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Results for “Targeted delivery”

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At least 109 records · Page 6Linked to original sources

PubMed2005

Biomedical aspects of targeted delivery of drugs to pulmonary endothelium.

Drug targeting to selected subcellular compartments of the pulmonary endothelium may optimise treatment of many diseases. This paper describes endothelial determinants that are potentially useful for such targeting, including endothelial ectopeptidases, cell adhesion molecules and novel candidates identified by high-throughput methods, as well as the means to achieve optimal subcellular targeting of drugs in the endothelium that have been explored in cell culture and animal studies. Criteria for determining the applicability for targeting include accessibility, specificity, safety and subcellular precision. The effects of endothelial delivery of therapeutic agents, including the effects mediated by the intervention in the function of the target determinants, must be characterised in the context of given pathological conditions.

Animals↗

PubMed2003

Targeted delivery of antiprotease to the epithelial surface of human tracheal xenografts.

The cystic fibrosis (CF) lung is uniquely susceptible to Pseudomonas aeruginosa, and infection with this organism incites an intense, compartmentalized inflammatory response that leads to chronic airway obstruction and bronchiectasis. Neutrophils migrate into the airway, and released neutrophil elastase contributes to the progression of the lung disease characteristic of CF. We have developed a strategy that permits the delivery of antiproteases to the inaccessible CF airways by targeting the respiratory epithelium via the human polymeric immunoglobulin receptor (hpIgR). A fusion protein consisting of a single-chain Fv directed against secretory component, the extracellular portion of the pIgR, linked to human alpha1-antitrypsin is effectively ferried across human tracheal xenografts and delivers the antiprotease to the apical surface to a much greater extent than occurs by passive diffusion of human alpha1-antitrypsin alone. Targeted antiprotease delivery paralleled hpIgR expression in the respiratory epithelium in vivo and was not increased by escalating dose, so airway penetration was receptor-dependent, not dose-dependent. Thus, this approach provides us with the ability to deliver therapeutics, like antiproteases, specifically to the lumenal surface of the respiratory epithelium, within the airway surface fluid, where it will be in highest concentration at this site.

Animals↗

PubMed1996

Brain-targeted delivery of a leucine-enkephalin analogue by retrometabolic design.

A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Try-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent analgesia than alanine. The antinociceptive effect of the CDSs was naloxone-reversible and methylnaloxonium-irreversible, confirming that central opiate receptors were solely responsible for mediating analgesia induced by the peptide CDS that delivered, retained, and then released the peptide in the brain.

Analgesia↗

PubMed2005

Acoustic radiation force enhances targeted delivery of ultrasound contrast microbubbles: in vitro verification.

Recent research has shown that targeted ultrasound contrast microbubbles achieve specific adhesion to regions of intravascular pathology, but not in areas of high flow. It has been suggested that acoustic radiation can be used to force free-stream microbubbles toward the target, but this has not been verified for actual targeted contrast agents. We present evidence that acoustic radiation indeed increases the specific targeted accumulation of microbubbles. Lipid microbubbles bearing an antibody as a targeting ligand were infused through a microcapillary flow chamber coated with P-selectin as the target protein. A 2.0 MHz ultrasonic pulse was applied perpendicular to the flow direction. Microbubble accumulation was observed on the flow chamber surface opposite the transducer. An acoustic pressure of 122 kPa enhanced microbubble adhesion up to 60-fold in a microbubble concentration range of 0.25 x 10(6) to 75 x 106) ml(-1). Acoustic pressure mediated the greatest adhesion enhancement at concentrations within the clinical dosing range. Acoustic pressure enhanced targeting nearly 80-fold at a wall shear rate of 1244 s(-1), suggesting that this mechanism is appropriate for achieving targeted microbubble delivery in high-flow vessels. Microbubble adhesion increased with the square of acoustic pressure between 25 and 122 kPa, and decreased substantially at higher pressures.

Antibodies↗

PubMed2004

In vitro studies on guar gum based formulation for the colon targeted delivery of Sennosides.

