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  • 1
    ISSN: 1520-4812
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1520-5835
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Macromolecules 25 (1992), S. 5451-5456 
    ISSN: 1520-5835
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1520-4812
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature America Inc.
    Nature biotechnology 17 (1999), S. 1101-1104 
    ISSN: 1546-1696
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: [Auszug] We have designed a new pathway for the synthesis of targeted polymeric drug delivery systems, using polymerizable antibody Fab′ fragments (MA-Fab′). The targeted systems can be directly prepared by copolymerization of the MA-Fab′, N-(2-hydroxypropyl)methacrylamide (HPMA) and ...
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  • 6
    ISSN: 1573-904X
    Keywords: adriamycin ; doxorubicin ; HPMA copolymer ; apoptosis, multidrug resistance ; gene expression ; signal transduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study peculiarities and the mechanism of the anticancer effect of free and HPMA copolymer-bound ADR in sensitive and resistant human ovarian carcinoma cells. Methods. Sensitive A2780 and ADR resistant A2780/AD cells were exposed to different doses of drugs during 12, 24, 36, 48, 60, and 72 hours. Cell viability, drug accumulation, apoptosis, cellular metabolism, lipid peroxidation, DNA content and gene expression were studied. Results. HPMA copolymer-bound ADR (P(GFLG)-ADR) possessed a comparable cytotoxicity to free ADR when comparison was based on intracellular concentrations. While free ADR up-regulated genes encoding ATP driven efflux pumps (MDR1, MRP), P(GFLG)-ADR overcame existing pumps and down regulated the MRP gene. Free ADR also activated cell metabolism and expression of genes responsible for detoxification and DNA repair. P(GFLG)-ADR down-regulated HSP-70, GSr-π, BUDP, Topo-IIα, β, and TK-1 genes. Apoptosis, lipid peroxidation and DNA damage were significantly higher after exposure to P(GFLG)-ADR, as reflected by simultaneous activation of p53, c-fos in A2780 cells) or c-jun (A2780/AD) signaling pathways and inhibition of the bcl-2 gene. Differences between free ADR and P(GFLG)-ADR increased with the time of incubation and drug concentration. Conclusions. P(GFLG)-ADR overcame drug efflux pumps, more significantly induced apoptosis and lipid peroxidation, inhibited DNA repair, replication, and biosynthesis when compared to free ADR.
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  • 7
    ISSN: 1573-904X
    Keywords: T-cells ; B-cells ; HPMA copolymer ; drug carrier ; targeting ; cancer therapy ; CD21 receptor ; adriamycin ; doxorubicin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The EDPGFFNVE nonapeptide (NP) was recognized as the CD21 (CR2) binding epitope of the Epstein-Barr virus (EBV) gp350/ 220 envelope glycoprotein which mediates the virus attachment to human B lymphocytes (Nemerow et al., Cell 56:369-377, 1989). Here we evaluated the targeting potential of a synthetic receptor binding epitope (NP) covalently attached to a water-soluble polymeric drug carrier. In particular, the biorecognition of N-(2-hydroxypropyl) metha-crylamide (HPMA) copolymer-NP conjugates by B- and T-cells and the cytotoxicity of HPMA copolymer-NP-adriamycin (ADR) conjugates toward B-cells, T-cells, and peripheral blood lymphocytes (PBL) were evaluated. Methods. HPMA copolymer-NP and optionally ADR conjugates varying in the NP density and mode of NP attachment were incubated with Raji B-cells (human Burkitt's lymphoma), CCRF-CEM T-cells (acute human lymphoblastic leukemia), and CCRF-HSB-2 T-cells (human lymphoblastic leukemia). The kinetics of binding was studied, the Langmuir adsorption isotherms analyzed, binding constants calculated, and IC50 doses determined. Results. Flow cytometry studies revealed that binding was homogeneous to both cell types. The apparent binding constants to T-cells were about two times higher when compared to B-cells. The binding and cytotoxicity increased with increased amount of epitopes per polymer chain. Attachment of the NP via a GFLG spacer resulted in increased biorecognition when compared with conjugates containing NP bound via a GG spacer. HPMA copolymer-NP-ADR conjugates possessed specific cytotoxicity to T- and B-malignant cells. Concentrations, which were lethal to the latter, were not toxic for PBL. Conclusions. The data obtained seem to indicate the potential of the HPMA copolymer-NP conjugates as polymer anticancer drug carriers targetable to immunocompetent cells.
