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At least 253 records · Page 14Linked to original sources
PubMed2002

Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature.

Interleukin-12 (IL-12) is a heterodimeric cytokine with potent immunostimulatory activity and anti-angiogenic properties. Its clinical applications are limited, however, by severe side-effects. Here we report that an IL-12 fusion protein, consisting of IL-12 fused to a human antibody fragment specific to the oncofetal ED-B domain of fibronectin, markedly enhances the antitumor activity of this cytokine, as demonstrated in a mouse lung-metastasis model and in two models of mice bearing different aggressive murine tumors. The residual small tumor masses seen in the treated mice were infiltrated with lymphocytes, macrophages, and natural killer cells and had elevated interferon gamma (IFN-gamma). These results are of therapeutic relevance as the ED-B domain of fibronectin, a naturally occurring marker of angiogenesis identical in mouse and man, is expressed in the majority of aggressive solid tumors but is not detectable in normal vessels and tissues.

Animals↗
PubMed2005

Preparation and characterization of PLGA nanospheres for the targeted delivery of NR2B-specific antisense oligonucleotides to the NMDA receptors in the brain.

Treatment of central nervous system (CNS) diseases with potentially useful pharmaceuticals is prevented by the blood-brain barrier (BBB). The BBB is a unique protective barrier in the body. It is formed by epithelial-like tight junctions, which are expressed by the brain capillary endothelial cells. Although most molecules are potentially active in the CNS, they cannot readily enter the brain because of their properties. Antisense oligonucleotides (ODNs) have a great potential as neuropharmaceuticals; however, the large size and polar nature of nucleic acid drugs prevent these molecules from bypassing the BBB and readily entering the CNS following systemic administration. One approach to improve both the pharmacokinetics and the pharmacodynamics of ODNs involves the use of sustained-release polymer formulations, such as poly(lactide-co-glycolide) (PLGA) nanoparticulate systems. In this study, nanospheres were prepared by the emulsification diffusion technique and characterized in terms of particle size, surface morphology, encapsulation efficiency, in vitro release profiles and ODN stability. The nanospheres produced were spherical with homogenous size distribution. Nanospheres were prepared with different encapsulation efficiency. Release profiles of formulations were also evaluated. The results show that formulations with different ODN content exhibited different release profiles. Moreover, the chemical integrity of ODN during the processes was conserved. These results demonstrate that a stable ODN formulation could be prepared utilizing PLGA nanospheres as a potential delivery system for the treatment of CNS diseases.

Brain↗
PubMed2006

Magnetic PECA nanoparticles as drug carriers for targeted delivery: synthesis and release characteristics.

Magnetic poly(ethyl-2-cyanoacrylate) (PECA) nanoparticles containing anti-cancer drugs (Cisplatin and Gemcitabine) were prepared by inter-facial polymerization. The spherical nanoparticles (d = 250 +/- 15 nm) with smooth surfaces and moderately uniform size distributions were obtained. The amount of magnetite encapsulated inside the polymer matrix was increased up to 14.26% (w/w) by controlling the initial weight ratio of monomer/magnetite. It was found that the amount of Cisplatin encapsulated in the magnetic nanoparticle is much higher than that of Gemcitabine because Cisplatin (hydrophobic) is highly soluble in the oil phase and encapsulated easier inside nanoparticles compared to Gemcitabine (hydrophilic). The presence of magnetite and its super-paramagnetic characteristic were confirmed by FTIR spectra and VSM. In-vitro experiments of drug release and magnetic mobility under external magnetic field demonstrated that magnetic poly(ethyl-2-cyanoacrylate) (PECA) nanoparticles can be a highly versatile magnetic drug carrier with sustained release behaviour and sufficient magnetic susceptibility.

Cyanoacrylates↗
PubMed2005

Targeted delivery of arjunglucoside I using surface hydrophilic and hydrophobic nanocarriers to combat experimental leishmaniasis.