PURPOSE: The objective of the present study is to develop colon targeted drug delivery systems for sennosides using guar gum as a carrier. METHODS: Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for content uniformity and in vitro drug release study as per BP method. T(50) % value from the dissolution studies was taken for selecting the best formulation. RESULTS: Guar gum matrix tablets released 4-18% sennosides in the physiological environment of gastrointestinal tract depending on the proportion of the guar gum used in the formulation. The matrix tablets containing 50% of guar gum were found to be suitable for targeting of sennosides for local action in the colon. Compared to tablets having 30% and 40% of guar gum, those with 50% guar gum gave better T(50)% (11.7 h) le and fewer amounts (5-8%) of drug release in upper GIT. These tablets with 50% guar gum released 43% and 96% sennosides with and without rat caecal fluids. This suggests the susceptibility of matrix to the colonic micro flora. The similarity factor (f2 value) for drug release with and without rat caecal fluids was found to be less than 30. When hydroxy propyl methylcellulose phthalate (10%) was used as a coat material on the matrix tablets, the initial loss of 5-8% sennosides in stomach could be completely averted. These tablets showed no change in physical appearance, content and dissolution profile upon storage at 45 degrees C / 75% relative humidity for 3 months. CONCLUSION: The results of our study indicates that matrix tablets containing 50% guar gum and coated with 10% hydroxy propyl methylcellulose phthalate are most suitable for drugs like sennosides which are mainly active in the lower GIT.

Administration, Oral↗

PubMed2019

Targeted delivery of CRISPR interference system against Fabp4 to white adipocytes ameliorates obesity, inflammation, hepatic steatosis, and insulin resistance.

Obesity is an increasing pathophysiological problem in developed societies. Despite all major progress in understanding molecular mechanisms of obesity, currently available anti-obesity drugs have shown limited efficacy with severe side effects. CRISPR interference (CRISPRi) mechanism based on catalytically dead Cas9 (dCas9) and single guide RNA (sgRNA) was combined with a targeted nonviral gene delivery system to treat obesity and obesity-induced type 2 diabetes. A fusion peptide targeting a vascular and cellular marker of adipose tissue, prohibitin, was developed by conjugation of adipocyte targeting sequence (CKGGRAKDC) to 9-mer arginine (ATS-9R). (dCas9/sgFabp4) + ATS-9R oligoplexes showed effective condensation and selective delivery into mature adipocytes. Targeted delivery of the CRISPRi system against Fabp4 to white adipocytes by ATS-9R induced effective silencing of Fabp4, resulting in reduction of body weight and inflammation and restoration of hepatic steatosis in obese mice. This RNA-guided DNA recognition platform provides a simple and safe approach to regress and treat obesity and obesity-induced metabolic syndromes.

3T3 Cells↗

PubMed2006

Targeted delivery of siRNA.

Therapeutic application of siRNA requires delivery to the correct intracellular location, to interact with the RNAi machinery within the target cell, within the target tissue responsible for the pathology. Each of these levels of targeting poses a significant barrier. To overcome these barriers several strategies have been developed, such as chemical modifications of siRNA, viral nucleic acid delivery systems, and nonviral nucleic acid delivery systems. Here, we discuss progress that has been made to improve targeted delivery of siRNA in vivo for each of these strategies.

Journal Article↗

PubMedDate not supplied

Bioerodible polymeric nanoparticles for targeted delivery of proteic drugs.

