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At least 235 records · Page 13Linked to original sources
PubMed2004

Conjugation of an antibody to cross-linked fibrin for targeted delivery of anti-restenotic drugs.

There is an urgent need to treat restenosis, a major complication of the treatment of arteries blocked by atherosclerotic plaque, using local delivery techniques. We observed that cross-linked fibrin (XLF) is deposited at the site of surgical injury of arteries. An antibody to XLF, conjugated to anti-restenotic agents, should deliver the drugs directly and only to the site of injury. An anti-XLF antibody (H93.7C.1D2/48; 1D2) was conjugated to heparin (using N-succinimidyl 3-(2-pyridyldithio)propionate), low molecular weight heparin (LMWH) (adipic acid dihydrazide) and rapamycin (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide), and the conjugates purified and tested for activity before use in vivo. Rabbits had their right carotid arteries de-endothelialised and then given a bolus of 1D2-heparin, 1D2-LMWH or 1D2-rapamycin conjugate or controls of saline, heparin, LMWH, rapamycin or 1D2 (+/-heparin bolus) and sacrificed after 2 or 4 weeks (12 groups, n=6/group). Rabbits given any of the conjugates had minimal neointimal development in injured arteries, with up to 59% fewer neointimal cells than those given control drugs. Rabbits given 1D2-heparin or 1D2-LMWH had an increased or insignificant reduction in luminal area, with positive remodelling, while the medial and total arterial areas of rabbits given 1D2-rapamycin were not affected by injury. Arteries exposed to 1D2-heparin or 1D2-rapamycin had more endothelial cells than rabbits given control drugs. Thus, XLF-antibodies can site-deliver anti-restenotic agents to injured areas of the artery wall, where the conjugates can influence remodelling, re-endothelialisation and neointimal cell density, with reduced neointimal formation.

Animals↗
PubMed2005

Structural optimization of a "smart" doxorubicin-polypeptide conjugate for thermally targeted delivery to solid tumors.

A thermoresponsive, genetically engineered, elastin-like polypeptide (ELP) containing a C-terminal cysteine residue was synthesized and purified by inverse transition cycling (ITC) and conjugated to doxorubicin (Dox) molecules through four different pH-sensitive, maleimide-activated, hydrazone linkers. The efficiency of Dox activation, conjugation ratios to ELP and biophysical characterization-hydrodynamic radius (Rh) and the temperature transition kinetics-of the ELP-Dox conjugates and pH-mediated release of Dox were quantified in this study. Conjugation ratios of the maleimide-activated Dox to the thiol group of a unique cysteine in the ELP were close to unity. The Rh of the conjugate increased as the linker length between the ELP backbone and Dox was increased. The linker structure and length had little effect on the Tt of the ELP-Dox conjugates, as all conjugates exhibited Tt's that were similar to the native ELP. However, the ELP-Dox conjugates with longer linkers exhibited slower transition kinetics compared to the ELP-Dox conjugates with shorter linkers. The highest release of the ELP-Dox conjugate by cleavage of the hydrazone bond at pH 4 was nearly 80% over 72 h and was exhibited by the conjugate with the shortest linker.

Antibiotics, Antineoplastic↗
PubMed2003

Targeted delivery of an ssrA-tagged substrate by the adaptor protein SspB to its cognate AAA+ protein ClpX.

In the bacterial cytosol, degradation of ssrA-tagged proteins is primarily carried out by the proteolytic machine ClpXP in a process which is stimulated by a ClpX-specific adaptor protein, SspB. Here we elucidate the steps required for binding and transfer of ssrA-tagged substrates from SspB to ClpX. The N-terminal region of SspB is essential for its interaction with ssrA-tagged substrates, while a short conserved region at the C terminus of SspB interacts specifically with the N domain of ClpX. A single point mutation within the conserved C-terminal region of SspB is sufficient to abolish the SspB-mediated degradation of ssrA-tagged proteins by ClpXP. We propose that this region represents a common motif for the recognition of ClpX as the C-terminal region of SspB shares considerable homology with the other ClpX-specific adaptor protein, RssB. Through docking of SspB to the N-terminal domain of ClpX, the substrate is delivered to the substrate binding site in ClpX.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2004

Targeted delivery of progenitor cells for cartilage repair.

An approach for promoting the adherence of chondrogenic progenitor cells to specific matrix molecules has been tested in a cartilage defect model. Culture-expanded pre-chondrocytes fluorescently labeled with a vital dye were coated by a two-step method wherein lipidated protein G was first allowed to intercalate into cell membranes, and a second incubation in a solution of antibodies to cartilage matrix antigens allowed the binding of the antibodies to the protein G, on the external surface of the cell. The coating technique (termed "cell painting") does not effect cell viability or inhibit growth and chondrogenic potential. Painted cells were then added to rabbit cartilage explants that had a partial-thickness defect, washed, and prepared for histological examination and for confocal microscopy. The histological observations and the confocal observations and fluorescent intensity quantification consistently demonstrated that progenitor cells painted with multiple antibodies were capable of preferential binding to the exposed cartilage matrix within the defect. These results demonstrate that painting cell membranes with antibodies to matrix molecules is an effective method for promoting the adherence of stem or progenitor cells to a cartilage injury site.