The purpose of the present study was to investigate the therapeutic efficacy of the indigenous drug arjunglucoside I (AG) against in vivo models of experimental leishmaniasis by incorporating it in surface hydrophilic co-polymeric nanogel particles of size less than 100 nm diameter and to compare its efficacy with that of the free drug as well as the drug encapsulated in hydrophobic poly-dl-lactide (PLA) nanoparticles. The drug AG, having glucose at the terminal end of the glycosidic chain, was isolated from an indigenous source. Drug-incorporated ultra-low-sized nanogels (approximately 90 nm in diameter) composed of cross-linked random co-polymer of N-isopropylacrylamide (NIPAAM) and N-vinyl pyrrolidone(VP) were prepared, characterized and used as delivery vehicles to combat experimental leishmaniasis in hamster models. For comparison, drug-encapsulated hydrophobic nanoparticles (approximately 250 nm in diameter) made from PLA were used as a control. The drug AG was incorporated in these nanocarriers and these drug-nanocarrier complexes were physically characterized. The efficacy of lowering spleen parasite load by the free drug, as well as that incorporated in nanogels and PLA nanoparticles were examined in vivo in equimolar concentration against hamsters undergoing experimental leishmaniasis. The reduction of drug toxicity by the nanogels and PLA nanoparticles was also assessed. The efficacy in the lowering of spleen parasite load with the free drug was found to be only 38% but was much higher when the drug was incorporated in co-polymeric nanogels (79%) or in polymeric nanoparticles (75%). Both the nanocarriers were found to be effective in reducing hepatotoxicity and nephrotoxicity nearly to the same extent. It was apparent that in addition to a smaller size and better drug release profile, the contribution of other parameters, e.g. overall surface hydrophilicity or hydrophobicity of the vehicles, also play an important role in the macrophage uptake of the drug. However, whatever be the exact mechanism, being highly efficient, non-hepatotoxic and non-nephrotoxic, AG in either of the two nanoparticulate forms may have useful application in humans

Animals↗
PubMedDate not supplied

New cationized LDL-DNA complexes: their targeted delivery to fibroblasts in culture.

Low density lipoproteins (LDL) have been cationized using the water-soluble carbodiimide, N-ethyl-N'-(3-trimethylpropylammonium) carbodiimide iodide at a reagent: lipoprotein mole ratio of 10 000:1. This was shown to increase the innate DNA-binding capacity of LDL 10-fold. [125I]-labeled carbodiimide-modified LDL ([125I])-labeled ECDI-LDL) appeared to recognize the LDL receptor on normal human skin fibroblasts, although some nonspecific binding also was detected. To demonstrate the large ionic component in the lipoprotein-DNA interactions, epsilon -NH2 amino groups on the apolipoprotein B-100 (apoB-100) component of LDL were acetylated with acetic anhydride. A nitrocellulose filter-binding assay revealed that acetylated LDL bound approximately 25% of the [3H]-labeled pBR322 plasmid DNA bound by native LDL under the same conditions. ECDI-LDL-[3H]-labeled plasmid DNA complexes were considerably more stable to NaCl challenge than complexes formed between [3H]-labeled plasmid DNA and native LDL. Thus, the half dissociation of ECDI-LDL containing complexes was achieved at 0.28 M NaCl, whereas for LDL-plasmid DNA complexes this was reached at 0.18 M NaCl. Displacement studies with native LDL studies showed that ECDI-LDL-[3H]-labeled plasmid DNA complexes retained the ability to recognize the LDL receptor on normal skin fibroblasts. Finally, ECDI-LDL complexes with pSV2CAT expression plasmid were shown to transfect CV-1 fibroblasts, a cell line known to specifically recognize apoB-liposome conjugates.

Animals↗
PubMed2002

Oligonucleotide conjugates as potential antisense drugs with improved uptake, biodistribution, targeted delivery, and mechanism of action.

This review summarizes the effect of conjugating small molecules and large biomacromolecules to antisense oligonucleotides to improve their therapeutic potential. In many cases, favorable changes in pharmacokinetic and pharmacodynamic properties were observed. Opportunities exist to change the terminating mechanism of antisense action or to enhance the RNase H mode of action via conjugate formation.

Animals↗
PubMed1998

New anti-Cu-TETA and anti-Y-DOTA monoclonal antibodies for potential use in the pre-targeted delivery of radiopharmaceuticals to tumor.

Monoclonal antibodies were raised against yttrium(III)-1, 4, 7, 10-tetraazacyclododecane-N,N',N''N'''--tetraacetic acid (Y-DOTA) and copper(II)-1, 4, 8, 11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (Cu-TETA). Four hybridomas with high Y-DOTA binding activity and one hybridoma with Cu-TETA activity were selected. MAbs were purified from mouse ascites by Protein A affinity chromatography and characterized. Affinity constants were determined by equilibrium dialysis and the highest affinity Y-DOTA MAb (K(aff) = 1.9 x 10(8) M(-1)) was further characterized by competitive ELISA. Gd-DOTA competed as well as Y-DOTA, whereas In-DOTA required 740x higher concentrations for 50% inhibition of this Y-DOTA MAb binding to human serum albumin-Y-DOTA-coated microtiter plates. These anti-metal chelate MAbs have potential use as vehicles for the pretargeted delivery of radiometal chelates to tumors.

Animals↗
PubMed1996

Targeted delivery of an antisense oligonucleotide in the retina: uptake, distribution, stability, and effect.

