Julia Suhorutsenko "Cell-penetrating peptides: cytotoxicity, immunogenicity and application for tumor targeting" | University of Tartu

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Contacts of UT units

Faculty of Arts and Humanities
Faculty phone: 
+372 737 5341
Faculty address: 
Jakobi 2, rooms 116–121, 51005 Tartu
  • Dean's Office
    Faculty phone: 
    + 372 737 5341
    Faculty address: 
    Jakobi 2, rooms 116–121, 51005 Tartu
  • Institute of History and Archaeology
    Faculty phone: 
    +372 737 5651
    Faculty address: 
    Jakobi 2, 51005 Tartu
  • Institute of Estonian and General Linguistics
    Faculty phone: 
    +372 737 5221
    Faculty address: 
    Jakobi 2, 51005 Tartu
  • Institute of Philosophy and Semiotics
    Faculty phone: 
    +372 737 5314
    Faculty address: 
    Jakobi 2, rooms 309–352, 51005 Tartu
  • Institute of Cultural Research
    Faculty phone: 
    (+372) 737 5223
    Faculty address: 
    Ülikooli 16, 51003 Tartu
  • School of Theology and Religious Studies
    Faculty phone: 
    +372 737 5301
    Faculty address: 
    Ülikooli 18–310, 50090 Tartu
  • College of Foreign Languages and Cultures
    Faculty address: 
    J. Liivi 4, 50409, Tartu
  • Viljandi Culture Academy
    Faculty phone: 
    +372 435 5232
    Faculty address: 
    Posti 1, 71004 Viljandi
Faculty of Social Sciences
Faculty phone: 
+372 737 5957
Faculty address: 
Lossi 36, 51003 Tartu
  • Dean's Office
    Faculty phone: 
    + 372 737 5900
    Faculty address: 
    Lossi 36, 51003 Tartu
  • Institute of Education
    Faculty phone: 
    +372 737 6440
    Faculty address: 
    Salme 1a–29, 50103 Tartu
  • Johan Skytte Institute of Political Studies
    Faculty phone: 
    +372 737 5582
    Faculty address: 
    Lossi 36–301, 51003 Tartu
  • School of Economics and Business Administration
    Faculty phone: 
    +372 737 6310
    Faculty address: 
    Narva mnt 18, 51009 Tartu
  • Institute of Psychology
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    Faculty address: 
    Näituse 2, 50409 Tartu
  • School of Law
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    Näituse 20–324, 50409 Tartu
  • Institute of Social Studies
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    Lossi 36, 51003 Tartu
  • Narva College
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  • Pärnu College
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    Ringi 35, 80012 Pärnu
Faculty of Medicine
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+372 737 5326
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Ravila 19, 50411 Tartu
  • Dean's Office
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    +372 737 5326
    Faculty address: 
    Ravila 19, 50411 Tartu
  • Institute of Biomedicine and Translational Medicine
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    +372 737 4210
    Faculty address: 
    Biomeedikum, Ravila 19, 50411 Tartu
  • Institute of Pharmacy
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    Nooruse 1, 50411 Tartu
  • Institute of Dentistry
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    Faculty address: 
    Raekoja plats 6, 51003 Tartu
  • Institute of Clinical Medicine
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    L. Puusepa 8, 50406 Tartu
  • Institute of Family Medicine and Public Health
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    +372 737 4190
    Faculty address: 
    Ravila 19, 50411 Tartu
  • Institute of Sport Sciences and Physiotherapy
    Faculty phone: 
    +372 737 5360
    Faculty address: 
    Jakobi 5–205, 51005 Tartu
Faculty of Science and Technology
Faculty phone: 
+372 737 5820
Faculty address: 
Vanemuise 46–208, 51014 Tartu
  • Dean's Office
    Faculty phone: 
    +372 737 5820
    Faculty address: 
    Vanemuise 46–208, 51003 Tartu
  • Institute of Computer Science
    Faculty phone: 
    +372 737 5445
    Faculty address: 
    Narva mnt 18, 51009 Tartu
