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Comparison of the pharmacological and biological properties of HPMA copolymer-pirarubicin conjugates: A single-chain copolymer conjugate and its biodegradable tandem-diblock copolymer conjugate
T. Etrych, K. Tsukigawa, H. Nakamura, P. Chytil, J. Fang, K. Ulbrich, M. Otagiri, H. Maeda,
Language English Country Netherlands
Document type Comparative Study, Journal Article
- MeSH
- Biological Availability MeSH
- Biological Transport MeSH
- Doxorubicin adverse effects analogs & derivatives chemistry pharmacology MeSH
- Polymethacrylic Acids chemical synthesis MeSH
- Humans MeSH
- Molecular Weight MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Drug Carriers chemical synthesis MeSH
- Half-Life MeSH
- Antineoplastic Agents adverse effects chemistry pharmacology MeSH
- Renal Reabsorption MeSH
- Tissue Distribution MeSH
- Drug Liberation MeSH
- Chromatography, High Pressure Liquid methods MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
In this study, we compared the enhanced permeability and retention (EPR) effect, toxicity, and therapeutic effect of the conjugate of the linear polymer poly(N-(2-hydroxypropyl)methacrylamide) (HPMA) with pirarubicin with an Mw below the renal threshold (39g/mol) (named LINEAR) and the disulfide-linked tandem-polymeric dimer of the poly(HPMA)-pirarubicin conjugate with an Mw above the renal threshold (93g/mol) (named DIBLOCK). The DIBLOCK conjugate, which was susceptible to reductive degradation, showed both a better EPR effect (tumor delivery) (2.5 times greater at 24h) and a prolonged plasma half-life. In addition, DIBLOCK had a better antitumor effect, as judged by percent survival, than did LINEAR (80% vs 65% at 150days), without any apparent toxicity in an S180 tumor model. However, the LD50 value of LINEAR was slightly higher than that of DIBLOCK (50mg/kg vs 37.5mg/kg, respectively). DIBLOCK required a longer time than LINEAR to reach maximum accumulation in the tumor. DIBLOCK also showed a greater time-dependent increase in the concentration in the tumor compared with the plasma concentration.
Faculty of Pharmaceutical Sciences Sojo University Ikeda 4 22 1 Nishi ku Kumamoto 860 0082 Japan
Institute for Drug Delivery Science Sojo University Ikeda 4 22 1 Nishi ku Kumamoto 860 0082 Japan
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- $a In this study, we compared the enhanced permeability and retention (EPR) effect, toxicity, and therapeutic effect of the conjugate of the linear polymer poly(N-(2-hydroxypropyl)methacrylamide) (HPMA) with pirarubicin with an Mw below the renal threshold (39g/mol) (named LINEAR) and the disulfide-linked tandem-polymeric dimer of the poly(HPMA)-pirarubicin conjugate with an Mw above the renal threshold (93g/mol) (named DIBLOCK). The DIBLOCK conjugate, which was susceptible to reductive degradation, showed both a better EPR effect (tumor delivery) (2.5 times greater at 24h) and a prolonged plasma half-life. In addition, DIBLOCK had a better antitumor effect, as judged by percent survival, than did LINEAR (80% vs 65% at 150days), without any apparent toxicity in an S180 tumor model. However, the LD50 value of LINEAR was slightly higher than that of DIBLOCK (50mg/kg vs 37.5mg/kg, respectively). DIBLOCK required a longer time than LINEAR to reach maximum accumulation in the tumor. DIBLOCK also showed a greater time-dependent increase in the concentration in the tumor compared with the plasma concentration.
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- $a Fang, Jun $u Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan; Institute for Drug Delivery Science, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan.
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- $a Otagiri, Masaki $u Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan; Institute for Drug Delivery Science, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan.
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