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At least 325 records · Page 18Linked to original sources

PubMed1989

Targeted drug delivery: a two-compartment growth inhibition assay demonstrates that fluorodeoxyuridine and fluorodeoxyuridine monophosphate are liposome-independent drugs.

The targeted delivery to cells by liposomes and leakage under delivery conditions of fluorodeoxyuridine (FdUR) and fluorodeoxyuridine monophosphate (FdUMP) have been evaluated using a two-compartment growth inhibition assay. Under cell culture conditions, FdUR leaks 100% from all liposomes regardless of charge or phase transition temperature. Under the same conditions, FdUMP leaks 100% from egg yolk phosphatidylglycerol liposomes, 47% from distearoylphosphatidylglycerol liposomes, 44% from egg yolk phosphatidylcholine liposomes, and 10% from distearoylphosphatidylcholine liposomes. All liposomes were prepared from a 67:33 mixture of phospholipid and cholesterol. The two-compartment assay demonstrates directly that neither of these drugs is delivered selectively to the target cells by the liposomes, suggesting that they are liposome independent drugs.

Biopharmaceutics↗

PubMed2002

Barriers to remember: brain-targeting chemical delivery systems and Alzheimer's disease.

Brain-targeted chemical delivery systems (CDSs) represent rational drug design attempts not only to deliver but also to target drugs to their site of action. Using a sequential metabolism approach, the special bidirectional properties of the blood-brain barrier can be exploited to smuggle the precursors of therapeutic compounds across the barrier and lock them inside the brain ready for sustained release of the active drugs. Many potential therapeutic applications can be envisioned for such CDSs; here, the potential of brain-targeted estradiol for the prevention and treatment of Alzheimer's disease is reviewed in detail.

Alzheimer Disease↗

PubMed2003

Calcium phosphate nanoparticles as novel non-viral vectors for targeted gene delivery.

Calcium phosphate nanoparticles present a unique class of non-viral vectors, which can serve as efficient and alternative DNA carriers for targeted delivery of genes. In this study we report the design and synthesis of ultra-low size, highly monodispersed DNA doped calcium phosphate nanoparticles of size around 80 nm in diameter. The DNA encapsulated inside the nanoparticle is protected from the external DNase environment and could be used safely to transfer the encapsulated DNA under in vitro and in vivo conditions. Moreover, the surface of these nanoparticles could be suitably modified by adsorbing a highly adhesive polymer like polyacrylic acid followed by conjugating the carboxylic groups of the polymer with a ligand such as p-amino-1-thio-beta-galactopyranoside using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride as a coupling agent. We have demonstrated in our studies that these surface modified calcium phosphate nanoparticles can be used in vivo to target genes specifically to the liver.

Animals↗

PubMed2004

A novel in situ gel for sustained drug delivery and targeting.

The objective of this study was to develop a novel chitosan-glyceryl monooleate (GMO) in situ gel system for sustained drug delivery and targeting. The delivery system consisted of 3% (w/v) chitosan and 3% (w/v) GMO in 0.33M citric acid. In situ gel was formed at a biological pH. In vitro release studies were conducted in Sorensen's phosphate buffer (pH 7.4) and drugs were analyzed either by HPLC or spectrophotometry. Characterization of the gel included the effect of cross-linker, determination of diffusion coefficient and water uptake by thermogravimetric analysis (TGA). Mucoadhesive property of the gel was evaluated in vitro using an EZ-Tester. Incorporation of a cross-linker (glutaraldehyde) retarded the rate and extent of drug release. The in vitro release can further be sustained by replacing the free drug with drug-encapsulated microspheres. Drug release from the gel followed a matrix diffusion controlled mechanism. Inclusion of GMO enhanced the mucoadhesive property of chitosan by three- to sevenfold. This novel in situ gel system can be useful in the sustained delivery of drugs via oral as well as parenteral routes.

Anesthetics, Local↗

PubMed2005

Synthesis and application of integrin targeting lipopeptides in targeted gene delivery.