Significant efforts are being devoted to develop nanotechnology for drug delivery, mainly because of the distinct advantages offered by nanometer-size polymeric systems. Moreover, targeted drug delivery can be obtained by polymer conjugation to biospecific ligands. The present investigation was aimed mainly at determining the targeting ability of hybrid nanoparticles based on synthetic polymer/protein hybrid matrices. These nanoparticles were designed for liver targeted release of proteic drugs with antiviral activity, such as alpha-interferon. Human serum albumin and the monoesters of alternating copolymers of maleic anhydride/alkyl vinyl ethers of oligo(ethylene glycol) were selected as proteic and synthetic components, respectively. Digalactosyl diacyl glycerol, a natural glycolipid selectively recognized by the asialofetuin receptor present on liver hepatocytes was used as active targeting agent. Nanoparticles of 100-300 nm average size were obtained by controlled coprecipitation method. Investigation of nanoparticle surface properties by spectroscopic analysis and by biological tests indicated that the synthesized nanoparticles do expose on their surface targeting moieties that selectively interact with liver hepatocytes receptors.

Animals↗

PubMed2005

Targeted delivery of therapeutic oligonucleotides to pulmonary circulation.

Functional oligodeoxynucleotides (ODN) such as antisense ODN (AS-ODN) show promise as new therapeutics for the treatment of a number of pulmonary diseases. They also hold potential to serve as a research tool for the study of gene function related to lung physiology. The success of their application is largely dependent on the development of an efficient delivery vehicle. This chapter summarizes work toward the development of lipidic vectors for targeted ODN delivery to pulmonary circulation. Recent advancements in the development of novel ODN are also discussed briefly.

Animals↗

PubMed2004

Quantitation and kinetics of CD51 surface receptor expression: implications for targeted delivery.

The CD51 integrin subunit is important in many functions ranging from mediation of adenovirus attachment and internalization to facilitation of angiogenesis. CD51 has also gained interest as an attractive ligand for directed therapy studies, including those for targeted gene delivery. While the function and importance of several CD51-specific targeting molecules have been examined, studies are often carried out without quantitative assessment of the receptor. A lack of this data complicates further mathematical analysis of targeting data and elucidation of the mechanism(s) underlying specific targeting. We performed a quantitative evaluation of CD51 receptors on the surface of HeLa cells, a common cell line utilized in many receptor-based studies, and compared them to other similar and dissimilar cell types. Unstimulated HeLa cells strongly express the CD51 receptor at a level of 212,700 +/- 12,000 (mean +/- SD) antibody binding capacity (ABC) cell(-1) (n = 3). Following irradiation with 3 Gy, receptor expression increases dramatically, peaking at a value of 403,700 +/- 26,400 (n = 4). The utility of this quantitative information is highlighted by the application of our data to targeting studies from the literature. Taken together, the results yield more detailed information than is available with experimental targeting data alone.

Adaptation, Physiological↗

PubMed2014

Combinatorial approaches for the identification of brain drug delivery targets.

The blood-brain barrier (BBB) represents a large obstacle for the treatment of central nervous system diseases. Targeting endogenous nutrient transporters that transcytose the BBB is one promising approach to selectively and noninvasively deliver a drug payload to the brain. The main limitations of the currently employed transcytosing receptors are their ubiquitous expression in the peripheral vasculature and the inherent low levels of transcytosis mediated by such systems. In this review, approaches designed to increase the repertoire of transcytosing receptors which can be targeted for the purpose of drug delivery are discussed. In particular, combinatorial protein libraries can be screened on BBB cells in vitro or in vivo to isolate targeting peptides or antibodies that can trigger transcytosis. Once these targeting reagents are discovered, the cognate BBB transcytosis system can be identified using techniques such as expression cloning or immunoprecipitation coupled with mass spectrometry. Continued technological advances in BBB genomics and proteomics, membrane protein manipulation, and in vitro BBB technology promise to further advance the capability to identify and optimize peptides and antibodies capable of mediating drug transport across the BBB.

Animals↗

PubMed1992

Cationic liposomes enhance targeted delivery and expression of exogenous DNA mediated by N-terminal modified poly(L-lysine)-antibody conjugate in mouse lung endothelial cells.

