J Kopecek

University of Utah, Salt Lake City, Utah, United States

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Publications (218)735.02 Total impact

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    S C Miller · H Pan · D Wang · B M Bowman · P Kopecková · J Kopecek
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    ABSTRACT: Macromolecular delivery systems have therapeutic uses because of their ability to deliver and release drugs to specific tissues. The uptake and localization of HPMA copolymers using Asp(8) as the bone-targeting moiety was determined in aged, ovariectomized (ovx) rats. PGE(1) was attached via a cathepsin K-sensitive linkage to HPMA copolymer-Asp(8) conjugate and was tested to determine if it could promote bone formation. The uptake of FITC-labeled HPMA copolymer-Asp(8) conjugate (P-Asp(8)-FITC) on bone surfaces was compared with the mineralization marker, tetracycline. Then a targeted PGE(1)-HPMA copolymer conjugate (P-Asp(8)-FITC-PGE(1)) was given as a single injection and its effects on bone formation were measured 4 weeks later. P-Asp(8)-FITC preferentially deposited on resorption surfaces, unlike tetracycline. A single injection of P-Asp(8)-FITC-PGE(1) resulted in greater indices of bone formation in aged, ovx rats. HPMA copolymers can be targeted to bone surfaces using Asp(8), with preferential uptake on resorption surfaces. Additionally, PGE(1) attached to the Asp(8)-targeted HPMA copolymers and given by a single injection resulted in greater bone formation measured 4 weeks later. This initial in vivo study suggests that macromolecular delivery systems targeted to bone may offer some therapeutic opportunities and advantages for the treatment of skeletal diseases.
    Full-text · Article · Sep 2008 · Pharmaceutical Research
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    ABSTRACT: The synergism in anticancer effect toward human renal carcinoma A498 cells by binary combinations of free and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound anticancer drugs, SOS thiophene (SOS), doxorubicin (DOX), and mesochlorin e6 monoethylenediamine (Mce6), was evaluated. The combination index (CI) analysis was used to quantify the synergism, antagonism, and additive effects. Both free drugs and HPMA copolymer conjugates, when used as single agents or in combination, exhibited cytotoxic activities against A498 cells, as determined using a modified MTT assay. As single agents, SOS and P-GFLG-SOS (HPMA copolymer conjugates containing SOS bound via glycylphenylalanylleucylglycine [GFLG] spacer) were significantly more effective than the other agents evaluated. The synergistic effects ranked in the order SOS+DOX>P-GFLG-DOX+P-GFLG-Mce6 approximately DOX+Mce6>P-GFLG-SOS+P-GFLG-DOX approximately SOS+Mce6>P-GFLG-SOS+P-GFLG-Mce6. The combination of SOS+DOX proved to be synergistic over all cell growth inhibition levels. All other combinations exhibited synergism in a wide range of drug effect levels. The SOS+Mce6 and P-GFLG-SOS+P-GFLG-Mce6 combinations displayed synergism up to drug affected fraction (fa) values of about 0.8 and reached slight antagonism and nearly additivity at fa=0.95, respectively. However, all other combinations were synergistic up to fa<0.9 and were additive at higher fa values. The observations that most combinations produced synergistic effects will be important for clinical translation.
    Preview · Article · Mar 2008 · International Journal of Pharmaceutics
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    A Malugin · P Kopecková · J Kopecek
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    ABSTRACT: Despite intensive study, the molecular mechanism for cell toxicity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound doxorubicin remains unclear. Moreover, the ability of the released drug to accumulate in the nucleus has also been questioned. We have hypothesized that the pattern of cell cycle progression is a useful indicator for the presence of free doxorubicin in the nucleus and its interaction with nuclear DNA. The effects of HPMA copolymer-bound doxorubicin on cell cycle progression were evaluated in this study in cultured human ovarian cancer A2780 cells. We determined that P-GFLG-DOX, but not P-GG-DOX, initiates cell cycle arrest and nuclear fragmentation in the same manner as free DOX, but with a time-delay. Our data indicate that drug release from the conjugate is required for the apoptotic activity associated with the conjugate.