One of the main problems facing gene therapy is the ability to target the delivery of DNA to specific cells of choice. Recently, we developed a synthetic nonviral vector platform system known as LMD (liposome:mu:DNA) that was designed for further modular upgrading with tool-kits of chemical components. First-generation LMD systems were prepared from DC-Chol/DOPE cationic liposomes (DC-Chol=3beta-[N-(N',N'-dimethylaminoethane)carbamoyl] cholesterol, DOPE=dioleoyl-L-alpha-phosphatidylethanolamine), mu peptide from the adenovirus core and plasmid DNA (pDNA). Here we report attempts to realise peptide-targeted gene delivery that build upon the LMD platform. Our strategy was to prepare novel lipopeptides with a lipid moiety designed to insert into the outer lipid bilayer of LMD particles whilst simultaneously presenting a peptide moiety for cell-surface receptor binding. One main functional peptide sequence was selected (PLAEIDGIELA; tenascin peptide sequence) known to target alpha(9)beta(1)-integrin proteins predominant on upper-airway epithelial cells. This sequence was investigated along with a corresponding control sequence. The syntheses of two classes (A and B) of lipopeptides are reported; the syntheses of class A lipopeptides requires a modification of Mitsunobu chemistry that could be of general utility to facilitate Mitsunobu reactions in other diverse systems. "Targeted" LMD and LD transfections with class A or B lipopeptides exhibit nonspecific peptide enhancements (up to one order of magnitude) over nonlipopeptide control transfections but few specific effects. Specific targeting effects can be seen if the overall LMD or LD particle cationic charge is lowered, but nonspecific effects are never eliminated. Whilst promising, these data now highlight the need for in vivo data and even a new modular, aqueous chemistry for the controlled adaptation of LMD particles in buffer in order for successful peptide-targeted, synthetic, nonviral gene delivery to be realised.

Animals↗

PubMed2004

Selective photodynamic therapy by targeted verteporfin delivery to experimental choroidal neovascularization mediated by a homing peptide to vascular endothelial growth factor receptor-2.

OBJECTIVE: To evaluate the feasibility, efficacy, and selectivity of photodynamic therapy (PDT) using targeted delivery of verteporfin to choroidal neovascularization (CNV) in the rat laser-injury model of CNV. METHODS: We performed PDT in rat eyes on experimental CNV and normal retina and choroid using verteporfin conjugates. A targeted verteporfin conjugate was made by conjugating verteporfin (after isolation from its liposomal formulation) to a modified polyvinyl alcohol (PVA) polymer (verteporfin-PVA) followed by linkage to the peptide ATWLPPR known to bind the receptor for vascular endothelial growth factor, VEGFR2. The verteporfin-PVA conjugate served as a control. We performed fluorescent fundus angiography to determine the optimal timing of light application for PDT using the conjugates. Closure of CNV was assessed angiographically and graded in a masked standardized fashion. We used standardized histological grading to compare the effects on normal retina and choroid. RESULTS: The verteporfin-PVA conjugation ratio was on average 28:1. The conjugate retained typical emission/excitation spectra and photosensitizing activity and was as efficient as an equivalent amount of verteporfin. Peak intensity of targeted verteporfin in CNV was detected angiographically at 1 hour after intravenous injection. Photodynamic therapy using targeted verteporfin (3 or 4.5 mg/m2) with light application 1 hour after drug injection showed angiographic closure of all treated CNV (17/17) 1 day after treatment. Photodynamic therapy using verteporfin-PVA at the same drug dose achieved closure in 18 of 20 CNV. Histological examination after PDT of normal retina and choroid using targeted verteporfin and irradiation at 1 hour showed minimal effect on retinal pigment epithelium and no injury to photoreceptors, whereas PDT using verteporfin-PVA resulted in retinal pigment epithelium necrosis and mild damage to photoreceptors. CONCLUSIONS: Verteporfin bound to the targeting peptide, ATWLPPR, retained its spectral and photosensitizing properties. Angiography demonstrated localization of the targeted verteporfin 1 hour after injection. Photodynamic therapy using targeted verteporfin and the control conjugate were more effective in causing CNV closure than standard liposomal verteporfin. The targeted verteporfin resulted in more selective treatment than the control conjugate or standard verteporfin. These results suggest that targeted PDT strategies based on selective expression of receptors on CNV vasculature may improve current therapy. CLINICAL RELEVANCE: Targeted PDT for CNV is feasible and may offer a qualitative improvement in current treatments for patients with age-related macular degeneration. This study provides the basis for further preclinical studies of targeted PDT strategies and subsequent clinical trials.

Animals↗

PubMed2005

Folate-linked lipid-based nanoparticle for targeted gene delivery.

Cancer gene therapy has been intensively developed using non-viral vectors, among which cationic liposomes and nanoparticles are the most thoroughly investigated. For targeted delivery to tumors, vitamin folic acid has been utilized for folate receptor (FR)-mediated drug delivery, since FR is frequently overexpressed on many types of human tumors. Liposomes conjugated to folate ligand have been used as carriers of chemotherapeutic agents and DNA to receptor-bearing tumor cells in vitro. As an alternative treatment for prostate cancer, suicide gene therapy by local injection using an adenoviral vector has been reported, but not that using non-viral vectors. The folate-linked, lipid-based nanoparticles which we developed could deliver genes extensively to FR-negative LNCaP and PC-3 cells, as well as FR-positive KB and Hela cells. In this review, we outline folate-linked liposomes and nanoparticles, and show the effectiveness of folate-linked, lipid-based nanoparticles as a vector for DNA transfection and for suicide gene therapy, to treat human nasopharyngeal and prostate tumors.