Animals↗
PubMed2002

Evaluation of cationic solid lipid microparticles as synthetic carriers for the targeted delivery of macromolecules to phagocytic antigen-presenting cells.

Biodegradable microparticles represent a promising carrier system for the efficient delivery of therapeutic macromolecules to phagocytic professional antigen-presenting cells (APC). Solid lipid microparticles (SLM) consisting of a tripalmitin matrix were prepared using a novel micromixer-based solvent extraction process. A positive surface charge was introduced by the incorporation of cationic lipids into the formulation. All obtained SLM were efficiently phagocytosed by primary macrophages in vitro. Complete intracellular degradation was observed already within 24 h, making SLM a suitable carrier for the immediate delivery of therapeutics to APC. Cationic SLM adsorbed plasmid DNA and bovine serum albumin (BSA) used as a model protein, and triggered the cellular internalization of the macromolecules by phagocytic macrophages. Surprisingly, the cationic SLM also triggered the internalization of these molecules by non-phagocytic 293 cells. This was probably due to the detachment of nanocomplexes formed of cationic lipid and DNA or BSA, respectively, from the surface of DNA- or BSA-loaded SLM and their subsequent uptake into the cells. Transfection efficiency of the DNA-loaded SLM was most pronounced in non-phagocytic cells and was not detected in the macrophage cell line or in primary macrophages. Our further studies revealed that cytotoxic effects of cationic SLM were more pronounced in the phagocytic cells, which could be explained by the very rapid uptake and degradation of the cationic SLM in these cells. In conclusion, SLM may provide a new, efficient means for the immediate intracellular delivery of therapeutic macromolecules into APC. Caution is warranted for cationic carriers, which may accentuate cytotoxic effects in the phagocytic cells.

Adsorption↗
PubMed2001

Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS.

This review article describes three aspects of polymeric drugs. The general mechanism of the EPR (enhanced permeability and retention) effect and factors involved in the effect are discussed, in view of the advantages of macromolecular therapeutics for cancer treatment, which are based on the highly selective EPR-related delivery of drug to tumor. Also described are advantages of more general water-soluble polymeric drugs as primary anticancer agents, using SMANCS as an example. Last, SMANCS/Lipiodol is discussed with reference to the type of formulation for arterial injection with most pronounced tumor selective delivery, as well as its advantages, precautions, and side effects from the clinical standpoint.

Amino Acid Sequence↗
PubMed2001

Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier.

Doxorubicin (DXR) commonly used in cancer therapy produces undesirable side effects such as cardiotoxicity. To minimize these, attempts have been made to couple the drug with dextran (DEX) and then to encapsulate this drug conjugate in hydrogel nanoparticles. By encapsulation of the drug conjugate in biodegradable, biocompatible long circulating hydrogel nanoparticles, we further improved the therapeutic efficacy of the conjugate. The size of these nanoparticles as determined by quasi-elastic light scattering, was found to be 100+/-10 nm diameter, which favors the enhanced permeability and retention effect (EPR) as observed in most solid tumors. The antitumor effect of these DEX-DXR nanoparticles, was evaluated in J774A.1 macrophage tumor cells implanted in Balb/c mice. The in vivo efficacy of these nanoparticles as antitumor drug carriers, was determined by tumor regression and increased survival time as compared to drug conjugate and free drug. These results suggest that encapsulation of the conjugate in nanoparticles not only reduces the side effects, but also improves its therapeutic efficacy in the treatment of solid tumors.

Animals↗
PubMed1998

Targeted delivery of plasmid DNA complexed with galactosylated poly(L-lysine).

Galactose was introduced to poly(L-lysine) (PLL) with an average molecular weight of 13,000 to develop a hepatocyte-specific carrier for gene drugs. The pharmacokinetic characteristics of a model plasmid, pCAT (plasmid DNA encoding chloramphenicol acetyltransferase reporter gene), complexed with galactosylated PLL (Gal-PLL) was studied in mice in relation to its physicochemical properties. pCAT/Gal-PLL complex at a ratio of 1:0.6 (w/w) has a zeta potential of -20 mV and a mean particle size of about 180 nm. After intravenous injection, [32P]pCAT/Gal-PLL was rapidly eliminated from the circulation and preferentially taken up by the liver's parenchymal cells. The hepatic uptake of [32P]pCAT/Gal-PLL was significantly inhibited by prior administration of Gal-bovine serum albumin, suggesting that the uptake was mediated by the asialoglycoprotein receptors on hepatocytes. In vitro transfection experiments using a hepatoma cell line expressing the asialoglycoprotein receptor revealed that pCAT/Gal-PLL gave a high CAT gene expression whereas pCAT complexed with unmodified PLL failed to transfect the cells.

Animals↗
PubMed2002

Biodegradable poly(epsilon -caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen.