A new and improved system for targeted gene delivery and expression is described. Transfection efficiency of N-terminal modified poly(L-lysine) (NPLL) conjugated with anti-thrombomodulin antibody 34A can be improved by adding to the system a lipophilic component, cationic liposomes. DNA, antibody conjugate and cationic liposomes form a ternary electrostatic complex which preserves the ability to bind specifically to the target cells. At the same time the addition of liposomes enhance the specific transfection efficiency of antibody-polylysine/DNA binary complex by 10 to 20-fold in mouse lung endothelial cells in culture.

Animals↗

PubMed2005

Identification and characterization of a novel peptide ligand of epidermal growth factor receptor for targeted delivery of therapeutics.

Epidermal growth factor receptor (ErbB1, EGFR) is overexpressed in a variety of human cancer cells. It has been considered as a rational target for drug delivery. To identify novel ligands with specific binding capabilities to EGFR, we screened a phage display peptide library and found an enriched phage clone encoding the amino acid sequence YHWYGYTPQNVI (designated as GE11). Competitive binding assay and Scatchard analysis revealed that GE11 peptide bound specifically and efficiently to EGFR with a dissociation constant of approximately 22 nM, but with much lower mitogenic activity than with EGF. We showed that the peptides were internalized preferentially into EGFR highly expressing cells, and they accumulated in EGFR overexpressing tumor xenografts after i.v. delivery in vivo. In gene delivery studies, GE11-conjugated polyethylenimine (PEI) vectors were less mitogenic, but still quite efficient at transfecting genes into EGFR highly expressing cells and tumor xenografts. Taken together, GE11 is a potentially safe and efficient targeting moiety for selective drug delivery systems mediated through EGFR.

Cell Line, Tumor↗

PubMed2005

Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound.

The blood-brain barrier (BBB) is a persistent obstacle for the local delivery of macromolecular therapeutic agents to the central nervous system (CNS). Many drugs that show potential for treating CNS diseases cannot cross the BBB and there is a need for a non-invasive targeted drug delivery method that allows local therapy of the CNS using larger molecules. We developed a non-invasive technique that allows the image-guided delivery of antibody across the BBB into the murine CNS. Here, we demonstrate that subsequent to MRI-targeted focused ultrasound induced disruption of BBB, intravenously administered dopamine D(4) receptor-targeting antibody crossed the BBB and recognized its antigens. Using MRI, we were able to monitor the extent of BBB disruption. This novel technology should be useful in delivering macromolecular therapeutic or diagnostic agents to the CNS for the treatment of various CNS disorders.

Animals↗

PubMed1999

Targeted delivery of multivalent phage display vectors into mammalian cells.

Novel peptide motives targeting endocytosing receptors were isolated from phage display libraries of random peptides by recovering internalized phage from mammalian cells. The peptide-presenting phage selected by internalization in HEp-2 and ECV304 human cells were taken up 1000- to 100,000-fold more efficiently than their parent libraries, and from 10 to 100 times faster than phage particles displaying integrin-binding peptides. A high degree of selectivity of phage uptake was observed in these cells: phage selected in ECV304 cells were internalized approximately 100-fold more efficiently in ECV304 cells than in HEp-2 cells. Likewise, phage selected in HEp-2 cells were subsequently taken up approximately 40-fold more efficiently by HEp-2 cells than by ECV304 cells. In multiple independent trials using a cyclic peptide library, an identical peptide sequence displayed on phage was internalized by and recovered from ECV304 cells. These findings indicate that the internalization process is highly selective, and is capable of capturing a specific peptide from 2 x 10(7) peptide variants. Immunofluorescence microscopy showed juxtanuclear localization of internalized phage. These results demonstrate the feasibility of using multivalent phage-display libraries to identify new targeting ligands for the intracellular delivery of macromolecules.

Amino Acid Sequence↗

PubMedDate not supplied

Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs. 1. In vitro evaluations.

A representative poly(beta-amino ester) (PbAE) with biodegradable and pH-sensitive properties was used to formulate a nanoparticle-based dosage form for tumor-targeted paclitaxel delivery. The polymer undergoes rapid dissolution when the pH of the medium is less than 6.5 and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells. PbAE nanoparticles were prepared by solvent displacement method and characterized for particle size, charge, and surface morphology. Pluronic F-108, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), was blended with PbAE to induce surface modification of the nanoparticles. In vitro cellular uptake of tritiated [(3)H]-paclitaxel in solution form and as a nanoparticulate formulation was studied in MDA-MB-231 human breast adenocarcinoma cells grown in 12-well plates. We also examined the intracellular degradation pattern of the formulations within the cells by estimating the drug release profile. Cytotoxicity assay was performed on the formulations at different doses and time intervals. Nanoparticles prepared from poly(epsilon-caprolactone) (PCL) that do not display pH-sensitive release behavior were used as control. Spherical nanoparticles having positive zeta potential ( approximately 40 mV) were obtained in the size range of 150-200 nm with PbAE. The PEO chains of the Pluronic were well-anchored within the nanomatrix as determined by electron spectroscopy for chemical analysis (ESCA). The intracellular accumulation of paclitaxel within tumor cells was significantly higher when administered in the nanoparticle formulations as compared to aqueous solution. Qualitative fluorescent microscopy confirmed the rapid release of the payload into the cytosol in the case of PbAE nanoparticles, while the integrity of the PCL nanoparticles remained intact. The cytotoxicity assay results showed significantly higher tumoricidal activity of paclitaxel when administered in the nanoparticle formulations. The cell-kill effect was maximal for paclitaxel-loaded PbAE nanoparticles when normalized with respect to intracellular drug concentrations. Thus, PEO-modified PbAE nanoparticles show tremendous potential as novel carriers of cytotoxic agents for achieving improved drug disposition and enhanced efficacy.

Cell Line, Tumor↗

PubMed2004

Targeted delivery of antisense oligodeoxynucleotides to folate receptor-overexpressing tumor cells.

A major problem in exploring the full potential of antisense ODN is the lack of a safe and efficient delivery system. In this study a new method has been developed that is highly efficient in encapsulating ODN inside folate receptor (FR)-targeted lipid vesicles. ODN formulated in these vesicles were efficiently protected from degradation by nucleases compared to free ODN. Folate efficiently mediated intracellular delivery of ODN to KB tumor cells that overexpress FR. Delivery of EGFR antisense ODN via FR-targeted lipid vesicles resulted in a significant down-regulation of EGFR expression in KB cells and cell growth inhibition, far more efficient than that with free ODN or ODN encapsulated in ligand-free lipid vesicles. Intracellular delivery of EGFR antisense ODN also sensitized KB cells to doxorubicin (DOX) treatment. Thus targeted delivery of ODN via this novel lipid vector may have potential in treating tumors that overexpress FR.

Blotting, Western↗

PubMed2004

Targeted delivery of adenoviral vectors by cytotoxic T cells.

Effective targeting of vectors to tumor cells that have metastasized to multiple different tissue sites remains a major challenge for gene therapy. Tumor-specific cytotoxic T lymphocytes (CTLs) have been shown in animal models and in humans to be able to cross tissue barriers and traffic to tumor cells. However, their capacity to eliminate malignancy has been limited by tumor immune evasion strategies. We now use a model of Epstein-Barr virus-mediated malignancy to show that human CTLs themselves may be modified to release therapeutic vectors following engagement of their antigen-specific receptors and that these vectors will effectively transduce and destroy tumor targets. We generated EBV-specific CTLs that were transgenic for the adenoviral E1 gene under the control of the cell activation-dependent CD40 ligand (CD40L) promoter. Following transduction with E1-deficient adenoviral vectors, these CTLs produced infectious virus when exposed to HLA-matched EBV-expressing targets, but not on exposure to major histocompatibility complex (MHC)-mismatched or otherwise irrelevant cells. This approach provides a means of delivering oncolytic/therapeutic vectors not only to locally accessible macroscopic tumors as is presently the case, but also to disseminated metastatic disease, while avoiding the risks associated with systemic administration of large doses of adenoviral vectors.

Adenoviridae↗