Carrier Proteins↗

PubMed1993

Review: recent advances in lipid microsphere technology for targeting prostaglandin delivery.

Although prostaglandin E1 (PGE1) and prostacyclin (PGI2) exhibit pharmacological activities in free form, it has been hypothesized and experimentally verified that carrier preparations can target them more effectively at lower doses, thus causing fewer side effects. Lipid microspheres (LM) with a diameter of 0.2 micron are drug carriers prepared from soybean oil and lecithin, and the drug is incorporated within the LM. Lipo-PGE1 and lipo-PGI2 are LM preparations of PGE1 and a PGI2 derivative that are designed to accumulate at the vascular lesions. The authors have achieved remarkable clinical effects against neuropathy and ulcers, severe hepatitis, congenital heart diseases, and acute cerebral thrombosis using these preparations. In this review, clinical observations, some basic studies including targeting delivery of lipo-PGE1 to the liver, and future indications for these preparations are introduced. Development of a new lipo-PGE1 (lipo-AS013) that overcomes the disadvantages of the preparation currently available is also discussed. Lipo-AS013, a prodrug of PGE1, is considered superior to free PGE1 in terms of its chemical stability in LM and the retention ratio of the drug in LM in the body.

Animals↗

PubMed2004

Ligands of the asialoglycoprotein receptor for targeted gene delivery, part 1: Synthesis of and binding studies with biotinylated cluster glycosides containing N-acetylgalactosamine.

In order to develop the non-viral Bioplex vector system for targeted delivery of genes to hepatocytes, we have evaluated the structure-function relationship for a number of synthetic ligands designed for specific interaction with the hepatic lectin ASGPr. Biotinylated ligand derivatives containing two, three or six beta-linked N-acetylgalactosamine (GalNAc) residues were synthesized, bound to fluorescent-labeled streptavidin and tested for binding and uptake to HepG2 cells using flow cytometry analysis (FACS). Uptake efficiency increased with number of displayed GalNAc units per ligand, in a receptor dependent manner. Thus, a derivative displaying six GalNAc units showed the highest uptake efficacy both in terms of number of internalizing cells and increased amount of material taken up per each cell. However, this higher efficiency was shown to be due not so much to higher number of sugar units, but to higher accessibility of the sugar units for interaction with the receptor (longer spacer). Improving the flexibility and accessibility of a trimeric GalNAc ligand through use of a longer spacer markedly influenced the uptake efficiency, while increasing the number of GalNAc units per ligand above three only provided a minor contribution to the overall affinity. We hereby report the details of the chemical synthesis of the ligands and the structure-function studies in vitro.

Acetylgalactosamine↗

PubMedDate not supplied

Polycation-based DNA complexes for tumor-targeted gene delivery in vivo.

BACKGROUND: Efficient and target-specific in vivo gene delivery is a major challenge in gene therapy. Compared to cell culture application, in vivo gene delivery faces a variety of additional obstacles such as anatomical size constraints, interactions with biological fluids and extracellular matrix, and binding to a broad variety of non-target cell types. METHODS: Polycation-based vectors, including adenovirus-enhanced transferrinfection (AVET) and transferrin-polyethylenimine (Tf-PEI), were tested for gene delivery into subcutaneously growing tumors after local and systemic application. DNA biodistribution and reporter gene expression was measured in the major organs and in the tumor. RESULTS: Gene transfer after intratumoral application was 10-100 fold more efficient with Tf-PEI/DNA or AVET complexes in comparison to naked DNA. Targeted gene delivery into subcutaneously growing tumors after systemic application was achieved using electroneutral AVET complexes and sterically stabilized PEGylated Tf-PEI/DNA complexes, whereas application of positively charged polycation/DNA complexes resulted in predominant gene expression in the lungs and was associated by considerable toxicity. CONCLUSION: For systemic application, the physical and colloidal parameters of the transfection complexes, such as particle size, stability, and surface charge, determine DNA biodistribution, toxicity, and transfection efficacy. By controlling these parameters, DNA biodistribution and gene expression can be targeted to different organs.

Adenoviridae↗

PubMed2006

Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme.