  • Estonian Marine Institute
    Faculty phone: 
    +372 671 8902
    Faculty address: 
    Mäealuse 14, 12618 Tallinn
  • Institute of Physics
    Faculty address: 
    W. Ostwaldi 1, 50411 Tartu
  • Institute of Chemistry
    Faculty phone: 
    +372 737 5261
    Faculty address: 
    Ravila 14a, 50411 Tartu
  • Institute of Mathematics and Statistics
    Faculty phone: 
    +372 737 5860
    Faculty address: 
    Narva mnt 18, 51009 Tartu
  • Institute of Molecular and Cell Biology
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    +372 737 5027
    Faculty address: 
    Riia 23, 23b–134, 51010 Tartu
  • Tartu Observatory
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    Observatooriumi 1, Tõravere, 61602 Tartumaa
  • Institute of Technology
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    Faculty address: 
    Nooruse 1, 50411 Tartu
  • Institute of Ecology and Earth Sciences
    Faculty phone: 
    +372 737 5835
    Faculty address: 
    Vanemuise 46, 51003 Tartu
Institutions
  • Library
    Faculty phone: 
    +372 737 5702
    Faculty address: 
    W. Struve 1, 50091 Tartu
  • Youth Academy
    Faculty phone: 
    +372 737 5581
    Faculty address: 
    Uppsala 10, 51003 Tartu
  • Institute of Genomics
    Faculty phone: 
    +372 737 4000
    Faculty address: 
    Riia 23b, 51010 Tartu
  • Museum
    Faculty phone: 
    +372 737 5674
    Faculty address: 
    Lossi 25, 51003 Tartu
  • University of Tartu Natural History Museum and Botanical Garden
    Faculty phone: 
    +372 737 6076
    Faculty address: 
    Vanemuise 46, 51003 Tartu
Support Units
  • Administrative Office
    Faculty phone: 
    +372 737 5606
    Faculty address: 
    Ülikooli 18a, 51005 Tartu
  • Centre for Entrepreneurship and Innovation
    Faculty phone: 
    +372 737 4809
    Faculty address: 
    Narva mnt 18, 51009, Tartu
  • University Office in Tallinn
    Faculty phone: 
    +372 737 6600
    Faculty address: 
    Teatri väljak 3, 10143 Tallinn
  • Estates Office
    Faculty phone: 
    +372 737 5137
    Faculty address: 
    Ülikooli 18a, 51005 Tartu
  • Finance Office
    Faculty phone: 
    +372 737 5125
    Faculty address: 
    Jakobi 4, 51005 Tartu
  • Grant Office
    Faculty phone: 
    +372 737 6215
    Faculty address: 
    Raekoja plats 9, 51004 Tartu
  • Information Technology Office
    Faculty phone: 
    +372 737 6000, IT-help: +372 737 5500
    Faculty address: 
    Ülikooli 18a, 51005 Tartu
  • Human Resources Office
    Faculty phone: 
    +372 737 5145
    Faculty address: 
    Ülikooli 18, rooms 302 and 304, 50090 Tartu
  • Internal Audit Office
    Faculty address: 
    Ülikooli 18-244, 51005 Tartu
  • Marketing and Communication Office
    Faculty phone: 
    +372 737 5687
    Faculty address: 
    Ülikooli 18, rooms 102, 104, 209, 210, 50090 Tartu
  • Office of Academic Affairs
    Faculty phone: 
    +372 737 5620
    Faculty address: 
    Ülikooli 18, 50090 Tartu
  • Procurement Office
    Faculty phone: 
    +372 737 6632
    Faculty address: 
    Ülikooli 18a, 51005 Tartu
  • Rector's Strategy Office
    Faculty phone: 
    +372 737 5600
    Faculty address: 
    Ülikooli 18, 50090 Tartu
  • Student Council
    Faculty address: 
    Ülikooli 18b, 51005 Tartu
  • University of Tartu Press
    Faculty phone: 
    +372 737 5945
    Faculty address: 
    W. Struve 1, 50091 Tartu
Other Units
  • University of Tartu Academic Sports Club
    Faculty phone: 
    +372 737 5371
    Faculty address: 
    Ujula 4, 51008 Tartu
  • Tartu Student Village
    Faculty phone: 
    +372 740 9959
    Faculty address: 
    Narva mnt 25, 51013 Tartu
  • Tartu Students’ Club
    Faculty phone: 
    +372 730 2400
    Faculty address: 
    Kalevi 24, 51010 Tartu
  • Tartu University Hospital
    Faculty address: 
    L. Puusepa 1a, 50406 Tartu
  • University of Tartu Foundation
    Faculty phone: 
    +372 737 5852
    Faculty address: 
    Ülikooli 18, 50090 Tartu
  • View all other units

