Research Statement
Research in the Kopeček Biomedical Polymers Laboratory focuses on two main areas:
Macromolecular therapeutics. Recent research focuses on the design of backbone degradable, long-circulating polymer carriers that contain enzymatically degradable oligopeptide sequences in the main chain. These N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug (epirubicin, gemcitabine, paclitaxel) conjugates have demonstrated enhanced efficacy in the treatment of animal tumor models when compared to non-degradable HPMA copolymer conjugates or free drugs. Combination therapy targeting both tumor-initiating and differentiated cancer cell populations is also studied.
Drug-free macromolecular therapeutics. A new therapeutic approach for the treatment of B cell malignancies has been developed.The effectiveness of the new system is based on biorecognition events without the participation of low molecular weight drugs. Apoptosis of cells can be initiated by the biorecognition of complementary peptide/oligonucleotide motifs at the cell surface resulting in the crosslinking of slowly internalizing receptors. Drug-free macromolecular therapeutics (DFMT) are composed from two nanoconjugates: 1) bispecific engager, Fab’-MOTIF1 (anti-CD20 Fab’ fragment conjugated with coiled-coil forming peptide or morpholino oligonucleotide), and 2) a crosslinking (effector) component P-(MOTIF2)X (HPMA copolymer or human serum albumin grafted with multiple copies of complementary oligopeptide or morpholino oligonucleotide).The efficacy of the system was validated in vitro, in vivo and on cells isolated from patients with various subtypes of B cell malignancies.
Education History
Doctoral Training |
Czechoslovak Academy of Sciences Chemistry |
D.Sc. |
---|---|---|
Postdoctoral Fellowship |
National Research Council of Canada Membrane Transport |
Postdoctoral Fellow |
Doctoral Training |
Czechoslovak Academy of Sciences Macromolecular Chemistry |
Ph.D. |
Graduate Training |
Institute of Chemical Technology Macromolecular Chemistry |
M.S. |
Selected Publications
- Wang J, Li L, Yang J, Clair PM, Glenn MJ, Stephens DM, Radford DC, Kosak KM, Deininger MW, Shami PJ, Kopeek J (2019). Drug-free macromolecular therapeutics induce apoptosis in cells isolated from patients with B cell malignancies with enhanced apoptosis induction by pretreatment with gemcitabine. Nanomedicine, 16, 217-225.
- Li L, Yang J, Soodvilai S, Wang J, Opanasopit P, Kopeek J (2018). Drug-free albumin-triggered sensitization of cancer cells to anticancer drugs. J Control Release, 293, 84-93.
- Li L, Yang J, Wang J, Kopeek J (2018). Drug-free macromolecular therapeutics exhibit amplified apoptosis in G2/M phase arrested cells. J Drug Target, 27(5-6), 566-572.
- Yang J, Li L, Kopeek J (2018). Biorecognition: A key to drug-free macromolecular therapeutics. Biomaterials, 190-191, 11-23.
- Zhang L, Fang Y, Li L, Yang J, Radford DC, Kopeek J (2018). Human Serum Albumin-Based Drug-Free Macromolecular Therapeutics: Apoptosis Induction by Coiled-Coil-Mediated Cross-Linking of CD20 Antigens on Lymphoma B Cell Surface. Macromol Biosci, 18(11), e1800224.
- Li L, Yang J, Wang J, Kopeek J (2017). Drug-Free Macromolecular Therapeutics Induce Apoptosis via Calcium Influx and Mitochondrial Signaling Pathway. Macromol Biosci, 18(1).
- Zhang L, Fang Y, Yang J, Kopeek J (2016). Drug-free macromolecular therapeutics: Impact of structure on induction of apoptosis in Raji B cells. J Control Release, 263, 139-150.
- Yang J, Kopeek J (2017). The Light at the End of the Tunnel-Second Generation HPMA Conjugates for Cancer Treatment. Curr Opin Colloid Interface Sci, 31, 30-42.