The low density lipoprotein (LDL) receptor has been shown to be upregulated in GBM tumor cells and is therefore a potential molecular target for the delivery of therapeutic agents. A synthetic nano-LDL (nLDL) particle was developed and tested to determine its utility as a drug delivery vehicle targeted to GBM tumors. nLDL particles were constructed by combining a synthetic peptide containing a lipid binding motif and the LDL receptor (LDLR) binding domain of apolipoprotein B-100 with a lipid emulsion consisting of phosphatidyl choline, triolein, and cholesteryl oleate. Composition analysis, fast protein liquid chromatography, and electron microscopy revealed that nLDL was highly reproducible and intermediate in size between high density lipoprotein and LDL particles (10.5+/-2.8 nm diameter). The binding and uptake of fluorescently labeled nLDL particles was assessed using fluorescence microscopy. Uptake of nLDL was time dependent, exhibiting saturation at approximately 3 h, and concentration dependent, exhibiting saturation at concentrations greater than 5 microM peptide. Using Lysotracker as a cellular marker, nLDL co-localized with lysosomes. nLDL binding was eliminated by blocking LDLRs with suramin and nLDL inhibited binding of plasma LDL to LDLRs. Collectively these data strongly suggest that the synthetic nano-LDLs described here are taken up by LDLR and can serve as a drug delivery vehicle for targeting GBM tumors via the LDLR.

Amino Acids↗

PubMed2002

Tumor-targeted gene delivery: an attractive strategy to use highly active effector molecules in cancer treatment.

We have developed surface-shielded ligand-polycation based gene delivery systems which are able to target gene expression to distant tumors after systemic application. Tumor-specific targeting is achieved by (1) incorporation of cell-binding ligands; and (2) shielding of the complexes from non-specific interactions with blood components and non-target cells. Shielding of polycation/DNA complexes can be achieved by coating with either polyethylene glycol or by incorporating the ligand transferrin at high densities. Following systemic application, surface-shielded DNA complexes coding for a highly active, yet highly toxic cytokine, tumor necrosis factor-alpha (TNFalpha), localized gene expression to distant tumors, resulting in hemorrhagic tumor necrosis and inhibition of tumor growth. TNFalpha activity was confined to the tumor without systemic TNF-related toxicity. These results indicate that targeted gene delivery may be an attractive strategy to use highly potent molecules in cancer treatment.

Animals↗

PubMedDate not supplied

Pharmacytes: an ideal vehicle for targeted drug delivery.

An ideal nanotechnology-based drug delivery system is a pharmacyte--a self-powered, computer-controlled medical nanorobot system capable of digitally precise transport, timing, and targeted delivery of pharmaceutical agents to specific cellular and intracellular destinations within the human body. Pharmacytes may be constructed using future molecular manufacturing technologies such as diamond mechanosynthesis which are currently being investigated theoretically using quantum ab initio and density-functional computational methods. Pharmacytes will have many applications in nanomedicine such as initiation of apoptosis in cancer cells and direct control of cell signaling processes.

Drug Delivery Systems↗

PubMed2002

Synthesis of targeted drug delivery system for fluorouracil using sulfadiazine as the carrier.

OBJECTIVE: To synthesize a targeted drug delivery system for 5-fluorouracil (5Fu) using sulfadiazine (SF) as a carrier with reduced side-effects and strong antitumor activity. METHODS: SF-poly (ethylene glycol) (PEG) conjugate was initially synthesized. 5Fu was subjected to reaction with trichloromethyl chloroformate to prepare chloroformyl 5Fu, which was linked to a spacer hydroxyl group of PEG that served as a macromolecular linking arm between SF and 5Fu. The content of 5Fu in the conjugate was determined by ultraviolet spectrophotometry. Spectrum of ultraviolet and infrared along with differential scanning calorimetry were employed to identify the structure of the conjugate of SFPEG-end capped 5Fu. RESULTS: The drug loading content of the conjugate was 3.2 %, and structural analysis confirmed the linkage between 5Fu and SF via PEG. CONCLUSION: Targeted drug delivery system for 5Fu using SF as a carrier has been successfully synthesized by this means.

Antimetabolites, Antineoplastic↗

PubMed2002

Open system gene expression profiling and identification of novel genes for targeted vaccine delivery.

Ongoing development of vaccines is limited by the techniques used to identify routes to immunization. Using open system gene expression profiling, researchers can now directly identify receptors used by M-cells in the transport of antigens to the mucosal immune system. These receptors will be ideal for targeted delivery of new synthetic vaccines. In addition, gene expression profiling will provide important new information on the biology of the M-cell and mucosal immune mechanisms.