Julia Suhorutsenko "Cell-penetrating peptides: cytotoxicity, immunogenicity and application for tumor targeting"

Date: 
04.10.2012 - 09:15 to 11:00

Supervisor: LOTI professor Ülo Langel

Oponent: Prof. Steven F. Dowdy, Howard Hughes Medical Institute, Dept. of Cellular and Molecular Medicine, University of California, San Diego, CA, USA

Ale Närvänen, University of Eastern Finland, Kuopio, Finland

Summary:
Cell-penetrating peptides: cytotoxicity, immunogenicity and application for tumor targeting
Suhorutšenko, Julia
URI: http://hdl.handle.net/10062/26400
Date: 2012-09-04
Abstract:

Viimastel aastatel, suur tähelepanu kasvajate ravis on pööratud mitmesugustele terapeutilise toimega ravimainete sisestamise strateegiatele, mis ühendavad endas nii ravimite spetsiifilist edastamist kui ka vähivastase kemoteraapiat. Rakku sisenevad peptiidid (RSPd või CPP-s, cell-penetrating peptides) osutunud väga tõhusateks vektoriteks selliste terapeutiliste ravimite sisseviimisel nagu proteiine ning nukleiinhappeid (plasmiidne DNA (pDNA) ja splaissingut korrigeerivaid oligonukleotiide (SKO)). RSPde kasutamine võib olla piiratud nende poolt põhjustatud kõrvaltoimete tõttu: tsütotoksilised efektid ning immunvastuse esilekutsumine. Käesoleva töö peamiseks eesmärgiks oli analüüsida uute RSPde, PepFect-ide immunogeenset ja tsütotoskilist aktiivsust in vitro ja in vivo; uurida p53 analoogsete peptiidide tsütotoksilisust ning apoptootilist toimet rinnavähi rakumudelil ning välja töötada uus RSP, mis on võimeline sisenema ja spetsiifiliselt ära tundma peaajuvähi rakke gliobalstoomi (U87 MG) rakumudelil nii in vitro kui ka in vivo. Esimeses töös näidati, et uued RSPd PepFect-id, mis põhinevad peptiidi transportaan järjestusel, ei avaldanud tsütotoksilist ega immunogeenset toimet immuunsüsteemi rakkudele peptiidi kontsentratsioonidel 5 µM ja 10 µM in vitro tingimustes. Sarnane tulemus saadi ka immunokompetentsete hiirte süstimisel, kui kasutatud annused olid suuremad kui 5 mg/kg kohta. Teises töös disainiti ning sünteesiti lühikesi p53-analoogseid peptiide, mis lisaks efektiivsele rakku sisenemisele avaldasid ka apoptootilist toimet rinnavähi rakkudele in vitro (seerumivabas keskkonnas). Lühikesed p53-analoogsed peptiidid omavad head perspektiivi vähivastase strateegia arendamiseks. Kolmandas töös kirjeldati uue transportvektori, gHoPe2, väljatöötamist, mis on võimeline spetsiifiliselt sihtmärkrakkudesse sisenema. Demonstreeriti ka selle potentsiaalseid kasutusvõimalusi ning toimet ainete transpordil vähirakkudesse. Neljandas töös näidati, et mitteamfipaatse ja sünteetilise (RxR)4 peptiidi stearüülhappega N-terminaalse modifitseerimine tagab efektiivse ning mitte toksilise nukleiinhappete transporti rakkudesse. Käesolev töö annab täiendava ülevaate vähispetsiifilistel RSPdel põhinevatest transportsüsteemidest, hinnates nende toksilisust, immunogeenset aktiivsust ning spetsiifilist transporti kasvajarakkudesse.

The delivery of therapeutic agents for the hard-to-treat tumors which comprise both targeting and anticancer chemotherapy strategies, have received much attention. Application of cell-penetrating peptides is one of very promising strategies for targeted drug delivery. However, similar issues as for any other drug delivery system: cytotoxicity and the tendency to induce innate immune response may limit their use. The current thesis is focused on the characterization of immunogenic and cytotoxic activities of cell-penetrating peptides PepFects, on the cytotoxic and apoptotic activities of newly designed cell-penetrating p53 analogues and on the development of a peptide-based glioma-targeted drug delivery vector. In Paper I, the cytotoxic and immunogenic activities of PepFect peptides and PepFect/nucleic acid complexes were analyzed in vitro and in vivo. The current study confirmed that PepFect peptides possess promising potential in nucleic acid delivery without evidence of undesired cytotoxicity and inflammation at the concentrations of 10 μM and 5 μM, respectively in vitro and at a dose of 5 mg/kg in vivo. In Paper II, we generated short p53-derived cell-penetrating protein analogues and analyzed their internalization efficacy, cytotoxic and apoptotic activities in the neuroblastoma and breast cancer cell lines. Even though the effect was observed under serum-free conditions, the novel protein analogues demonstrated selective apoptotic activity in the p53-non-active breast cancer cell line suggesting promising perspectives for a future anticancer strategy. In Paper III, a novel tumor-selective peptide-based drug delivery platform gHoPe2 has been developed demonstrating potential application of CPP-s for tumor-targeted delivery. In Paper IV, we showed that N-terminal modification of non-amphipathic (RxR)4 with stearic acid moiety resulted in efficient peptide vector for nucleic acids delivery in non-toxic manner. In conclusion, the current work provides evidence for the development of apoptotic protein-derived cell-penetrating peptides and tumor-targeted cell-penetrating peptide-based drug delivery vector with reduced toxicity and immunogenicity.

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