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Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice.

Abstract
Previously we showed that linear poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (THP), LP-THP, with MW about 39 kDa, exhibited far better tumor accumulation and therapeutic effect than that of parental free THP. To improve the pharmacokinetics of LP-THP further, high-MW conjugate of poly(amido amine) (PAMAM) dendrimer grafted with semitelechelic HPMA copolymer (PHPMA) was synthesized [star polymer (SP); 400 kDa] and conjugated with THP via hydrazone bond-containing spacer (SP-THP). THP was conjugated to SP to form SP-THP via acid cleavable hydrazone bonding, which responds to acidic milieu of tumor tissue. As a consequence, it would release free THP, by active therapeutic principle. SP-THP exhibits larger hydrodynamic diameter (25.9 nm) in aqueous solution than that of LP-THP (8.2 nm) as observed by light scattering and size exclusion chromatography. Because of the larger size, the tumor AUC5h-72 h of SP-THP was 3.3 times higher than that of LP-THP. More importantly, released free THP was retained selectively in the tumor tissue for at least up to 72 h after administration of SP-THP. We found that SP-THP exhibited superior antitumor effect to LP-THP against both S-180 tumor-bearing mice in vivo, and with chemically AOM/DSS-induced colon tumor-bearing mice, most probably due to their different molecular size. In our comparison study of in vitro and in vivo behavior of SP-THP and LP-THP we concluded that SP-THP exhibited enhanced therapeutic efficacy not only in implanted tumor but also in orthotopic/spontaneous tumor despite its higher toxicity compared to LP-THP. Upon these findings further investigation using various tumors including transgenic, and metastatic tumors is going to be conducted soon.
AuthorsHideaki Nakamura, Eva Koziolová, Tomáš Etrych, Petr Chytil, Jun Fang, Karel Ulbrich, Hiroshi Maeda
JournalEuropean journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 90 Pg. 90-6 (Feb 2015) ISSN: 1873-3441 [Electronic] Netherlands
PMID25460144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.
Chemical References
  • 2,3,10,11-tetrahydroxytetrahydroprotoberberine
  • Antineoplastic Agents
  • Berberine Alkaloids
  • Dendrimers
  • Drug Carriers
  • Methacrylates
  • PAMAM Starburst
  • Polymers
  • Doxorubicin
  • pirarubicin
  • hydroxypropyl methacrylate
Topics
  • Animals
  • Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
  • Berberine Alkaloids (chemistry, pharmacokinetics)
  • Cell Line, Tumor
  • Dendrimers (chemistry, pharmacokinetics)
  • Doxorubicin (analogs & derivatives, chemistry, pharmacokinetics, pharmacology)
  • Drug Carriers (chemistry, pharmacokinetics)
  • HeLa Cells
  • Humans
  • Male
  • Melanoma, Experimental
  • Methacrylates (chemistry, pharmacokinetics)
  • Mice
  • Mice, Inbred ICR
  • Neoplasms (drug therapy)
  • Polymers (chemistry, pharmacokinetics)

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