Gene Expression Profiling↗

PubMed2005

[Study on liver targeted drug delivery system of the effective anticancer component from Bolbstemma paniculatum].

OBJECTIVE: To study the liver targeted drug delivery system of TBMS--the effective anticancer component from Bolbstemma paniculatum, and to discuss the system's function of decreasing toxicity. METHOD: BCA was used as carrier material. The preparation through overall feedback dynamic techniques. The properties of preparation and toxicology were also technology of nanoparticles was optimized studied. Thenanoparticles' targeting in mice vivo was observed with transmission electron microscopy. The function of decreasing toxicity was researched by the XXTX-2000 automatic quantitative analysis management system. RESULT: D50 was 0.68 microm. Drug-loading rate and entrapment rate were 37.3% and 88.6% respectively. The release in vitro accorded with Weibull equation. The reaching release balance time and the t 1/2 extended 26 times and 19 times respectively comparing with injection. Nanoparticles mainly distributed in liver tissue. Their toxicity to lung and liver was evidently lower than injection. Nanoparticles' LD50 exceeded injection's by 13.5% and their stimulus was much lower than injection. CONCLUSION: The TBMS can be targeted to liver by liver targeted drug delivery system. At the same time, the problem about the toxicity hindering clinical application could be solved, which lays the foundation for the further studies on TBMS.

Animals↗

PubMedDate not supplied

Synthesis and characterization of a hemoglobin-ribavirin conjugate for targeted drug delivery.

A novel conjugate of human hemoglobin (Hb) and the nucleoside analogue ribavirin (RBV) was synthesized to demonstrate the utility of Hb as a biocompatible drug carrier for improved drug delivery in the treatment of liver disease. RBV is used in combination with interferon for the treatment of hepatitis C, but its side effects can result in dose limitation or discontinuation of treatment. Targeted delivery of RBV may help to prevent or minimize its toxicity. The hemoglobin-ribavirin conjugate (Hb-RBV) was designed to release bioactive drug upon endocytosis by cells and tissues involved in extracellular Hb catabolism and clearance. Ribavirin-5'-monophosphate (RBV-P) was prepared from RBV and activated as the 5'-monophosphorimidazolide (RBV-P-Im) for reaction with carbonmonoxyhemoglobin to yield Hb-RBV consisting of multiple RBV drugs covalently attached as physiologically labile phosphoramidates via their 5'-hydroxyl groups. A molar drug ratio of six to eight RBV molecules per Hb tetramer was obtained with near complete haptoglobin (Hp) binding of the drug modified Hb maintained. The conjugate complex (Hp-Hb-RBV) was selectively taken up in vitro by cells that express the hemoglobin-haptoglobin receptor, CD163. Recovered ribavirin enzymatically cleaved from Hb-RBV showed equipotent antiproliferative activity compared to control unconjugated RBV against human HepG2 and mouse AML12 liver cell lines. Based upon the reported high level of Hb uptake in the liver, Hb-RBV may be useful in the treatment of certain liver diseases, as well as inflammatory disorders associated with CD163-positive macrophages.

Animals↗

PubMedDate not supplied

Targeted vascular delivery of antisense molecules using intravenous microbubbles.

OBJECTIVE: Perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind the antisense to the c-myc protooncogene (anti-c-myc) which prevents neointimal hyperplasia following vascular endothelial injury. The microbubbles also adhere to sites of damaged vascular endothelium and thus may be a method of systemically targeting delivery of anti-c-myc. METHODS: Laser scanning microscopy was performed on the aorta of 10 mice (five which were complement depleted) that received intravenous FITC-PESDA following aortic endothelial injury. C-myc expression was quantified following selective intracoronary injury in nine pigs that received intravenous (IV) anti-c-myc bound to PESDA. Finally, neointimal formation was measured following intracoronary stent deployment in 30 pigs that received either IV anti-c-myc alone or the same dose bound to PESDA. RESULTS: Fluorescent microscopy confirmed selective PESDA microbubble adherence to aortic endothelium in all mice with aortic injury. This binding was nearly abolished when serum complement was depleted prior to injury. C-myc expression at the site of coronary endothelial injury was significantly lower in pigs treated with systemic anti-c-myc bound to PESDA. There was a 33% reduction in % stenosis and a 28% reduction in intimal area at 45 days post-stent deployment in pigs that received IV antisense plus PESDA. The stent margins also had reduced neointimal formation. CONCLUSION: Systemic administration of anti-c-myc bound to PESDA microbubbles may be a good method for preventing coronary neointimal formation within and around implanted stents.

Analysis of Variance↗