title: 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.
authors.affiliation: Research Institute for Drug Delivery Science, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan; Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Koziolová
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Etrych
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Chytil
authors.affiliation: Research Institute for Drug Delivery Science, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan; Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.affiliation: Research Institute for Drug Delivery Science, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan. Electronic address: hirmaeda@ph.sojo-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental; D008689:Methacrylates / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008813:Mice, Inbred ICR; D009369:Neoplasms / Q000188:drug therapy*; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: C103306:2,3,10,11-tetrahydroxytetrahydroprotoberberine; D000970:Antineoplastic Agents; D001600:Berberine Alkaloids; D050091:Dendrimers; D004337:Drug Carriers; D008689:Methacrylates; C104700:PAMAM Starburst; D011108:Polymers; D004317:Doxorubicin; C027260:pirarubicin; C032802:hydroxypropyl methacrylate
keywords: Acid-cleavable linkage; Chemical carcinogenesis; Controlled drug release; Dendrimer-derived polymer conjugate; EPR effect; HPMA polymer conjugate; Pirarubicin (THP)