- Zhang L, Fang Y, Kopeek J, Yang J (2017). A new construct of antibody-drug conjugates for treatment of B-cell non-Hodgkin's lymphomas. Eur J Pharm Sci, 103, 36-46.
- Pelaz B, Alexiou C, Alvarez-Puebla RA, Alves F, Andrews AM, Ashraf S, Balogh LP, Ballerini L, Bestetti A, Brendel C, Bosi S, Carril M, Chan WC, Chen C, Chen X, Chen X, Cheng Z, Cui D, Du J, Dullin C, Escudero A, Feliu N, Gao M, George M, Gogotsi Y, Grnweller A, Gu Z, Halas NJ, Hampp N, Hartmann RK, Hersam MC, Hunziker P, Jian J, Jiang X, Jungebluth P, Kadhiresan P, Kataoka K, Khademhosseini A, Kopeek J, Kotov NA, Krug HF, Lee DS, Lehr CM, Leong KW, Liang XJ, Ling Lim M, Liz-Marzn LM, Ma X, Macchiarini P, Meng H, Mhwald H, Mulvaney P, Nel AE, Nie S, Nordlander P, Okano T, Oliveira J, Park TH, Penner RM, Prato M, Puntes V, Rotello VM, Samarakoon A, Schaak RE, Shen Y, Sjqvist S, Skirtach AG, Soliman MG, Stevens MM, Sung HW, Tang BZ, Tietze R, Udugama BN, VanEpps JS, Weil T, Weiss PS, Willner I, Wu Y, Yang L, Yue Z, Zhang Q, Zhang Q, Zhang XE, Zhao Y, Zhou X, Parak WJ (2017). Diverse Applications of Nanomedicine. ACS Nano, 11(3), 2313-2381.
- Low SA, Galliford CV, Jones-Hall YL, Roy J, Yang J, Low PS, Kopeek J (2017). Healing efficacy of fracture-targeted GSK3β inhibitor-loaded micelles for improved fracture repair. Nanomedicine (Lond), 12(3), 185-193.
- Zhang R, Yang J, Radford DC, Fang Y, Kopeek J (2016). FRET Imaging of Enzyme-Responsive HPMA Copolymer Conjugate. Macromol Biosci, 17(1).
- Yang J, Kopeek J (2015). Design of smart HPMA copolymer-based nanomedicines. J Control Release, 240, 9-23.
- Zhang L, Zhang R, Yang J, Wang J, Kopeek J (2016). Indium-based and iodine-based labeling of HPMA copolymer-epirubicin conjugates: Impact of structure on the in vivo fate. J Control Release, 235, 306-318.
- Hartley JM, Zhang R, Gudheti M, Yang J, Kopeek J (2016). Tracking and quantifying polymer therapeutic distribution on a cellular level using 3D dSTORM. J Control Release, 231, 50-9.
- Chu TW, Feng J, Yang J, Kopeek J (2015). Hybrid polymeric hydrogels via peptide nucleic acid (PNA)/DNA complexation. J Control Release, 220(Pt B), 608-16.
- Yang J, Kopeek J (2015). POLYMERIC BIOMATERIALS AND NANOMEDICINES. J Drug Deliv Sci Technol, 30(Pt B), 318-330.
- Yang J, Zhang R, Radford DC, Kopeek J (2015). FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy. J Control Release, 218, 36-44.
- Yang J, Zhang R, Christopher Radford D, Kopeek J (2015). Design and synthesis of FRET-trackable HPMA-based biodegradable conjugates for drug/gene delivery. J Control Release, 213, e58.
- Hartley JM, Chu TW, Peterson EM, Zhang R, Yang J, Harris J, Kopeek J (2015). Super-Resolution Imaging and Quantitative Analysis of Membrane Protein/Lipid Raft Clustering Mediated by Cell-Surface Self-Assembly of Hybrid Nanoconjugates. Chembiochem, 16(12), 1725-9.
