title: Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin.
abstract: Previously, we prepared a pirarubicin (THP)-encapsulated micellar drug using styrene-maleic acid copolymer (SMA) as the drug carrier, in which active THP was non-covalently encapsulated. We have now developed covalently conjugated SMA-THP (SMA-THP conjugate) for further investigation toward clinical development, because covalently linked polymer-drug conjugates are known to be more stable in circulation than drug-encapsulated micelles. The SMA-THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation. Consequently, SMA-THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor-targeting efficiency by the enhanced permeability and retention (EPR) effect. As a result, remarkable antitumor effect was achieved against two types of tumors in mice without apparent adverse effects. Significantly, metastatic lung tumor also showed the EPR effect, and this conjugate reduced metastatic tumor in the lung almost completely at 30 mg/kg once i.v. (less than one-fifth of the maximum tolerable dose). Although SMA-THP conjugate per se has little cytotoxicity in vitro (1/100 of free drug THP), tumor-targeted accumulation by the EPR effect ensures sufficient drug concentrations in tumor to produce an antitumor effect, whereas toxicity to normal tissues is much less. These findings suggest the potential of SMA-THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor-targeting properties in vivo.
authors.affiliation: Institute for Drug Delivery Science, Sojo University, Kumamoto, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsukigawa
authors.forename: Long
authors.initials: L
authors.lastname: Liao
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008298:Maleates / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D024101:Mitochondrial Proteins; D011137:Polystyrenes / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008298:Maleates; D008823:Micelles; D024101:Mitochondrial Proteins; D011137:Polystyrenes; C558496:SPATA18 protein, human; C024074:styrene-maleic acid polymer; D004317:Doxorubicin; C027260:pirarubicin
keywords: Antimetastatic property; SMA-THP conjugate; antitumor effect; enhanced permeability and retention effect; prolonged plasma half-life