To increase the local concentration of tamoxifen in estrogen receptor (ER) positive breast cancer, we have developed and characterized nanoparticle formulation using poly(epsilon -caprolactone) (PCL). The nanoparticles were prepared by solvent displacement method using acetone-water system. Particle size analysis, scanning electron microscopy, zeta potential measurements, and differential scanning calorimetry (DSC) were used for nanoparticle characterization. Biodegradation studies were performed in the presence and absence of Pseudomonas lipase in phosphate-buffered saline (PBS, pH 7.4) at 37 degrees C. Tamoxifen loading over different concentrations was analyzed by high-performance liquid chromatography (HPLC) and the optimum loading concentration was determined. In vitro release studies were performed in 0.5% (w/v) sodium lauryl sulfate (SLS) containing PBS at 37 degrees C. Cellular uptake and distribution of fluorescent-labeled nanoparticles was examined in MCF-7 breast cancer cells. SEM micrographs and Coulter analysis showed nanoparticles with spherical shape and uniform size distribution (250-300 nm), respectively. Zeta potential analysis revealed a positive surface charge of +25 mV on the tamoxifen-loaded formulation. Being hydrophobic crystalline polyester, PCL did not degrade in PBS alone, but the degradation was enhanced by the presence of lipase. The maximum tamoxifen loading efficiency was 64%. Initial burst release of tamoxifen was observed, probably due to significant surface presence of the drug on the nanoparticles. A large fraction of the administered nanoparticle dose was taken up by MCF-7 cells through non-specific endocytosis. The nanoparticles were found in the perinuclear region after 1 h. Results of the study suggest that nanoparticle formulations of selective ER modulators, like tamoxifen, would provide increased therapeutic benefit by delivering the drug in the vicinity of the ER.

Absorbable Implants↗
PubMedDate not supplied

Development of EGF-conjugated liposomes for targeted delivery of boronated DNA-binding agents.

Liposomes are of interest as drug delivery tools for therapy of cancer and infectious diseases. We investigated conjugation of epidermal growth factor, EGF, to liposomes using the micelle-transfer method. EGF was conjugated to the distal end of PEG-DSPE lipid molecules in a micellar solution and the EGF-PEG-DSPE lipids were then transferred to preformed liposomes, either empty or containing the DNA-binding compound, water soluble acridine, WSA. We found that the optimal transfer conditions were a 1-h incubation at 60 degrees C. The final conjugate, (125)I-EGF-liposome-WSA, contained approximately 5 mol % PEG, 10-15 EGF molecules at the liposome surface, and 10(4) to 10(5) encapsulated WSA molecules could be loaded. The conjugate was shown to have EGF-receptor-specific cellular binding in cultured human glioma cells.

Acridines↗
PubMed2003

Structure-activity relationships in carboxamide derivatives based on the targeted delivery of radionuclides and boron atoms by means of peripheral benzodiazepine receptor ligands.

The structure-activity relationship studies on 2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands have been refined with the aim of using these ligands as carriers of radionuclides and boron atoms. Some new ligands show enhanced affinity and steroidogenic activity with respect to reference compound 1 and are interesting candidates for radiolabeling and PET studies. Moreover, carborane derivative 3q, representing the first example of PBR ligand bearing a carborane cage, can be useful to explore an alternative mechanism in BNCT.

Amides↗
PubMed1989

Macromolecular prodrugs. XVI. Colon-targeted delivery--comparison of the rate of release of naproxen from dextran ester prodrugs in homogenates of various segments of the pig gastrointestinal (GI) tract.

We have determined initial rates of naproxen formation from dextran-naproxen ester prodrugs incubated in homogenates of various segments of the pig GI tract. Drug liberation proceeded 15-17 times faster in cecum and colon homogenates than in aqueous pH 7.4 buffer or homogenates of the small intestine. The degree of conjugate substitution did not affect the liberation rates, whereas enhanced drug activation was observed with decreasing molecular size of the carrier dextran. During incubation in colon homogenates the average molecular weight of the dextran prodrugs decreased. The mechanism of drug activation from the prodrugs may therefore involve an initial depolymerization step of the dextran chains by dextranases secreted from bacteria in the pig colon. The generated small fragments then serve as substrates for esterases and other hydrolases.

Animals↗
PubMed1989

Macromolecular prodrugs. XV. Colon-targeted delivery--bioavailability of naproxen from orally administered dextran-naproxen ester prodrugs varying in molecular size in the pig.

The bioavailability of naproxen after oral administration of aqueous solutions of various dextran-naproxen ester prodrugs in pigs was determined. The dextran prodrugs employed ranged in molecular weight from 10,000 to 500,000. As calculated relative to an equivalent oral dose of parent naproxen, the absorption fractions of all the derivatives were close to 100%. Only small interindividual variation of naproxen bioavailability was observed. The naproxen plasma profiles for all the administered prodrugs exhibited a characteristic lag time of naproxen appearance in the blood (2-3 hr). Compared to administration of the prodrugs alone, coadministration of excess of the parent dextran further delayed the absorption of naproxen from the GI tract. The results of the present study demonstrate the potential of dextran prodrugs for colon site-specific delivery of drugs containing a carboxylic acid functional group.

Administration, Oral↗