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  • 8
    ISSN: 1573-904X
    Keywords: HPMA copolymer ; enhanced permeability and retention effect ; VEGF gene ; antitumor activity ; necrosis ; doxorubicin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the influence of cytotoxicity of macromolecules,VEGF gene expression, and vascular permeability on the enhancedpermeability and retention (EPR) effect. Methods. Mice bearing xenografts of A2780 multidrug resistant humanovarian carcinoma were treated by free doxorubicin (DOX) andN-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound DOX(P(GFLG)-DOX), Texas Red (P-TR), and FITC (P-FITC). Antitumoractivity, drug distribution in tumor, vascular permeability, VEGF geneexpression, and DNA fragmentation were studied. Results. The accumulation of free DOX led to the VEGF geneoverexpression and increased the vascular permeability, which in turnenhanced the drug accumulation in the same location. This positivefeedback loop led to a highly inhomogeneous distribution of the drugwithin the tumor. In contrast, P(GFLG)-DOX down-regulated theVEGF gene and decreased vascular permeability. This negativefeedback seemed to prevent additional drug accumulation in dead necrotictissue, resulting in a more uniform drug distribution and enhanced theantitumor activity P(GFLG)-DOX. Conclusions. The EPR effect significantly differed for macromoleculescontaining DOX when compared to macromolecules without drug. Thecytotoxicity of P(GFLG)-DOX amplified the EPR effect, led to amore homogenous distribution of the drug, increased the average drugconcentration in tumor and augmented its efficacy.
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  • 9
    Electronic Resource
    Electronic Resource
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 191 (1990), S. 2037-2045 
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers (11a, b) containing side chains terminating in 5-aminosalicylic acid (5-ASA) and fucosylamine (10) were synthesized. A reactive polymeric precursor (9), a copolymer of HPMA (7) and N-methacryloylglycylglycine p-nitrophenyl ester (8), was consecutively aminolyzed with 5-[4-(2-aminoethylcarbamoyl)phenylazo]-salicylic acid (6) and fucosylamine (10). The latter renders the copolymers bioadhesive in the gastrointestinal tract. The release of 5-ASA from 11a, b was studied in vitro by incubation with cell-free extracts isolated from rat cecum, and factors influencing the degradation were determined. The rate of azo bond cleavage of 11a, b was similar to the rate of cleavage of low-molecular-weight substrates, methyl orange and compound 6. Addition of benzyl viologen, a low potential electron carrier, increased the rate of cleavage. At optimal benzyl viologen and substrate concentration ratios, a zero order release was observed. At higher substrate concentration, the rate of 5-ASA release decreased.
    Additional Material: 4 Ill.
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  • 10
    Electronic Resource
    Electronic Resource
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 193 (1992), S. 2605-2619 
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: N-(2-Hydroxypropyl)methacrylamide copolymers containing oligopeptide side chains terminated with p-nitroaniline, and low-molecular-weight oligopeptide p-nitroanilides, were synthesized. They were used as substrates to evaluate the enzymatic activity in the gastrointestinal tract of guinea pigs. Brush border membrane enzymes and luminal enzymes (supernatant and pellet) were isolated from guinea pig small intestine and colon, and the cleavage of the substrates was studied in vitro. The results indicate the presence of endopeptidase activity in both small intestine and colon brush border. Phosphoramidon, a potent inhibitor of endopeptidase-24.11, was effective in the cleavage of low-molecular-weight substrates, but ineffective in the cleavage of polymeric substrates, indicating the participation of a different endopeptidase in the cleavage of the latter. Luminal enzymes were more active in the cleavage of polymeric substrates (when compared to low-molecular-weight ones) in accordance with the physiological function of the gastrointestinal tract. The enzymatic activity, both luminal and brush border, was considerably lower in the colon than in the small intestine. This suggests that the colon might be a suitable site for the oral delivery of peptides and proteins.
    Additional Material: 2 Ill.
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