title: S-Nitrosated human serum albumin dimer as novel nano-EPR enhancer applied to macromolecular anti-tumor drugs such as micelles and liposomes.
abstract: The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors, and it can serve as a basis for the development of macromolecular anticancer therapy. We have previously found that recombinant human serum albumin dimer, and especially its S-nitrosated form (SNO-HSA-Dimer), is an enhancer of the EPR effect. In this study, we investigated the influence of SNO-HSA-Dimer on the anti-tumor effect of two types of macromolecular anti-tumor drugs, namely N-(2-hydroxypropyl)methacrylamide polymer conjugated with zinc protoporphyrin, which forms micelles and can be used for fluorescence studies. The other was PEGylated liposomal doxorubicin (Doxil), a typical example of a stealth liposome approved for medical usage. In mice having C26 tumors with highly permeable vasculature, SNO-HSA-Dimer increases tumor accumulation of the drugs by a factor 3-4 and thereby their anti-tumor effects. Experiments with Evans blue revealed increased EPR effect in all parts of the tumor. Furthermore, SNO-HSA-Dimer improves the anti-metastatic effects of Doxil and reduces its minor uptake in non-tumorous organs such as liver and kidney. Tumor accumulation of Doxil in B16 tumors, which are characterized by a low permeable vasculature, increased even more (6-fold) in the presence of SNO-HSA-Dimer, and the improved accumulation lead to decreased tumor volume and increased survival of the animals. The administration of SNO-HSA-Dimer itself is safe, because it has no effect on blood pressure, heart rate or on several biochemical parameters. The present findings indicate that SNO-HSA-Dimer is promising for enhancing the EPR effect and consequently the specific, therapeutic effects of macromolecular anticancer drugs.
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors: Ryo
authors: R
authors: Kinoshita
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Science, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors: Yu
authors: Y
authors: Ishima
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors: Mayumi
authors: M
authors: Ikeda
authors: Department of Biomedicine, University of Aarhus, DK-8000 Aarhus C, Denmark.
authors: Ulrich
authors: U
authors: Kragh-Hansen
authors: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan.
authors: Jun
authors: J
authors: Fang
authors: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan.
authors: Hideaki
authors: H
authors: Nakamura
authors: School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Perth 6845, Western Australia.
authors: Victor T G
authors: VT
authors: Chuang
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors: Ryota
authors: R
authors: Tanaka
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors: Hitoshi
authors: H
authors: Maeda
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors: Azusa
authors: A
authors: Kodama
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Science, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors: Hiroshi
authors: H
authors: Watanabe
authors: Drug Delivery System Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan.
authors: Hiroshi
authors: H
authors: Maeda
authors: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan; Drug Delivery System Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan. Electronic address: otagirim@ph.sojo-u.ac.jp.
authors: Masaki
authors: M
authors: Otagiri
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Science, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. Electronic address: tomaru@gpo.kumamoto-u.ac.jp.
authors: Toru
authors: T
authors: Maruyama
mesh_terms: D000178:Acrylamides / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009603:Nitroso Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010539:Permeability; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use; D055503:Protein Multimerization; D011524:Protoporphyrins / Q000493:pharmacokinetics / Q000627:therapeutic use; D012709:Serum Albumin / Q000494:pharmacology* / Q000627:therapeutic use; D000075462:Serum Albumin, Human; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D008081:Liposomes; D008823:Micelles; D009603:Nitroso Compounds; D011524:Protoporphyrins; C511514:S-nitrosoalbumin, human; D012709:Serum Albumin; C506643:liposomal doxorubicin; C017803:zinc protoporphyrin; D011092:Polyethylene Glycols; D004317:Doxorubicin; C032976:N-(2-hydroxypropyl)methacrylamide; D000075462:Serum Albumin, Human
keywords: Anti-metastatic effects; Anticancer; Enhanced permeability and retention; Human serum albumin dimer; Macromolecular drugs; Nitric oxide