J Kopecek

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

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Publications (294)997.99 Total impact

  • Rui Zhang, Jiyuan Yang, Monika Sima, Yan Zhou, Jindřich Kopeček
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    ABSTRACT: For rapid and effective clinical translation, polymer-based anticancer therapeutics need long circulating conjugates that produce a sustained concentration gradient between the vasculature and solid tumor. To this end, we designed second-generation backbone-degradable diblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers and evaluated sequential combination therapy of HPMA copolymer-paclitaxel and HPMA copolymer-gemcitabine conjugates against A2780 human ovarian carcinoma xenografts. First, extensive in vitro assessment of administration sequence impact on cell cycle, viability, apoptosis, migration, and invasion revealed that treatment with paclitaxel conjugate followed by gemcitabine conjugate was the most effective scheduling strategy. Second, in an in vivo comparison with first-generation (nondegradable, molecular weight below the renal threshold) conjugates and free drugs, the second-generation degradable high-molecular weight conjugates showed distinct advantages, such as favorable pharmacokinetics (three- to five-times half-life compared with the first generation), dramatically enhanced inhibition of tumor growth (complete tumor regression) by paclitaxel and gemcitabine conjugate combination, and absence of adverse effects. In addition, multimodality imaging studies of dual-labeled model conjugates confirmed the efficacy of second-generation conjugates by visualizing more than five-times enhanced tumor accumulation, rapid conjugate internalization, and effective intracellular release of payload. Taken together, the results indicate that the second-generation degradable HPMA copolymer carrier can provide an ideal platform for the delivery of a range of antitumor compounds, which makes it one of the most attractive candidates for potential clinical application.
    Proceedings of the National Academy of Sciences of the United States of America. 08/2014;
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    ABSTRACT: A two-component CD20 (non-internalizing) receptor crosslinking system based on the biorecognition of complementary coiled-coil forming peptides was evaluated. Exposure of B cells to Fab'-peptide1 conjugate decorates the cell surface with peptide1; further exposure of the decorated cells to P-(peptide2)x (P is the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone) results in the formation of coiled-coil heterodimers at the cell surface with concomitant induction of apoptosis. The aim of this study was to determine the potential immunogenicity of this therapeutic system that does not contain low molecular weight drugs. Enantiomeric peptides (l- and d-CCE and l- and d-CCK), HPMA copolymer-peptide conjugates, and Fab' fragment-peptide conjugates were synthesized and the immunological properties of peptide conjugates evaluated in vitro on RAW264.7 macrophages and in vivo on immunocompetent BALB/c mice. HPMA copolymer did not induce immune response in vitro and in vivo. Administration of P-peptide conjugates with strong adjuvant resulted in antibody response directed to the peptide. Fab' was responsible for macrophage activation of Fab'-peptide conjugates and a major factor in the antibody induction following i.v. administration of Fab'-conjugates. There was no substantial difference in the ability of conjugates of d-peptides and conjugates of l-peptides to induce Ab response.
    Biomaterials 04/2014; 35(22):5886–5896. · 8.31 Impact Factor
  • Jiyuan Yang, Jindřich Kopeček
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    ABSTRACT: This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated.
    Journal of Controlled Release 04/2014; · 7.63 Impact Factor
  • Jindřich Kopeček
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    ABSTRACT: Jindřich Kopeček speaks to Hannah Stanwix, Managing Comissioning Editor: Jindřich Henry Kopeček received his PhD in Macromolecular Chemistry and DSc in Chemistry from the Czechoslovak Academy of Sciences (Czech Republic). His postdoctoral studies were at the National Research Council of Canada. He is currently a Distinguished Professor at the University of Utah (UT, USA) in Pharmaceutics and Pharmaceutical Chemistry, and Bioengineering. Dr Kopeček has received numerous awards in his career, including the Millennial Pharmaceutical Scientist accolade. His laboratory is credited with first developing N-(2-hydroxypropyl)methacrylamide copolymer as a delivery vehicle for cancer therapy. Dr Kopeček has authored and coauthored over 400 publications and been cited over 15,000 times.
    Nanomedicine 04/2014; 9(5):577-9. · 5.26 Impact Factor
  • Zheng-Hong Peng, Jindřich Kopeček
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    ABSTRACT: In this Letter, we present a concise strategy to prepare a conjugate of the tumor homing peptide iRGD and histone deacetylase inhibitor valproic acid, VPA-GFLG-iRGD. The conjugate VPA-GFLG-iRGD and a mixture of VPA and GFLG-iRGD have shown similar cytotoxicity against DU-145 prostate cancer cells. However, the treatment of DU-145 cells with conjugate VPA-GFLG-iRGD resulted in a decreased percentage of cells in the G2 phase, whereas the exposure of a mixture of VPA and GFLG-iRGD led to an increased percentage of cells in the G2 phase. We also found that GFLG-iRGD possessed cytotoxicity at the tested concentrations.
    Bioorganic & medicinal chemistry letters 03/2014; · 2.65 Impact Factor
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    ABSTRACT: A two-component CD20 (non-internalizing) receptor crosslinking system based on the biorecognition of complementary coiled-coil forming peptides was evaluated. Exposure of B cells to Fab'-peptide1 conjugate decorates the cell surface with peptide1; further exposure of the decorated cells to P-(peptide2)x (P is the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone) results in the formation of coiled-coil heterodimers at the cell surface with concomitant induction of apoptosis. The aim of this study was to determine the potential immunogenicity of this therapeutic system that does not contain low molecular weight drugs. Enantiomeric peptides (l- and d-CCE and l- and d-CCK), HPMA copolymer-peptide conjugates, and Fab' fragment-peptide conjugates were synthesized and the immunological properties of peptide conjugates evaluated in vitro on RAW264.7 macrophages and in vivo on immunocompetent BALB/c mice. HPMA copolymer did not induce immune response in vitro and in vivo. Administration of P-peptide conjugates with strong adjuvant resulted in antibody response directed to the peptide. Fab' was responsible for macrophage activation of Fab'-peptide conjugates and a major factor in the antibody induction following i.v. administration of Fab'-conjugates. There was no substantial difference in the ability of conjugates of d-peptides and conjugates of l-peptides to induce Ab response.
    Biomaterials 01/2014; 35(22):5886–5896. · 8.31 Impact Factor
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    Te-Wei Chu, Jiyuan Yang, Rui Zhang, Monika Sima, Jindřich Kopeček
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    ABSTRACT: Hybrid nanomaterials composed of synthetic and biological building blocks possess high potential for the design of nanomedicines. The use of self-assembling nanomaterials as “bio-mimics” may trigger cellular events and result in new therapeutic effects. Motivated by this rationale, we designed a therapeutic platform that mimics the mechanism of immune effector cells to cross-link surface receptors of target cells and induce apoptosis. This platform was tested against B-cell lymphomas that highly express the surface antigen CD20. Here, two nanoconjugates were synthesized: (1) an anti-CD20 Fab′ fragment covalently linked to a single-stranded morpholino oligonucleotide (MORF1), and (2) a linear polymer of N-(2-hydroxypropyl)methacrylamide (HPMA) grafted with multiple copies of the complementary oligonucleotide MORF2. We show that the two conjugates self-assemble via MORF1-MORF2 hybridization at the surface of CD20+ malignant B-cells, which cross-links CD20 antigens and initiates apoptosis. When tested in a murine model of human non-Hodgkin’s lymphoma, the two conjugates, either administered consecutively or as a premixture, eradicated cancer cells and produced long-term survivors. The designed therapeutics contains no small-molecule cytotoxic compounds and is immune-independent, aiming to improve over chemotherapy, radiotherapy and immunotherapy. This therapeutic platform can be applied to cross-link any noninternalizing receptor and potentially treat other diseases.
    ACS Nano 12/2013; 8(1):719-30. · 12.03 Impact Factor
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    ABSTRACT: Multiblock, backbone degradable HPMA copolymer-drug conjugates containing gemcitabine and DACH platinum (mP-GEM and mP-DACH Pt), respectively were synthesized by reversible additionfragmentation (RAFT) polymerization and subsequent chain extension by click chemistry. Using combination index analysis, the cytotoxicities of the two multiblock conjugates, as single agents and in combination, were evaluated in vitro in A2780 human ovarian cancer cells, with free drugs as controls. The greatest synergistic cytotoxic effect was observed when A2780 cells were sequentially exposed to mP-GEM for 24 h and mP-DACH Pt for 48 h. In addition, mechanistic studies support the rationale of the synergy between mP-GEM and mP-DACH Pt: mP-GEM pretreatment was able to enhance the platinum-DNA adduct accumulation and inhibit cell proliferation to a higher extent than single mPDACH Pt treatment. These observations are useful for the development of combination macromolecular therapeutics for ovarian cancer based on the second-generation backbone degradable HPMA copolymers.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 12/2013; · 3.15 Impact Factor
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    ABSTRACT: Abstract Combination of targeted delivery and controlled release is a powerful technique for cancer treatment. In this paper, we describe the design, synthesis, structure validation and biological properties of targeted and non-targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel conjugates. Docetaxel (DTX) was conjugated to HPMA copolymer via a tetrapeptide spacer (-GFLG-). 3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA) was used as the targeting moiety to actively deliver DTX for treatment of Prostate-Specific Membrane Antigen (PSMA) expressing prostate cancer. Short and long spacer DUPA monomers were prepared, and four HPMA copolymer - DTX conjugates (non-targeted, two targeted with short spacer of different molecular weight and targeted with long spacer) were prepared via Reversible Addition-Fragmentation Chain Transfer (RAFT) copolymerization. Following confirmation of PSMA expression on C4-2 cell line, the DTX conjugates' in vitro cytotoxicity was tested against C4-2 tumor cells and their anticancer efficacies were assessed in nude mice bearing s.c. human prostate adenocarcinoma C4-2 xenografts. The in vivo results show that the spacer length between targeting moieties and HPMA copolymer backbone can significantly affect the treatment efficacy of DTX conjugates against C4-2 tumor bearing nu/nu mice. Moreover, histological analysis indicated that the DUPA-targeted DTX conjugate with longer spacer had no toxicity in major organs of treated mice.
    Journal of Drug Targeting 12/2013; 21(10):968-80. · 2.77 Impact Factor
  • Yan Zhou, Jiyuan Yang, Johng S Rhim, Jindřich Kopeček
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    ABSTRACT: Current treatments for prostate cancer are still not satisfactory, often resulting in tumor regrowth and metastasis. One of the main reasons for the ineffective anti-prostate cancer treatments is the failure to deplete cancer stem-like cells (CSCs) - a subset of cancer cells with enhanced tumorigenic capacity. Thus, combination of agents against both CSCs and bulk tumor cells may offer better therapeutic benefits. Several molecules with anti-cancer stem/progenitor cell activities have been under preclinical evaluations. However, their low solubility and nonspecific toxicity limit their clinical translation. Herein, we designed a combination macromolecular therapy containing two drug conjugates: HPMA copolymer-cyclopamine conjugate (P-CYP) preferentially toxic to cancer stem/progenitor cells, and HPMA copolymer-docetaxel conjugate (P-DTX) effective in debulking the tumor mass. Both conjugates were synthesized using RAFT (reversible addition-fragmentation chain transfer) polymerization resulting in narrow molecular weight distribution. The killing effect of the two conjugates against bulk tumor cells and CSCs were evaluated in vitro and in vivo. In PC-3 or RC-92a/hTERT prostate cancer cells, P-CYP preferentially kills and impairs the function of CD133+ prostate cancer stem/progenitor cells; P-DTX was able to kill bulk tumor cells instead of CSCs. In PC-3 xenograft mice model, combination of P-DTX and P-CYP showed the most effective and persistent tumor growth inhibitory effect. In addition, residual tumors contained less CD133+ cancer cells following combination or P-CYP treatments, indicating selective killing of cancer cells with stem/progenitor cell properties.
    Journal of Controlled Release 09/2013; · 7.63 Impact Factor
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    ABSTRACT: The synthesis, characterization, and in vitro evaluation of a combination delivery of multiblock poly(N-2-hydroxypropyl)methacrylamide (HPMA) gemcitabine (GEM) and paclitaxel (PTX) conjugates is described in this study. Multiblock copolymer conjugates of a large molecular weight (Mw>200kDa) were studied and compared to traditional, small molecular weight (Mw<45kDa) conjugates. Stability of the conjugates in different pH was assessed, and their cytotoxicity in combination towards A2780 human ovarian cancer cells was evaluated by combination index analysis. Treatment duration (4 and 72h) and sequence of addition were explored. In addition, an HPMA copolymer conjugate with both GEM and PTX in the side chains was evaluated in a similar manner and compared to a physical mixture of individual conjugates. Conjugates with narrow molecular weight distribution (Mw/Mn<1.1) were obtained via RAFT polymerization, and drug loadings of between 5.5 and 9.2 wt% were achieved. Conjugates demonstrated moderate stability with less than 65% release over 24h at pH 7.4, and near complete drug release in the presence of the lysosomal enzyme cathepsin B in 3h. In combination, the cytotoxic effects of a mixture of the conjugates were primarily additive. Synergistic effects were observed when A2780 human ovarian cancer cells were treated simultaneously for 4h with multiblock conjugates (CI<0.7). When both GEM and PTX were conjugated to the same copolymer backbone, moderate antagonism (CI 1.3-1.6) was observed. These results demonstrate that multiblock HPMA copolymer-GEM and-PTX conjugates, when delivered as a mixture of individual agents, are promising for the treatment of ovarian cancer.
    International Journal of Pharmaceutics 07/2013; · 3.99 Impact Factor
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    ABSTRACT: Multiblock, high molecular weight, linear, backbone degradable HPMA copolymer-prostaglandin E1 (PGE1) conjugate has been synthesized by RAFT polymerization mediated by a new bifunctional chain transfer agent (CTA), which contains an enzymatically degradable oligopeptide sequence flanked by two dithiobenzoate groups, followed by postpolymerization aminolysis and thiol-ene chain extension. The multiblock conjugate contains Asp8 as the bone targeting moiety and enzymatically degradable bonds in the polymer backbone; in vivo degradation produces cleavage products that are below the renal threshold. Using an ovariectomized (OVX) rat model, the accumulation in bone and efficacy to promote bone formation was evaluated; low molecular weight conjugates served as control. The results indicated a higher accumulation in bone, greater enhancement of bone density, and higher plasma osteocalcin levels for the backbone degradable conjugate.
    Biomaterials 05/2013; · 8.31 Impact Factor
  • Huaizhong Pan, Monika Sima, Jiyuan Yang, Jindřich Kopeček
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    ABSTRACT: Backbone degradable, linear, multiblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (DOX) conjugates are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol-ene click reaction. The examination of molecular-weight-dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second-generation, higher molecular weight conjugates when compared with traditional HPMA copolymer-DOX conjugates. The examination of body weight changes during treatment indicates the absence of non-specific adverse effects.
    Macromolecular Bioscience 01/2013; · 3.74 Impact Factor
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    ABSTRACT: The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer-PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents.
    Journal of Controlled Release 12/2012; · 7.63 Impact Factor
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    Jindřich Kopeček
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    ABSTRACT: This overview focuses on bioconjugates of water-soluble polymers with low molecular weight drugs and proteins. After a short discussion of the origins of the field, the state-of-the-art is reviewed. Then research directions needed for the acceleration of the translation of nanomedicines into the clinic are outlined. Two most important directions, synthesis of backbone degradable polymer carriers and drug-free macromolecular therapeutics, a new paradigm in drug delivery, are discussed in detail. Finally, the future perspectives of the field are briefly discussed.
    Advanced drug delivery reviews 11/2012; · 11.96 Impact Factor
  • Yan Zhou, Jindřich Kopeček
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    ABSTRACT: Understanding the biological features of cancer is the basis for designing efficient anti-cancer nanomedicines. On one hand, important therapeutic targets for anti-cancer nanomedicines need to be identified based on cancer biology, to address the unmet medical needs. On the other hand, the unique pathophysiological properties of cancer affect the delivery and interactions of anti-cancer nanomedicines with their therapeutic targets. This review discusses several critical cancer biological properties that challenge the currently available anti-cancer treatments, including cancer heterogeneity and cancer stem cells, the complexcity of tumor microenvironment, and the inevitable cancer metastases. In addition, the biological bases of the enhanced permeability and retention (EPR) effect and tumor-specific active targeting, as well as the physiological barriers for passive and active targeting of anti-cancer nanomedicines are covered in this review. Correspondingly, possible nanomedicine strategies to target cancer heterogeneity, cancer stem cells and metastases, to overcome the challenges related to tumor passive targeting and tumor penetration, and to improve the interactions of therapeutic payloads with the therapeutic targets are discussed. The focus is mainly on the designs of polymeric anti-cancer nanomedicines.
    Journal of Drug Targeting 09/2012; · 2.77 Impact Factor
  • Jindřich Kopeček, Jiyuan Yang
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    ABSTRACT: Hybrid biomaterials are systems created from components of at least two distinct classes of molecules, for example, synthetic macromolecules and proteins or peptide domains. The synergistic combination of two types of structures may produce new materials that possess unprecedented levels of structural organization and novel properties. This Review focuses on biorecognition-driven self-assembly of hybrid macromolecules into functional hydrogel biomaterials. First, basic rules that govern the secondary structure of peptides are discussed, and then approaches to the specific design of hybrid systems with tailor-made properties are evaluated, followed by a discussion on the similarity of design principles of biomaterials and macromolecular therapeutics. Finally, the future of the field is briefly outlined.
    Angewandte Chemie International Edition 07/2012; 51(30):7396-417. · 11.34 Impact Factor
  • Jindřich Kopeček, Jiyuan Yang
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    ABSTRACT: Hybridbiomaterialien sind Systeme, die aus Bausteinen von mindestens zwei individuellen Molekülklassen erzeugt werden, z. B. aus synthetischen Makromolekülen sowie Proteinen oder Peptiddomänen. Die synergistische Kombination von zwei Strukturarten kann neue Materialien ergeben, die einen beispiellosen Grad an struktureller Organisation sowie neuartige Eigenschaften aufweisen. Dieser Aufsatz diskutiert die durch Bioerkennung gesteuerte Selbstorganisation von hybriden Makromolekülen zu funktionalen Hydrogel‐Biomaterialien. Zuerst werden die grundlegenden Regeln besprochen, die die Sekundärstruktur von Peptiden bestimmen, und im Anschluss bewerten wir die Ansätze zur spezifischen Entwicklung von Hybridsystemen mit maßgeschneiderten Eigenschaften. Nach einer Diskussion der Ähnlichkeiten der verschiedenen Designprinzipien für Biomaterialien und makromolekulare Therapeutika werden wir die zukünftige Entwicklung dieses Forschungsgebietes kurz zusammenfassen.
    Angewandte Chemie 07/2012; 124(30).
  • Te-Wei Chu, Jiyuan Yang, Jindřich Kopeček
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    ABSTRACT: A hybrid biomimetic system comprising high-molecular-weight, linear copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) grafted with multiple Fab' fragments of anti-CD20 monoclonal antibody (mAb) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by attachment of Fab' fragments via thioether bonds. Exposure of human non-Hodgkin's lymphoma (NHL) Raji B cells to the multivalent conjugates resulted in crosslinking of CD20 receptors and commencement of apoptosis. Five conjugates with varying molecular weight and valence (amount of Fab' per polymer chain) were synthesized. One of the copolymers contained enzyme degradable peptide sequences (GFLG) in the backbone. The multivalency led to higher avidity and apoptosis induction compared to unconjugated whole mAb. Time-dependent studies showed that the cytotoxicity of conjugates exhibited a slower onset at shorter exposure times than mAb hyper-crosslinked with a secondary Ab; however, at longer time intervals the HPMA copolymer conjugates achieved significantly higher biological efficacies. In addition, study of the relationship between the structure of conjugates and Raji B cell apoptosis revealed that both valency and polymer molecular weight influenced biological activities, while insertion of peptide sequences into the backbone was not a factor in vitro.
    Biomaterials 07/2012; 33(29):7174-81. · 8.31 Impact Factor
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    ABSTRACT: To evaluate the effect of the size of low molecular weight hyaluronan (LMW-HA) oligomers on the targeting ability of the HA-containing copolymers to the CD44-overexpressing cells for delivering Paclitaxel (PTX) to ovarian cancer. LMW-HA oligosaccharides of 4, 6, 8, 10, 12 and 14 sugar residues were attained by digestion of HMW-HA using hyaluronate lyase at different incubation times and then attached to FITC-labeled HPMA copolymer precursor. The binding and uptake of the HA-modified HPMA-copolymer into CD44-expressing cells was studied by flow cytometry and confocal microscopy. PTX was further attached to HPMA-copolymer precursor bearing HA oligosaccharide at the size of 34 monosaccharides, through an acid-sensitive hydrazone linker. The cytotoxicity of the polymer was tested using cell viability assay. Polymer conjugates bearing HA oligomers at the size of 10 oligosaccharides and above (HA(10-14)) bind actively and profoundly to CD44-overexpressing ovarian cancer cells (SK-OV-3) and internalize to the greatest extent relative to HA-polymer conjugates of 8 oligomers and below (HA(4-8)). The HA-modified HPMA-copolymer PTX conjugate (P-(HA)(34)-PTX) exhibited 50-times higher cytotoxicity towards CD44-overexpressing cells relative to the control, non-targeted, HPMA-copolymer PTX conjugate (P-PTX). P-(HA)(34)-PTX was significantly more toxic than the non-targeted P-PTX in cells expressing high levels of CD44.
    Pharmaceutical Research 04/2012; 29(4):1121-33. · 4.74 Impact Factor

Publication Stats

5k Citations
997.99 Total Impact Points

Institutions

  • 1991–2014
    • University of Utah
      • • Department of Pharmaceutics and Pharmaceutical Chemistry
      • • Department of BioEngineering
      • • Department of Obstetrics and Gynecology
      Salt Lake City, Utah, United States
    • Université Paris 13 Nord
      Île-de-France, France
  • 2013
    • University of Phayao
      Krung Thep, Bangkok, Thailand
  • 1995–2009
    • Academy of Sciences of the Czech Republic
      • • Ústav makromolekulární chemie
      • • Hydrobiologický ústav
      Praha, Hlavni mesto Praha, Czech Republic
  • 2001–2004
    • Hebrew University of Jerusalem
      • School of Pharmacy
      Jerusalem, Jerusalem District, Israel
    • St. Elizabeth's Medical Center
      Boston, Massachusetts, United States
  • 1987–2003
    • Institute of Macromolecular Chemistry
      Praha, Praha, Czech Republic
  • 1980–2003
    • 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