In this article, we describe the preliminary results of the development of an animal model that will enable us to study the effect of photoreceptor-derived debris accumulation on the normal function of the retina in vivo. An antisense oligonucleotide (Cat 5), saline, and two control oligonucleotides were injected into the vitreous of 7-week-old RCS-rdy+ rats. The uptake, distribution, and persistence of the antisense oligonucleotide in the retina was demonstrated by fluorescent confocal microscopy, and the stability of the oligonucleotide was shown by GeneScan analysis using a fluorescein-labeled derivative of Cat 5 (Cat 5F). The accumulation of photoreceptor-derived debris was monitored by the number of undigested phagosomes in the RPE layer by light microscopy. Following intravitreal injection of Cat 5F, penetration of the oligonucleotide was observed in the ganglion cell layer in 2 hours and in the photoreceptor and pigment epithelial layers 3 days later. However, at 7, 28, and 56 days postinjection, only the RPE layer had significant amounts of Cat 5F present. Using GeneScan analysis, it was demonstrated that the fluorescein-labeled oligonucleotide present in the RPE layer was not degraded and it retained its original 19-mer length. There was no statistically significant difference in the number of phagosomes found in the RPE layer of control uninjected, saline-injected, and two sense and two antisense oligonucleotides-injected animals at 7 and 28 days postinjection. In contrast, the number of phagosomes was significantly higher (p < 0.001) in the RPE layer of Cat 5 antisense oligonucleotide-injected animals at 7 and 28 days postinjection. This difference, however, disappeared by 56 days postinjection. The inner nuclear layers of the retina of control and experimental animals were not affected by the injections.

Adolescent↗
PubMed1999

Intranuclear targeted delivery of functional NF-kappaB by 70 kDa heat shock protein.

The 70 kDa heat shock protein (Hsp70) is a highly conserved, ubiquitous protein involved in chaperoning proteins to various cellular organelles. Here we show that when added exogenously to cells, Hsp70 is readily imported into both cytoplasmic and nuclear compartments in a cell-type-specific fashion. We exploited this ability of Hsp70 to deliver NF-kappaB, a key transcriptional regulator of inflammatory responses. We demonstrate that a fusion protein composed of a C-terminal Hsp70 peptide and the p50 subunit of NF-kappaB was directed into the nucleus of cells, could bind DNA specifically, and activated Igkappa expression and TNFalpha production. We therefore propose that Hsp70 can be used as a vehicle for intracytoplasmic and intranuclear delivery of proteins or DNA to modulate gene expression and thereby control immune responses.

B-Lymphocytes↗
PubMed1995

Targeted delivery of nerve growth factor via fibronectin conduits assists nerve regeneration in control and diabetic rats.

This study examined the influence of fibronectin conduits joining two halves of a sectioned sciatic nerve, with and without preimpregnation with nerve growth factor, on regeneration in rats with streptozotocin-induced diabetes mellitus. Regeneration, measured morphometrically in fibres containing immunoreactivity to calcitonin gene-related peptide (CGRP) and GAP-43, was significantly less (P < 0.0001 for all comparisons) in diabetic rats with fibronectin mat grafts without nerve growth factor compared to similarly treated controls. Regeneration distances in diabetic rats were reduced to 43% (CGRP-reactive fibres) and 44% (GAP-43-reactive fibres) of controls, and the total amounts of immunoreactivities in the conduits were also reduced, though by lesser amounts (55 and 61% of controls respectively). Impregnation of the conduits with nerve growth factor before implantation increased the distance and amounts of regenerating immunoreactivity in both control and diabetic rats for both CGRP and GAP-43, such that these regeneration parameters were similar in nerve growth factor-treated diabetic rats to those in control rats implanted with untreated fibronectin mat conduits. These findings implicate impaired neurotrophic support in the defective regeneration characteristic of diabetic. neuropathy.

Animals↗
PubMed2005

A beta-lactamase with reduced immunogenicity for the targeted delivery of chemotherapeutics using antibody-directed enzyme prodrug therapy.

Antibody-directed enzyme prodrug therapy (ADEPT) delivers chemotherapeutic agents in high concentration to tumor tissue while minimizing systemic drug exposure. beta-Lactamases are particularly useful enzymes for ADEPT systems due to their unique substrate specificity that allows the activation of a variety of lactam-based prodrugs with minimal interference from mammalian enzymes. We evaluated the amino acid sequence of beta-lactamase from Enterobacter cloacae for the presence of human T-cell epitopes using a cell-based proliferation assay using samples from 65 community donors. We observed a low background response that is consistent with a lack of preexposure to this enzyme. beta-Lactamase was found to contain four CD4+ T-cell epitopes. For two of these epitopes, we identified single amino acid changes that result in significantly reduced proliferative responses while retaining stability and activity of the enzyme. The beta-lactamase variant containing both changes induces significantly less proliferation in human and mouse cell assays, and 5-fold lower levels of IgG1 in mice were observed after repeat administration of beta-lactamase variant with adjuvant. The beta-lactamase variant should be very suitable for the construction of ADEPT fusion proteins, as it combines high activity toward lactam prodrugs, high plasma stability, a monomeric architecture, and a relatively low risk of eliciting an immune response in patients.