    Full-text · Article · Jan 2008 · Journal of Controlled Release
  • B. Obereigner · M. Burešová · A. Vrána · J. Kopeček
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    ABSTRACT: Polymerizable derivatives of an antidiabetic N-(4-aminobenzenesulfonyl)-N′-butylurea were prepared. Hypoglycemic effects of sodium salts of the starting drug, the monomers, and their copolymers with N-(2-hydroxypropyl) methacrylamide were investigated.
    No preview · Article · Mar 2007 · Journal of Polymer Science Polymer Symposia
  • J. Kopeček · P. Rejmanová
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    ABSTRACT: Polymeric amine (Ia) was prepared by reacting a copolymer of N-(2-hydroxypropyl) methacrylamide (HPMA) and N-methacryloyl ρ-aminocaproyl L-leucine p-nitrophenyl ester with 1,6-diaminohexane in excess. The rate of reaction of (Ia) with reactive copolymers of HPMA and p-nitrophenyl esters of methacryloylated amino acids was investigated. The results indicate that interpenetration of polymeric coils occurs in dimethylsulfoxide solution! . A study of the stability of cross-links towards chymotrypsin in vitro showed that in addition to steric factors, subsite interactions between substrate and chymotrypsin must also be borne in mind. An aimed synthesis of crosslinks allowing such interactions leads to an increase in the enzymatic degradability of the polymers studied.
    No preview · Article · Mar 2007 · Journal of Polymer Science Polymer Symposia
  • K. Ulbrich · J. Kopeček
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    ABSTRACT: By using radical solution copolymerization of N,N-diethylacrylamide and N-tert-butylacrylamide in the presence of a small amount of the cross-linking agent, gels were prepared swollen to equilibrium in water at 25°C and possessing much better mechanical properties (elongation at break, stress at break) than those of the cross-linked poly-(N,N-diethylacrylamide) alone. This is probably due to an increased possibility of hydrophobic interactions of copolymers. At the same time, the effect of the comonomer structure on the mechanical properties of the resulting gel is considered. The equilibrium degree of swelling of the gels steeply decreases with increasing temperature. Some parameters are compared which characterize the three-dimensional network prepared both by the cross-linking polymerization of N,N-diethylacrylamide and by its copolymerization with N-tert-butylacrylamide (moduli of elasticity, X parameters, concentration of elastically effective chains, crosslinking effectivity, etc.), and the effect of these quantities on the gel properties is discussed.
    No preview · Article · Mar 2007 · Journal of Polymer Science Polymer Symposia
  • D Wang · W Li · M Pechar · P Kopecková · D Brömme · J Kopecek
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    ABSTRACT: The role of the newly discovered cysteine protease, cathepsin K, in osteoporosis and rheumatoid arthritis is reviewed. The current development of cathepsin K inhibitors and their targeted delivery using synthetic polymer carriers are discussed. Future challenges and possible strategies to improve these delivery systems are addressed.
    No preview · Article · Jul 2004 · International Journal of Pharmaceutics
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    ABSTRACT: N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymers have been shown to be efficient carriers for anticancer drugs because of their versatile chemistry and good biocompatibility. As demonstrated with hepatocytes, targeting efficacy of anticancer drugs could be further improved when the drug (doxorubicin) was conjugated to HPMA copolymers with biorecognisable groups, such as simple carbohydrates. The present study was devised to learn whether the cluster (multivalent) construction of carbohydrate residues could improve the targeting capability of HPMA copolymer-doxorubicin (DOX) conjugates towards human colon adenocarcinoma cells. DOX was linked via a lysosomally degradable tetrapeptide sequence to HPMA copolymers bearing galactosamine (GalN), lactose (Lac), or multivalent galactose residues (TriGal) to produce targetable polymeric drug carriers. The effect of the type of sugar moiety and its three-dimensional cluster arrangement on biorecognition by three human colon-adenocarcinoma cell lines was studied. The role of galectin-3 in the biorecognition of HPMA copolymer conjugates was explored. Biorecognition of the targetable (glycoside-bearing) conjugates decreased their IC(50) doses in comparison to the non-targetable (non-glycosylated) conjugates. The biorecognition of the TriGal-containing HPMA copolymer-doxorubicin conjugate by the cells was superior with concomitant decrease of its IC(50) doses. It is suggested that the increased cytotoxicity of the glycosylated HPMA-copolymer-DOX conjugates toward human colon-adenocarcinoma cells was caused by their biorecognition and effective internalisation via receptor-mediated endocytosis. All three human colon adenocarcinoma cell lines tested, Colo-205, SW-480 and SW-620, expressed the galectin-3 protein and the galectin-3-specific RNA. However, contrary to expectation, Colo-205 cells did not express a detectable amount of galectin-3 on the cell surface. This suggests that the binding of the glycoside-bearing HPMA copolymer-DOX conjugates to the cells was mediated not only by galectin-3. We conclude that targeting of the anticancer agent, doxorubicin, using HPMA copolymer conjugates bearing multivalent galactoside residues can improve their cytotoxicity.
    No preview · Article · Feb 2004 · European Journal of Cancer
  • J Kopecek · YF Hallock · SE Tabibi

    No preview · Article · Aug 2003 · Journal of Controlled Release
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    ABSTRACT: Water-soluble copolymers based on poly[N-(2-hydroxypropyl)methacrylamide] and bearing in their side chains a chromogenic substrate for chymotrypsin were prepared by direct copolymerization or polymeranalogous reaction. The substrate was L-phenylalanine-4′-nitroanilide linked by its amino group to the terminal carboxylic group of the side chain. The cleavage of the substrate thus bonded, was expressed by means of the Michaelis constant, the maximum velocity, and the percentage of substrate unit accesible to the enzyme. The effect of length and chemical structure of the side chain was investigated in the first place. It was found that the chain must be longer than 6 atoms; longer chains are generally more favourable for this cleavage. The ε-aminocaproyl group provides a chain that is most favourable for the cleavage, whereas chains with several glycyl units, though longer, are less favourable. Polymers with higher content of the substrate units undergo cleavage more readily.Durch direkte Copolymerisation oder durch polymeranaloge Reaktion wurden auf der Basis von Poly[N-(2-hydroxypropyl)methacrylamid] wasserlösliche Copolymere hergestellt, die in Seitenketten farbige Substratgruppen für Chymotrypsin tragen. Substrat war L-Phenylalanin-p-nitroanilid, das über seine Aminogruppe an die endständige Carboxylgruppe der Seitenkette gebunden war. Die Spaltbarkeit des so gebundenen Substrates wurde durch die Michaelis-Konstante, durch die maximale Geschwindigkeit und durch den Prozentsatz an Substrateinheiten ausgedrückt, der für das Enzym zugänglich ist. Hauptsächlich wurde der Effekt der Länge und der chemischen Struktur der Seitenkette untersucht. Es wurde gefunden, daß sie länger als 6 Atome sein muß, daß allgemein die Spaltung durch längere Ketten begünstigt wird. Die ε-Aminocapryl-Gruppe als Seitenkette ist für die Spaltung am günstigsten, Während Seitenketten mit einigen Glycyl-Gruppen obwohl länger weniger günstig sind. Polymere mit einem höheren Gehalt an Substrateinheiten sind besser spaltbar.
    Full-text · Article · Mar 2003 · Die Makromolekulare Chemie
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    ABSTRACT: Copolymers of N-(2-hydroxypropyl)methacrylamide with p-nitrophenyl esters of (meth)acryloylaminophenoxyacetic acids were prepared and characterized. The aminolysis of monomeric and polymeric p-nitrophenyl esters by 6-aminopenicillanic acid was studied. The aminolysis rate was structure-dependent. Acryloyl derivatives were more reactive than methacryloyl derivatives. In both cases, the ortho-derivatives were more reactive than the para-derivatives. This phenomenon can be explained by the formation of an intramolecular hydrogen bond in the ortho-derivatives. The synthetic methods studied are suitable for the binding of biologically active compounds containing an aliphatic amino group to polymeric carriers.
    No preview · Article · Mar 2003 · Die Makromolekulare Chemie
  • J. Strohalm · J. Kopeček
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    ABSTRACT: Kinetics of radical heterogeneous polymerization of N-(2-hydroxypropyl)methacrylamide was studied in acetone at 55°C. The values of reaction order with respect to the monomer (1.6) and to the initiator (0.5) indicate a bimolecular termination and degradative transfer during the chain growth. The over-all rate constant of polymerization was found to be 5.6.10-4. Addition of a small amount of a solvent (methanol) to the polymerization mixture led to an increased polymerization rate and increased molecular weight of the resulting polymer, but a higher amount of the solvent brought about a decrease of both characteristics. The Occurence of maxima on the dependences of Rp, as well as M̄w on the monomer concentration was interpreted in terms of the classical Bamford and Jenkins theory.Die Kinetik der radikalischen, heterogenen Polymerisation von N-(2-Hydroxypropyl) methacrylamid wurde in Aceton bei 55°C untersucht. Die Reaktionsordnung, bezogen auf das Monomere (1.6) und auf den Initiator (0,5), deutet auf einen bimolekularen Abbruch und eine kettenverkiirzende hxtragungsreaktion hin. Die Gesamtgeschwindigkeitskonstante der Polymerisation wurde zu 5.6. gefunden. Die Zugabe einer kleinen Menge von Losungsmittel (Methanol) zur Polymerisationsmischung verursachte hohere Polymerisationsgeschwindigkeit und hoheres Molekulargewicht, aber größere Mengen von Losungsmittel erniedrigten beide Grokn. Das Auftreten eines Maximums bei R, und R, in Abhangigkeit von der Monomerkonzentration wurde nach der klassischen Bamford-Jenkins-Theorie diskutiert.
    No preview · Article · Mar 2003 · Angewandte Makromolekulare Chemie
  • J. Kopeček
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    ABSTRACT: Reactive copolymers of N-(2-hydroxypropyl)methacrylamide (1) with p-nitrophenyl esters of N-methacryloylglycyl-L-leucine (3a), N-methacryloylglycyl-L-phenylalanine (3b), N-methacryloyl-ε-aminocaproyl-L-leucine (7a), and N-methacryloyl-ε-aminocaproyl-L-phenylalanine (7b) (i.e. copolymers 8–11) were synthesized. The polymers thus obtained were characterized by the content of active groups, by intrinsic viscosity [η], and by the rate constant of aminolysis with tert-butylamine in dimethyl sulfoxide. Polymers containing free NH2 groups were prepared by a polymeranalogous reaction with diamines, predominantly 1,6-hexanediamine. The effect of the copolymer structure, of diamine, and of the reaction conditions on the course of the polymeranalogous reaction was studied.
    No preview · Article · Mar 2003 · Die Makromolekulare Chemie
  • Z.-R. Lu · J.G. Shiah · P. Kopečková · J. Kopeček
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    ABSTRACT: The targeting activity of monoclonal antibodies in immunoconjugates is often impaired by random chemical conjugation, and decreaseswith a drug loading increase onto the antibody. We have developed a new approach to improve the efficiency of antibody targeting using a polymerizable antibody Fab'fragment (MA-Fab'). An antibody Fab'fragment targeted N-(2-hydroxypropy)methacrylamide (HPMA) copolymer-mesochlorin e6 (Mce6) conjugate (P-Fab'-Mce6) was prepared by the copolymerization of MA-Fab'(from OV-TL 16 antibody), HPMA and an Mce6 containing monomer for photodynamic cancer therapy. The molar ratio of Mce6 to Fab' in the conjugate was 11:1, controlled by the molar ratio of the monomers in copolymerization. The P-Fab'-Mce6 specific to the OA-3 antigen expressed on most human ovarian carcinomas, exhibited more efficient tumor targeting, and higher antitumor efficacy than an HPMA copolymer-Mce6 conjugate (P-Mce6) at the same Mce6 equivalent dose in nu/nu mice bearing s.c. human ovarian carcinoma OVCAR-3 xenografts. Treatment with P-Fab'-Mce6 at a single Mce6 equivalent dose of 6 mg/kg and an single light irradiation inhibited tumor growth for up to 6 weeks. Treatment with multiple administrations (1.5 mg/kg Mce6 equivalent x 3) and multiple irradiations demonstrated an improved therapeutic efficacy as compared with that of a single dose and irradiation.
    No preview · Article · Jan 2003
  • S Sakuma · ZR Lu · B Pecharova · P Kopeckova · J Kopecek
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    ABSTRACT: An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate containing 9-aminocamptothecin (9-AC) bound via a spacer containing an aromatic azo bond and leucylalanine (P-Azo-Leu-Ala-9-AC) was synthesized. The in vivo pharmacokinetic profile after oral administration was examined in rats and compared to free 9-AC. The aromatic azo bond of P-Azo-Leu-Ala-9-AC was stable in stomach and small intestine; the delivery of a large amount of intact conjugate to the colon was achieved. In the colon, the azoreductase activity first cleaved the azo bond followed by peptidase catalyzed cleavage of the leucylalanyl drug derivative resulting in the release of free 9-AC. However, the release rate from the conjugate was not fast enough to achieve high colon concentrations of free 9-AC. The results of the study suggest design features for the second generation of conjugates, including the use of a side-chain with a higher cleavage rate in the colon, combined with the incorporation of bioadhesion technology, to increase colon transit time.
    No preview · Article · Sep 2002 · Journal of Bioactive and Compatible Polymers
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    ABSTRACT: The development of macromolecules as drugs and drug carriers requires knowledge of their fate in cells. To this end, we studied the internalization and subcellular Fate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers in Hep G2 (human hepatocellular carcinoma) cells. Semiquantitative fluorometry confirmed that galactose was an effective ligand for receptor-mediated endocytosis for Hep G2 cells. The rate of internalization of a galactose-targeted copolymer was almost 2 orders of magnitude larger than that of the nontargeted copolymer. Confocal fluorescent microscopy of both fixed and live cells revealed that the polymer entered the cells by endocytosis. After longer incubation times (typically >8 hours), polymer escaped from small vesicles and distributed throughout the cytoplasm and nuclei of the cells. Polymer that entered the cytoplasm tended to accumulate in the nucleus. Microinjection of the HPMA copolymers into cells' cytoplasm and nuclei indicated that the polymers partitioned to the nucleus. The data from fixed cells was confirmed by microscopy of live, viable cells. To examine the effect of the fluorescent dye on the intracellular fate, polymers with fluorescein, Oregon Green 488, Lissamine rhodamine B, and doxorubicin were tested; no significant differences were observed.
    Preview · Article · Dec 2001 · AAPS PharmSci
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    ABSTRACT: N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing pendant saccharide moieties (galactosamine, lactose, and triantennary galactose) were synthesized. The relationship between the content of saccharide moieties and three-dimensional arrangement of galactose residues and their biorecognition and internalization by human hepatocarcinoma HepG2 cells was investigated. The results obtained clearly indicated preferential binding of the trivalent galactose and the lactose-containing copolymers to these cells. The higher the saccharide moieties content in HPMA copolymers, the higher the levels of binding. The biorecognition of the glycosylated HPMA copolymers by HepG2 cells was inhibited by free lactose. The data on the internalization and subcellular trafficking of HPMA copolymer conjugates obtained by confocal fluorescence microscopy correlated well with the flow cytometric analysis of their biorecognition by target cells. Structural features of the glycosides responsible for the specific recognition of the HPMA copolymers have been identified. The results underline the potential of glycosylated HPMA copolymers for delivery of pharmaceutical agents to hepatocarcinoma cells.
    No preview · Article · Nov 2001 · Bioconjugate Chemistry
  • Yuji Kasuya · ZR Lu · P Kopecková · J Kopecek
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    ABSTRACT: The 17-methoxy group of geldanamycin was substituted with 1,3-diaminopropane and 1,3-diamino-2-hydroxypropane to introduce a primary amino group useful for conjugation with targeting moieties and drug carriers. We have developed a procedure that has provided improved yield and reproducibility of the syntheses. Both geldanamycin derivatives demonstrated antiproliferative activity towards the human ovarian carcinoma cell line, A2780.
    No preview · Article · Sep 2001 · Bioorganic & Medicinal Chemistry Letters
  • S Sakuma · Z R Lu · P Kopecková · J Kopecek
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    ABSTRACT: N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates for colon-specific delivery of 9-aminocamptothecin (9-AC) were designed. They hold 9-AC bound via spacers containing amino acid residues and aromatic azo bonds. In vitro release profiles of 9-AC from HPMA copolymer conjugates were evaluated under artificial conditions that simulated large intestinal azoreductase and peptidase activities. The studies indicated that the azo bond was reduced first, followed by the release of unmodified 9-AC from the 9-AC containing fragment by peptidases. Release profiles depended on the chemical structure of the peptide part of the spacer. Conjugates containing leucylalanine showed high colon-specific release of 9-AC when compared to alanine containing conjugates. It appears that the studied conjugates are suitable as colon-specific drug delivery systems.
    No preview · Article · Aug 2001 · Journal of Controlled Release
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    ABSTRACT: N-(2-Hydroxypropyl)methacrylamide (HPMA)-lectin (wheat germ agglutinin (WGA), peanut agglutinin (PNA)) drug conjugates for treatment of the pre-cancerous conditions ulcerative colitis and Barrett's esophagus are being developed. Cell-surface glycoproteins that are altered in disease and development bind lectins. PNA binds alpha-lactose and the Thomsen-Friedenreich (TF) antigen, a disease- and development-associated glycoprotein. PNA incorporation in conjugates may allow for preferential delivery to diseased over healthy tissues. Conjugates were prepared by attaching lectins to HPMA copolymers via an amide linkage. Frontal affinity chromatography was used to measure dissociation constants (K(d)) of free and conjugated lectins. Animal models of colitis (DSS, TNBS/EtOH) were developed. Human biopsy specimens were obtained. Free and HPMA copolymer-conjugated FITC-labeled lectin and anti-TF antigen antibody binding patterns were examined in normal neonatal, adult and diseased rodent tissues and normal and diseased human tissues. K(d) values of free and conjugated lectins were similar ( approximately 10(-5) M(-1)). Free and conjugated lectins had comparable binding patterns. In health, strong WGA binding was seen in goblet cells; PNA binding was minimal, occurring only in the supranuclear goblet cell region. In disease, WGA binding was not altered, but PNA binding was increased in both human and rodent tissues; entire goblets bound the lectin. Anti-TF antigen antibody binding was minimal, but did overlap with PNA binding patterns both in normal and diseased tissues. Conjugation of lectins to HPMA copolymers does not affect binding affinity. Alterations in glycoprotein structures in development and disease resulted in modified lectin binding patterns. In development and disease, the PNA binding seen was to the TF antigen and other lactose-containing glycoproteins. The results suggest that site-specific delivery of therapeutic agents such as cyclosporin A (CsA) for ulcerative colitis and mesochlorin e(6) for Barrett's esophagus may be achieved. P(HPMA)-lectin-CsA conjugates have been prepared and preliminary in vivo studies are underway.
    No preview · Article · Aug 2001 · Journal of Controlled Release

Publication Stats

8k Citations
735.02 Total Impact Points

Institutions

  • 1988-2008
    • University of Utah
      • • Department of Pharmaceutics and Pharmaceutical Chemistry
      • • Department of BioEngineering
      • • Department of Obstetrics and Gynecology
      Salt Lake City, Utah, United States
  • 2001-2004
    • Hebrew University of Jerusalem
      • School of Pharmacy
      Jerusalem, Jerusalem District, Israel
  • 1968-2003
    • Institute of Macromolecular Chemistry
      Praha, Praha, Czech Republic
  • 1995
    • Academy of Sciences of the Czech Republic
      • Hydrobiologický ústav
      Praha, Hlavni mesto Praha, Czech Republic
  • 1980-1990
    • Keele University
      Newcastle-under-Lyme, England, United Kingdom
  • 1983
    • Russian Academy of Sciences
      • Institute of Macromolecular Compounds
      Moskva, Moscow, Russia
  • 1976
    • Institute for Clinical and Experimental Medicine (IKEM)
      Praha, Praha, Czech Republic