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High-molecular weight star conjugates containing docetaxel with high anti-tumor activity and low systemic toxicity in vivo
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SYSNO ASEP 0439488 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title High-molecular weight star conjugates containing docetaxel with high anti-tumor activity and low systemic toxicity in vivo Author(s) Etrych, Tomáš (UMCH-V) RID, ORCID
Strohalm, Jiří (UMCH-V)
Šírová, Milada (MBU-M) RID, ORCID
Tomalová, Barbora (MBU-M) ORCID
Rossmann, Pavel (MBU-M)
Říhová, Blanka (MBU-M) RID
Ulbrich, Karel (UMCH-V) RID
Kovář, Marek (MBU-M) RID, ORCIDSource Title Polymer Chemistry . - : Royal Society of Chemistry - ISSN 1759-9954
Roč. 6, č. 1 (2015), s. 160-170Number of pages 11 s. Language eng - English Country GB - United Kingdom Keywords star polymer ; HPMA copolymers ; docetaxel Subject RIV CD - Macromolecular Chemistry Subject RIV - cooperation Institute of Microbiology - Immunology R&D Projects GAP301/11/0325 GA ČR - Czech Science Foundation (CSF) GCP207/12/J030 GA ČR - Czech Science Foundation (CSF) EE2.3.20.0055 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UMCH-V - RVO:61389013 ; MBU-M - RVO:61388971 UT WOS 000345898100017 EID SCOPUS 84914680188 DOI 10.1039/C4PY01120A Annotation Here we present the polymer conjugates where the core formed by poly(amido amine) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing docetaxel (DTX) attached by a pH-sensitive hydrazone bond. DTX was derivatized with three different keto acids prior to attachment to the polymer carrier to introduce reactive keto groups into the drug. The therapeutic efficacy of such high-molecular-weight star conjugates is based on: (a) the enhanced permeability and retention (EPR) effect facilitating selective accumulation within solid tumors; (b) pH-controlled release of the drug, thus ensuring faster DTX release in the mildly acidic tumor microenvironment. The star DTX conjugate had a remarkably higher maximum tolerated dose in comparison with free DTX when administered as a single i.v. injection ([similar]160 mg kg−1vs. 40 mg kg−1 of DTX) in C57BL/6 mice. The star DTX conjugate showed significantly higher antitumor activity than free drug in the EL4 T cell lymphoma growing in syngeneic C57BL/6 mice even when given at the same dose (20 mg kg−1 of DTX eq.). Thus, the star DTX conjugates exert a much higher therapeutic activity and yet a lower systemic toxicity than free DTX. Workplace Institute of Macromolecular Chemistry Contact Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Year of Publishing 2015
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