Amino Acid Sequence↗
PubMed2002

Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques.

The feasibility, safety, and efficacy of liver-directed gene transfer was evaluated in 5 male macaques (aged 2.5 to 6.5 years) by using a recombinant adeno-associated viral (rAAV) vector (rAAV-2 CAGG-hFIX) that had previously mediated persistent therapeutic expression of human factor IX (hFIX; 6%-10% of physiologic levels) in murine models. A dose of 4 x 10(12) vector genomes (vgs)/kg of body weight was administered through the hepatic artery or portal vein. Persistence of the rAAV vgs as circular monomers and dimers and high-molecular-weight concatamers was documented in liver tissue by Southern blot analysis for periods of up to 1 year. Vector particles were present in plasma, urine, or saliva for several days after infusion (as shown by polymerase chain reaction analysis), and the vgs were detected in spleen tissue at low copy numbers. An enzyme-linked immunosorption assay capable of detecting between 1% and 25% of normal levels of hFIX in rhesus plasma was developed by using hyperimmune serum from a rhesus monkey that had received an adenoviral vector encoding hFIX. Two macaques having 3 and 40 rAAV genome equivalents/cell, respectively, in liver tissue had 4% and 8% of normal physiologic plasma levels of hFIX, respectively. A level of hFIX that was 3% of normal levels was transiently detected in one other macaque, which had a genome copy number of 25 before abrogation by a neutralizing antibody (inhibitor) to hFIX. This nonhuman-primate model will be useful in further evaluation and development of rAAV vectors for gene therapy of hemophilia B.

Animals↗
PubMed1996

Preparation and characterization of poly(lactic-co-glycolic acid) microspheres for targeted delivery of a novel anticancer agent, taxol.

This study describes the preparation and characterization of poly(lactic-co-glycolic acid) microspheres containing a novel anticancer agent, taxol (namely, Taxol-PLGA-MS). A solvent evaporation technique was utilized to prepare Taxol-PLGA-MS. The trapping efficiency of taxol in the microspheres was greater than 90% and reproducible. The in vitro release rate of taxol from the microspheres was very low, and less than 15% of the initial amount of taxol was released in three weeks, irrespective of the drug loading level. When a chemical additive, isopropyl myristate (IPM), was introduced at the level of 30% (w/w), the release of taxol increased significantly; approximately 70% of the initial amount of taxol was released at a nearly constant rate for three weeks. Elevation of the loaded IPM level to 50% (w/w) produced a more rapid release of the drug. Scanning electron microscopy showed that Taxol-PLGA-MS were spherical with a smooth surface. More than half (55-65%) of the microspheres had a diameter of 20-45 microns. Incorporation of IPM had no significant influence on the particle size, surface morphology, or degradation behavior of the microspheres. It was strongly suggested that the release of taxol from the microspheres was dominated mainly by the drug diffusion in the matrix. As evaluated from the particle size, drug content, and in vitro release property, IPM-containing Taxol-PLGA-MS may be suitable for chemoembolization therapy of cancer diseases.

Adsorption↗
PubMed2006

Toward a new generation of therapeutics: artificial cell targeted delivery of live cells for therapy.

Scientific evidence in the prevention and treatment of various disorders is accumulating regarding probiotics. The health benefits supported by adequate clinical data include increased resistance to infectious disease, decreased duration of diarrhea, management of inflammatory bowel disease, reduction of serum cholesterol, prevention of allergy, modulation of cytokine gene expression, and suppression of carcinogen production. Recent ventures in metabolic engineering and heterologous protein expression have enhanced the enzymatic and immunomodulatory effects of probiotics and, with time, may allow more active intervention among critical care patients. In addition, a number of approaches are currently being explored, including the physical and chemical protection of cells, to increase probiotic viability and its health benefits. Traditional immobilization of probiotics in gel matrices, most notably calcium alginate and kappa-carrageenan, has frequently been employed, with noted improvements in viability during freezing and storage. Conflicting reports exist, however, on the protection offered by immobilization from harsh physiologic environments. An alternative approach, microencapsulation in "artificial cells," builds on immobilization technologies by combining enhanced mechanical stability of the capsule membrane with improved mass transport, increased cell loading, and greater control of parameters. This review summarizes the current clinical status of probiotics, examines the promises and challenges of current immobilization technologies, and presents the concept of artificial cells for effective delivery of therapeutic bacterial cells.

Biological Therapy↗