- Peng ZH, Kopeek J (2015). Enhancing Accumulation and Penetration of HPMA Copolymer-Doxorubicin Conjugates in 2D and 3D Prostate Cancer Cells via iRGD Conjugation with an MMP-2 Cleavable Spacer. J Am Chem Soc, 137(21), 6726-9.
- Zhang R, Yang J, Chu TW, Hartley JM, Kopeek J (2015). Multimodality imaging of coiled-coil mediated self-assembly in a "drug-free" therapeutic system. Adv Healthc Mater, 4(7), 1054-65.
- Zhou Y, Yang J, Zhang R, Kopeek J (2014). Combination therapy of prostate cancer with HPMA copolymer conjugates containing PI3K/mTOR inhibitor and docetaxel. Eur J Pharm Biopharm, 89, 107-15.
- Peng ZH, Kopeek J (2014). HPMA Copolymer CXCR4 Antagonist Conjugates Substantially Inhibited the Migration of Prostate Cancer Cells. ACS Macro Lett, 3(12), 1240-1243.
- Chu TW, Kosak KM, Shami PJ, Kopeek J (2015). Drug-free macromolecular therapeutics induce apoptosis of patient chronic lymphocytic leukemia cells. Drug Deliv Transl Res, 4(5-6), 389-94.
- Low SA, Yang J, Kopeek J (2014). Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics. Bioconjug Chem, 25(11), 2012-20.
- Zhang R, Yang J, Sima M, Zhou Y, Kopeek J (2014). Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates. Proc Natl Acad Sci U S A, 111(33), 12181-6.
- Duangjai A, Luo K, Zhou Y, Yang J, Kopeek J (2013). Combination cytotoxicity of backbone degradable HPMA copolymer gemcitabine and platinum conjugates toward human ovarian carcinoma cells. Eur J Pharm Biopharm, 87(1), 187-96.
- Kopeek J, Stanwix H (2014). Interview with Professor Jindřich Kopeček. Nanomedicine (Lond), 9(5), 577-9.
- Chu TW, Yang J, Zhang R, Sima M, Kopeek J (2013). Cell surface self-assembly of hybrid nanoconjugates via oligonucleotide hybridization induces apoptosis. ACS Nano, 8(1), 719-30.
- Zhou Y, Yang J, Rhim JS, Kopeek J (2013). HPMA copolymer-based combination therapy toxic to both prostate cancer stem/progenitor cells and differentiated cells induces durable anti-tumor effects. J Control Release, 172(3), 946-53.
- Larson N, Yang J, Ray A, Cheney DL, Ghandehari H, Kopeek J (2013). Biodegradable multiblock poly(N-2-hydroxypropyl)methacrylamide gemcitabine and paclitaxel conjugates for ovarian cancer cell combination treatment. Int J Pharm, 454(1), 435-43.
- Zhang R, Luo K, Yang J, Sima M, Sun Y, Jant-Amsbury MM, Kopeek J (2012). Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel. J Control Release, 166(1), 66-74.
- Pan H, Sima M, Yang J, Kopeek J (2013). Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy. Macromol Biosci, 13(2), 155-60.
- Zhou Y, Kopeek J (2012). Biological rationale for the design of polymeric anti-cancer nanomedicines. J Drug Target, 21(1), 1-26.
- Kopeek J (2012). Polymer-drug conjugates: origins, progress to date and future directions. Adv Drug Deliv Rev, 65(1), 49-59.
- Low SA, Kopeek J (2012). Targeting polymer therapeutics to bone. Adv Drug Deliv Rev, 64(12), 1189-204.
- Kopeek J, Yang J (2012). Smart self-assembled hybrid hydrogel biomaterials. Angew Chem Int Ed Engl, 51(30), 7396-417.
- Fowers KD, Kopeek J (2012). Targeting of multidrug-resistant human ovarian carcinoma cells with anti-P-glycoprotein antibody conjugates. Macromol Biosci, 12(4), 502-14.
