title: Liposome-encapsulated hemoglobin ameliorates tumor hypoxia and enhances radiation therapy to suppress tumor growth in mice.
abstract: We hypothesize that liposome-encapsulated hemoglobin with high O₂ affinity (P₅₀0₂ = 12 mm Hg, h-LEH) may increase O₂ delivery to hypoxic tumors and enhance radiation therapy synergistically to suppress tumor growth. First, h-LEH (5, 10, and 20 mL/kg) was intravenously infused 30 min before radiation (20 Gy) of SCCVII tumor grown in C3H/HeN mice. Second, 10 mL/kg of h-LEH was administered 30, 60, 90, and 120 min prior to radiation to determine optimal timing. Tumor size was monitored thereafter to titrate tumor growth suppression. Third, additional mice with SCCVII tumor were infused with h-LEH or empty liposome (EL), and tumors were excised at various time points for immunohistochemical examination of h-LEH and hypoxia-inducible factor-1α (HIF-1α). h-LEH was most effective at 10 mL/kg in comparison to 5 or 20 mL/kg of h-LEH or EL. Tumor growth was most suppressed when the interval between h-LEH infusion and radiation was shortest, 30 min. As a result, 10 mL/kg of h-LEH infusion 30 min prior to radiation prolonged 5-fold tumor-growth time from 20.0 days (radiation and EL) to 26.5 days, P<0.01, synergy ratio 1.42. While human hemoglobin (h-LEH) was detected in tumors 0.5 to 24 h after administration, HIF-1α accumulation was sparse and became significantly reduced compared to controls 48 and 72 h after h-LEH infusion. h-LEH (10 mL/kg) was highly effective in enhancing radiation therapy synergistically under ambient respiration against tumor growth in mice. Decreased accumulation of HIF-1α in h-LEH-treated tumor may suggest targeted tumor oxygenation as a potential mechanism.
authors.affiliation: Department of Radiation Oncology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Murayama
authors.forename: Akira T
authors.initials: AT
authors.lastname: Kawaguchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Akemi
authors.initials: A
authors.lastname: Kamijo
authors.forename: Nobusuke
authors.initials: N
authors.lastname: Kato
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ohizumi
authors.forename: Sotaro
authors.initials: S
authors.lastname: Sadahiro
authors.forename: Munetaka
authors.initials: M
authors.lastname: Haida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001802:Blood Substitutes / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D010100:Oxygen / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D001802:Blood Substitutes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008081:Liposomes; D010100:Oxygen