J Kopecek

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

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Publications (308)1194.68 Total impact

  • Jiyuan Yang, Jindřich Kopeček
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    ABSTRACT: This overview intends to demonstrate the close relationship between the design of smart biomaterials and water-soluble polymer-drug conjugates. First, the discovery and systematic studies of hydrogels based on crosslinked poly(meth)acrylic acid esters and substituted amides is described. Then, the lessons learned for the design of water-soluble polymers as drug carriers are highlighted. The current state-of-the-art in water-soluble, mainly poly[N-(2-hydroxypropyl)methacylamide (HPMA), polymer-drug conjugates is shown including the design of backbone degradable HPMA copolymer carriers. In the second part, the modern design of hybrid hydrogels focuses on the self-assembly of hybrid copolymers composed from the synthetic part (backbone) and biorecognizable grafts (coiled-coil forming peptides or morpholino oligonucleotides) is shown. The research of self-assembling hydrogels inspired the invention and design of drug-free macromolecular therapeutics – a new paradigm in drug delivery where crosslinking of non-internalizating CD20 receptors results in apoptosis in vitro and in vivo. The latter is mediated by biorecognition of complementary motifs; no low molecular weight drug is needed.
    Journal of Drug Delivery Science and Technology 05/2015; DOI:10.1016/j.jddst.2015.05.012 · 1.09 Impact Factor
  • Te-Wei Chu, Jindřich Kopeček
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    ABSTRACT: This review highlights a unique research area in polymer-based nanomedicine designs. Drug-free macromolecular therapeutics induce apoptosis of malignant cells by the crosslinking of surface non-internalizing receptors. The receptor crosslinking is mediated by the biorecognition of high-fidelity natural binding motifs (such as antiparallel coiled-coil peptides or complementary oligonucleotides) that are grafted to the side chains of polymers or attached to targeting moieties against cell receptors. This approach features the absence of low-molecular-weight cytotoxic compounds. Here, we summarize the rationales, different designs, and advantages of drug-free macromolecular therapeutics. Recent developments of novel therapeutic systems for B-cell lymphomas are discussed, as well as relevant approaches for other diseases. We conclude by pointing out various potential future directions in this exciting new field.
    02/2015; DOI:10.1039/C4BM00442F
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    ABSTRACT: Two complementary coiled-coil peptides CCE/CCK are used to develop a “drug free” therapeutic system, which can specifically kill cancer cells without a drug. CCE is attached to the Fab′ fragment of anti-CD20 1F5 antibody (Fab′-CCE), and CCK is conjugated in multiple grafts to poly[N-(2-hydroxypropyl)methacrylamide] (P-(CCK)x). Two conjugates are consecutively administered: First, Fab′-CCE coats peptide CCE at CD20 antigen of lymphoma cell surface; second, CCE/CCK biorecognition between Fab′-CCE and P-(CCK)x leads to coiled-coil formation, CD20 crosslinking, membrane reorganization, and ultimately cell apoptosis. To prove that two conjugates can assemble at cell surface, multiple fluorescence imaging studies are performed, including 2-channel FMT, 3D confocal microscopy, and 4-color FACS. Confocal microscopy shows colocalization of two fluorescently labeled conjugates on non-Hodgkin's lymphoma (NHL) Raji cell surface, indicating “two-step” targeting specificity. The fluorescent images also reveal that these two conjugates can disrupt normal membrane lipid distribution and form lipid raft clusters, leading to cancer cell apoptosis. This “two-step” biorecognition capacity is further demonstrated in a NHL xenograft model, using fluorescent images at whole-body, tissue and cell levels. It is also found that delaying injection of P-(CCK)x can significantly enhance targeting efficacy. This high-specificity therapeutics provide a safe option to treat NHL and other B cell malignancies.
    Advanced Healthcare Materials 01/2015; 4(7). DOI:10.1002/adhm.201400679 · 4.88 Impact Factor
  • Theranostics 01/2015; 5(8):834-846. DOI:10.7150/thno.12040 · 7.83 Impact Factor
  • Zheng-Hong Peng, Jindřich Kopeček
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    ABSTRACT: A N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-CXCR4 antagonist (BKT140) conjugate (P-BKT140) was developed and its biological activities were tested. Both free BKT140 and monomer MA-GGPLGLAG-BKT140 (MA is methacryloyl) were prepared by solid phase synthesis. P-BKT140 was prepared by reversible addition-fragmentation chain transfer (RAFT) copolymerization of monomers HPMA and MA-GGPLGLAG-BKT140. The in vitro results show that the free BKT140 and P-BKT140 have similar cytotoxicity against human prostate carcinoma PC-3 cells, indicating that conjugation of BKT140 to HPMA did not significantly impact the cytotoxicity of BKT140. Both BKT140 and P-BKT140 inhibited the CXCL12-induced migration of PC-3 prostate cancer cells, but the P-BKT140 conjugate possessed a substantially higher inhibition activity than free BKT140.
    ACS Macro Letters 12/2014; 3(12):1240-1243. DOI:10.1021/mz5006537 · 5.24 Impact Factor
  • Yan Zhou, Jiyuan Yang, Rui Zhang, Jindřich Kopeček
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    ABSTRACT: Combination therapies have been investigated to address the current challenges of anti-cancer therapeutics. In particular, a novel paradigm of combination therapy targeting both cancer stem/progenitor cells and bulk tumor cells is promising to improve the long-term therapeutic benefit against prostate cancer. Among the therapeutic agents with anti-CSC activities, the PI3K/mTOR inhibitors exhibit preferential inhibitory effect on prostate cancer stem/progenitor cells and potent cytotoxicity against bulk tumor cells. The combination of PI3K/mTOR inhibitor and traditional chemotherapy docetaxel may show superior therapeutic effect over single drug treatment. Aiming to further improve the combinational anti-tumor and anti-CSC effect, we developed the combination therapy containing two HPMA copolymer-drug conjugates, incorporated with PI3K/mTOR inhibitor GDC-0980 (P-(GDC-0980)) and docetaxel (P-DTX), respectively. The anti-tumor and anti-CSC effects of the single and combination therapy were investigated in vitro and on PC-3 prostate cancer xenografts in nude mice. Our evaluations showed that P-(GDC-0980) suppressed CD133+ prostate stem/progenitor cell growth even at the low dose which does not cause significant growth inhibition in bulk tumor cells. The combination therapy exhibited effective anti-CSC effect as well as enhanced anti- bulk tumor effect in vitro. Among all the single and combination dosing regimens of free drugs and conjugates, the macromolecular combination therapy showed significantly prolonged mice survival in vivo. Copyright © 2014. Published by Elsevier B.V.
    European Journal of Pharmaceutics and Biopharmaceutics 12/2014; 89. DOI:10.1016/j.ejpb.2014.11.025 · 4.25 Impact Factor
  • Te-Wei Chu, Ken M Kosak, Paul J Shami, Jindřich Kopeček
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    ABSTRACT: A new drug-free nanotherapeutic approach for B-cell malignancies was developed. Exposure of B-cells to an anti-CD20 Fab'-morpholino oligonucleotide1 (MORF1) conjugate decorated the cell surface with MORF1; further exposure of the decorated cells to multivalent polymer-oligonucleotide2 conjugates (P-MORF2) resulted in CD20 clustering at the cell surface with induction of apoptosis. We evaluated this concept in chronic lymphocytic leukemia (CLL) cells isolated from 10 patients. Apoptosis and cytotoxicity were observed in eight samples, including 2 samples with the 17p13 deletion, which suggested a p53-independent mechanism of apoptosis induction. When compared to an anti-CD20 monoclonal antibody (mAb), the nanotherapeutic showed significantly more potent apoptosis-inducing activity and cytotoxicity. This was due to the multivalency effect (8 binding sites per polymer chain) of our design in comparison to the divalent mAb. In conclusion, we have developed a novel and potent therapeutic system against CLL and other B-cell malignancies with significant advantages over conventional chemo-immunotherapy.
    12/2014; 4(5-6):389-394. DOI:10.1007/s13346-014-0209-8
  • 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 08/2014; 111(33). DOI:10.1073/pnas.1406233111 · 9.81 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 04/2014; 35(22):5886–5896. DOI:10.1016/j.biomaterials.2014.03.063 · 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; 190. DOI:10.1016/j.jconrel.2014.04.013 · 7.26 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. DOI:10.2217/nnm.14.20 · 5.82 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; 24(8). DOI:10.1016/j.bmcl.2014.03.006 · 2.33 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
  • Jiyuan Yang, Jindřich Kopeček
    Encyclopedia of Polymeric Nanomaterials, 01/2014: pages 1-9; , ISBN: 978-3-642-36199-9
  • Source
    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. DOI:10.1021/nn4053827 · 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; DOI:10.1016/j.ejpb.2013.11.008 · 4.25 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. DOI:10.3109/1061186X.2013.833207 · 2.72 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; 172(3). DOI:10.1016/j.jconrel.2013.09.005 · 7.26 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; 454(1). DOI:10.1016/j.ijpharm.2013.06.046 · 3.79 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; 34(27). DOI:10.1016/j.biomaterials.2013.05.003 · 8.31 Impact Factor

Publication Stats

8k Citations
1,194.68 Total Impact Points

Institutions

  • 1988–2015
    • University of Utah
      • • Department of Pharmaceutics and Pharmaceutical Chemistry
      • • Department of BioEngineering
      • • Center for Controlled Chemical Delivery (CCCD)
      • • Department of Obstetrics and Gynecology
      Salt Lake City, Utah, United States
  • 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
  • 1980–2003
    • Keele University
      Newcastle-under-Lyme, England, United Kingdom
  • 1968–2003
    • Institute of Macromolecular Chemistry
      Praha, Praha, Czech Republic
  • 1991
    • Université Paris 13 Nord
      Île-de-France, France
  • 1985
    • Deen Dayal Rustagi College
      Khandela, Rajasthan, India
  • 1983
    • Russian Academy of Sciences
      • Institute of Macromolecular Compounds
      Moskva, Moscow, Russia
  • 1976
    • Institute for Clinical and Experimental Medicine (IKEM)
      Praha, Praha, Czech Republic