- Johnson RN, Kopekov P, Kopeek J (2012). Biological activity of anti-CD20 multivalent HPMA copolymer-Fab' conjugates. Biomacromolecules, 13(3), 727-35.
- Liu J, Kopekov P, Pan H, Sima M, Bhler P, Wolf P, Elssser-Beile U, Kopeek J (2012). Prostate-cancer-targeted N-(2-hydroxypropyl)methacrylamide copolymer/docetaxel conjugates. Macromol Biosci, 12(3), 412-22.
- Zhou Y, Yang J, Kopeek J (2011). Selective inhibitory effect of HPMA copolymer-cyclopamine conjugate on prostate cancer stem cells. Biomaterials, 33(6), 1863-72.
- Krimmer SG, Pan H, Liu J, Yang J, Kopeek J (2011). Synthesis and characterization of poly(ε-caprolactone)-block-poly[N-(2-hydroxypropyl)methacrylamide] micelles for drug delivery. Macromol Biosci, 11(8), 1041-51.
- Wu LC, Yang J, Kopeek J (2011). Hybrid hydrogels self-assembled from graft copolymers containing complementary β-sheets as hydroxyapatite nucleation scaffolds. Biomaterials, 32(23), 5341-53.
- Luo K, Yang J, Kopekov P, Kopeek J (2011). Biodegradable Multiblock Poly[N-(2-hydroxypropyl)methacrylamide] via Reversible Addition-Fragmentation Chain Transfer Polymerization and Click Chemistry. Macromolecules, 44(8), 2481-2488.
- Yang J, Luo K, Pan H, Kopekov P, Kopeek J (2011). Synthesis of Biodegradable Multiblock Copolymers by Click Coupling of RAFT-Generated HeterotelechelicPolyHPMA Conjugates. React Funct Polym, 71(3), 294-302.
- Pan H, Yang J, Kopeckov P, Kopecek J (2010). Backbone degradable multiblock N-(2-hydroxypropyl)methacrylamide copolymer conjugates via reversible addition-fragmentation chain transfer polymerization and thiol-ene coupling reaction. Biomacromolecules, 12(1), 247-52.
- Kopecek J (2010). Biomaterials and drug delivery: past, present, and future. Mol Pharm, 7(4), 922-5.
- Yang J, Jacobsen MT, Pan H, Kopecek J (2010). Synthesis and characterization of enzymatically degradable PEG-based peptide-containing hydrogels. Macromol Biosci, 10(4), 445-54.
- Liu J, Bauer H, Callahan J, Kopeckov P, Pan H, Kopecek J (2010). Endocytic uptake of a large array of HPMA copolymers: Elucidation into the dependence on the physicochemical characteristics. J Control Release, 143(1), 71-9.
- Wu K, Liu J, Johnson RN, Yang J, Kopecek J (2010). Drug-free macromolecular therapeutics: induction of apoptosis by coiled-coil-mediated cross-linking of antigens on the cell surface. Angew Chem Int Ed Engl, 49(8), 1451-5.
- Kopeek J (2009). HYDROGELS FROM SOFT CONTACT LENSES AND IMPLANTS TO SELF-ASSEMBLED NANOMATERIALS. J Polym Sci A Polym Chem, 47(22), 5929-5946.
- Gao SQ, Sun Y, Kopeckov P, Peterson CM, Kopecek J (2009). Antitumor efficacy of colon-specific HPMA copolymer/9-aminocamptothecin conjugates in mice bearing human-colon carcinoma xenografts. Macromol Biosci, 9(11), 1135-42.
- Sheparovych R, Roiter Y, Yang J, Kopeek J, Minko S (2009). Stimuli-responsive properties of peptide-based copolymers studied via directional growth of self-assembled patterns on solid substrate. Biomacromolecules, 10(7), 1955-61.
- Callahan J, Kopekov P, Kopeek J (2009). Intracellular trafficking and subcellular distribution of a large array of HPMA copolymers. Biomacromolecules, 10(7), 1704-14.
- Duek K, Dukov-Smrkov M, Yang J, Kopeek J (2010). Coiled-Coil Hydrogels. Effect of Grafted Copolymer Composition and Cyclization on Gelation. Macromolecules, 42(6), 2265-2274.
- Kopecek J, Yang J (2008). Peptide-directed self-assembly of hydrogels. Acta Biomater, 5(3), 805-16.
- Johnson RN, Kopeckov P, Kopecek J (2009). Synthesis and evaluation of multivalent branched HPMA copolymer-Fab' conjugates targeted to the B-cell antigen CD20. Bioconjug Chem, 20(1), 129-37.
- Segal E, Pan H, Ofek P, Udagawa T, Kopeckov P, Kopecek J, Satchi-Fainaro R (2009). Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics. PLoS One, 4(4), e5233.
- Yuan W, Yang J, Kopeckov P, Kopecek J (2008). Smart hydrogels containing adenylate kinase: translating substrate recognition into macroscopic motion. J Am Chem Soc, 130(47), 15760-1.
- Hongrapipat J, Kopeckov P, Liu J, Prakongpan S, Kopecek J (2008). Combination chemotherapy and photodynamic therapy with fab' fragment targeted HPMA copolymer conjugates in human ovarian carcinoma cells. Mol Pharm, 5(5), 696-709.
- Pan H, Liu J, Dong Y, Sima M, Kopeckov P, Brandi ML, Kopecek J (2008). Release of prostaglandin E(1) from N-(2-hydroxypropyl)methacrylamide copolymer conjugates by bone cells. Macromol Biosci, 8(7), 599-605.
- Pan H, Sima M, Kopeckov P, Wu K, Gao S, Liu J, Wang D, Miller SC, Kopecek J (2008). Biodistribution and pharmacokinetic studies of bone-targeting N-(2-hydroxypropyl)methacrylamide copolymer-alendronate conjugates. Mol Pharm, 5(4), 548-58.
- Cuchelkar V, Kopeckov P, Kopecek J (2008). Synthesis and biological evaluation of disulfide-linked HPMA copolymer-mesochlorin e6 conjugates. Macromol Biosci, 8(5), 375-83.
- Hongrapipat J, Kopeckov P, Prakongpan S, Kopecek J (2007). Enhanced antitumor activity of combinations of free and HPMA copolymer-bound drugs. Int J Pharm, 351(1-2), 259-70.
- Xu C, Kopecek J (2007). Genetically engineered block copolymers: influence of the length and structure of the coiled-coil blocks on hydrogel self-assembly. Pharm Res, 25(3), 674-82.
- Yang J, Wu K, Konk C, Kopecek J (2008). Dynamic light scattering study of self-assembly of HPMA hybrid graft copolymers. Biomacromolecules, 9(2), 510-7.
- Malugin A, Kopeckov P, Kopecek J (2007). Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells. J Control Release, 124(1-2), 6-10.
- Kopecek J (2007). Hydrogel biomaterials: a smart future? Biomaterials, 28(34), 5185-92.
- Pan H, Kopeckov P, Liu J, Wang D, Miller SC, Kopecek J (2007). Stability in plasmas of various species of HPMA copolymer-PGE1 conjugates. Pharm Res, 24(12), 2270-80.
- Wang D, Miller SC, Shlyakhtenko LS, Portillo AM, Liu XM, Papangkorn K, Kopeckov P, Lyubchenko Y, Higuchi WI, Kopecek J (2007). Osteotropic Peptide that differentiates functional domains of the skeleton. Bioconjug Chem, 18(5), 1375-8.
- Ding H, Kopeckov P, Kopecek J (2007). Self-association properties of HPMA copolymers containing an amphipathic heptapeptide. J Drug Target, 15(7-8), 465-74.
