title: Effective delivery of chemotherapeutic nanoparticles by depleting host Kupffer cells.
abstract: Although chemotherapeutic nanoparticles would confer various advantages, the majority of administrated nanoparticles are known to be spoiled by the reticuloendothelial system (RES). Intending to more effectively deliver therapeutic nanoparticles to target regions in vivo, host RES, especially Kupffer cells in the liver, have been depleted ahead of drug administration. To demonstrate this hypothesis, clodronate liposomes were preinjected into BALB/c nude mice for depletion of Kupffer cells 2 days before, and pegylated liposomal doxorubicin (Doxil) at the doses of 1.25, 2.5 and 5.0 mg/kg was administered. As a result, doxorubicin accumulation in the liver was decreased from 36 to 26% injected dose/organ by the Kupffer cells depletion, and consequently, the plasma concentration of doxorubicin was significantly enhanced threefold (from 11 to 33 μg/mL) on day 1 at 1.25 mg/kg-dose group. Doxorubicin accumulation in the tumor was increased from 0.78 to 3.0 μg/g-tissue on day 3, and tumor growth inhibition by Doxil was significantly boosted (tumor volumes from 751 to 482 mm(3)  on day 24) by the Kupffer cells depletion. In conclusion, Kupffer cells depletion by clodronate liposomes enhanced the plasma concentration and antitumor effects of Doxil, and would be widely applicable for various clinical cancer chemotherapies using nanoparticles.
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohara
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Oda
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yamada
authors.forename: Shinji
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Akashi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Miyamoto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Ryoko
authors.initials: R
authors.lastname: Sasaki
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ohkohchi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058726:Nanoconjugates / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D058726:Nanoconjugates; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin