acyclovir↗
PubMed1993

Targeting and delivery of bactericide to adsorbed oral bacteria by use of proteoliposomes.

Proteoliposomes having surface-bound succinylated concanavalin A (s-conA) have been prepared from a range of phospholipid mixtures by sonication (SUV) and reverse phase evaporation (REV) covering a range of size (weight-average diameter (dw)) from approx. 35 to 310 nm and weight-average number of protein molecules per liposomes (Pw) from approx. 50 to 3000. The targeting of the proteoliposomes to adsorbed biofilms of the bacteria Streptococcus sanguis and Streptococcus mutans has been assessed from the extent of inhibition of an enzyme-linked immunosorbent assay (ELISA) for bacterial cell surface antigens. The surface-bound lectin enhances targeting relative to 'naked' liposomes of comparable concentration by factors of 2-50 depending on the liposomal lipid composition and Pw. The effect of the bactericide Triclosan on the thermal properties and permeability characteristics of liposomes has been studied. At and above a molar ratio of Triclosan to lipid of 0.6, Triclosan eliminates the gel to liquid-crystalline phase transition in dipalmitoylphosphatidylcholine (DPPC) containing liposomes and increases the bilayer permeability of both liposomes and proteoliposomes to D-glucose. The proteoliposomes have been used to deliver Triclosan to S. sanguis biofilms and the inhibition of growth of the bacteria after treatment with liposomally delivered Triclosan has been determined using a microtitre plate re-growth assay and compared with growth inhibition by 'free' Triclosan. It is shown that for short exposure times (1 to 2 min) proteoliposomally delivered Triclosan is a more effective growth inhibitor than free Triclosan. The results are discussed in terms of the targeting, retention and subsequent release of Triclosan into the bacterial biofilms.

Concanavalin A↗
PubMedDate not supplied

Receptor-targeted liposomal delivery of boron-containing cholesterol mimics for boron neutron capture therapy (BNCT).

Liposomes have been a main focus of tumor-selective boron delivery strategies in boron neutron capture therapy (BNCT), a binary method for the treatment of cancer that is based on the nuclear reaction between boron atoms and low-energy thermal neutrons. Three novel carboranyl cholesterol derivatives were prepared as lipid bilayer components for the construction of nontargeted and receptor-targeted boronated liposomes for BNCT. A major structural feature of these novel boronated cholesterol mimics is the replacement of the B and the C ring of cholesterol with a carborane cluster. Computational analyses indicated that all three boronated compounds have structural features and physicochemical properties that are very similar to those of cholesterol. One of the synthesized boronated cholesterol mimics was stably incorporated into non-, folate receptor (FR)-, and vascular endothelial growth factor receptor-2 (VEGFR-2)-targeted liposomes. No major differences were found in appearance, size distribution, and lamellarity between conventional dipalmitoylphosphatidylcholine (DPPC)/cholesterol liposomes, nontargeted, and FR-targeted liposomal formulations of this carboranyl cholesterol derivative. FR-targeted boronated liposomes were taken up extensively in FR overexpressing KB cells in vitro, and the uptake was effectively blocked in the presence of free folate. In contrast, a boronated cholesterol mimic incorporated into nontargeted liposomes showed significantly lower cellular uptake. There was no apparent in vitro cytotoxicity in FR overexpressing KB cells and VEGFR-2 overexpressing 293/KDR cells when these were incubated with boronated FR- and (VEGFR-2)-targeted liposomes, respectively, although the former accumulated extensively in KB cells and the latter effectively interacted with VEGFR-2 by causing autophosphorylation and protecting 293/KDR cells from SLT (Shiga-like toxin)-VEGF cytotoxicity.

Boron Compounds↗
PubMedDate not supplied

[Drug delivery to target the posterior segment of the eye].

Retinal diseases are nowadays the most common causes of vision threatening in developed countries. Therapeutic advances in this field are hindered by the difficulty to deliver drugs to the posterior segment of the eye. Due to anatomical barriers, the ocular biodisponibility of systemically administered drugs remains poor, and topical instillation is not adequate to achieve therapeutic concentrations of drugs in the back of the eye. Ocular drug delivery has thus become one of the main challenges of modern ophthalmology. A multidisciplinary research is being conducted worldwide including pharmacology, biomaterials, ophthalmology, pharmaceutics, and biology. New promising fields have been developed such as implantable or injectable slow release intravitreal devices and degradable polymers, dispersed polymeric systems for intraocular drug delivery, and transscleral delivery devices such as iontophoresis, osmotic pumps or intra-scleraly implantable materials. The first clinical applications emerging from this research are now taking place, opening new avenues for the treatment of retinal diseases.

Biomedical Research↗
PubMed2000

Targeted antigen delivery to antigen-presenting cells including dendritic cells by engineered Fas-mediated apoptosis.

Immunity to tumors as well as to viral and bacterial pathogens is often mediated by cytotoxic T lymphocytes (CTLs). Thus, the ability to induce a strong cell-mediated immune response is an important requirement of novel immunotherapies. Antigen-presenting cells (APCs), including dendritic cells (DCs), are specialized in initiating T-cell immunity. Harnessing this innate ability of these cells to acquire and present antigens, we sought to improve antigen presentation by targeting antigens directly to DCs in vivo through apoptosis. We engineered Fas-mediated apoptotic death of antigen-bearing cells in vivo by co-expressing the immunogen and Fas in the same cell. We then observed that the death of antigen-bearing cells results in increased antigen acquisition by APCs including DCs. This in vivo strategy led to enhanced antigen-specific CTLs, and the elaboration of T helper-1 (Th1) type cytokines and chemokines. This adjuvant approach has important implications for viral and nonviral delivery strategies for vaccines or gene therapies.

Animals↗