- Shiah JG, Konk C, Spikes JD, Kopecek J (2009). Influence of pH on aggregation and photoproperties of n-(2-hydroxypropyl)methacrylamide copolymer-meso-chlorin e6 conjugates. Drug Deliv, 5(2), 119-26.
- Kopecek J, et al (1995). Colonic-targeted oral drug-dosage forms based on crosslinked hydrogels containing azobonds and exhibiting pH-dependent swelling. U.S. Patent No. 5,415,864. Washington, D.C.:U.S. Patent and Trademark Office.
- Kopecek J, et al (1993). Drug delivery system for the simultaneous delivery of drugs activatable by enzymes and light. U.S. Patent No. 5,258,453. Washington, D.C.:U.S. Patent and Trademark Office.
- Kopecek J, et al (1991). Synthetic polymeric drugs. U.S. Patent No. 5,037,883. Washington, D.C.:U.S. Patent and Trademark Office.
- Andrade, Kopecek J, et al (1991). Polymer supersurfactants for protein resistance and protein removal. U.S. Patent No. 5,075,400. Washington, D.C.:U.S. Patent and Trademark Office.
- Lim, Kopecek J, et al (1978). Hydrophilic N,N-diethyl acrylamide copolymers. U.S. Patent No. 4,074,039. Washington, D.C.:U.S. Patent and Trademark Office.
- Drobnik, Kopecek J, et al (1978). Preparation of biogically active substances bearing -NH2 groups in a form releasable by enzymatic cleavage. U.S. Patent No. 4,097,470. Washington, D.C.:U.S. Patent and Trademark Office.
- Kopecek J, et al (1976). Copolymers based on N-substituted acrylamides, N-substituted methacrylamides and N,N-disubstituted acrylamides and the method of their manufacturing. U.S. Patent No. 4,062,831. Washington, D.C.:U.S. Patent and Trademark Office.
- Kopecek J, et al (1976). Soluble hydrophilic polymers and process for processing the same. U.S. Patent No. 3,997,660. Washington, D.C.:U.S. Patent and Trademark Office.
- Lim, Kopecek J, et al (1976). Infusion solutions and method of manufacturing same. U.S. Patent No. 3,997,660. Washington, D.C.:U.S. Patent and Trademark Office.
- Kopecek J, et al (1976). Soluble hydrophilic polymers and process for processing the same. U.S. Patent No. 3,931,111. Washington, D.C.:U.S. Patent and Trademark Office.
- Vacik, Kopecek J (1976). Hydrophilic nitrite copolymers. U.S. Patent No. 3,931,123. Washington, D.C.:U.S. Patent and Trademark Office.
- Lim, Kopecek J, et al (1975). Method for producing of articles from hydrophilic polymers appropriate for repeated or long-term contact with living tissue or mucous membrane. U.S. Patent No. 3,876,594. Washington, D.C.:U.S. Patent and Trademark Office.
- Lim, Kopecek J, et al (1973). Device for connecting or joining the ends of interrupted tubular organs in surgical operations without stiching. U.S. Patent No. 3,774,615. Washington, D.C.:U.S. Patent and Trademark Office.
- Lim, Kopecek J, et al (1973). Method of hydrophilization of transparent objects made of hydrophobic organic polymers. U.S. Patent No. 3,745,042. Washington, D.C.:U.S. Patent and Trademark Office.
- Kopecek J, et al (1970). Increasing permeability of reverse osmosis membranes. U.S. Patent No. 3,536,612. Washington, D.C.:U.S. Patent and Trademark Office.
Global Impact
Education History
Type | School | Degree |
---|---|---|
Doctoral Training | Czechoslovak Academy of Sciences Chemistry |
D.Sc. |
Doctoral Training | Czechoslovak Academy of Sciences Macromolecular Chemistry |
Ph.D. |
Graduate Training | Institute of Chemical Technology Macromolecular Chemistry |
M.S. |
Postdoctoral Fellowship | National Research Council of Canada Membrane Transport |
Postdoctoral Fellow |