Liposome-Encapsulated Hemoglobin Ameliorates Tumor Hypoxia and Enhances Radiation Therapy to Suppress Tumor Growth in Mice

摘要

We hypothesize that liposome-encapsulated hemoglobin with high O 2 affinity (P 500 2=12mmHg, h-LEH) may increase O 2 delivery to hypoxic tumors and enhance radiation therapy synergistically to suppress tumor growth. First, h-LEH (5, 10, and 20mL/kg) was intravenously infused 30min before radiation (20Gy) of SCCVII tumor grown in C3H/HeN mice. Second, 10mL/kg of h-LEH was administered 30, 60, 90, and 120min 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 10mL/kg in comparison to 5 or 20mL/kg of h-LEH or EL. Tumor growth was most suppressed when the interval between h-LEH infusion and radiation was shortest, 30min. As a result, 10mL/kg of h-LEH infusion 30min prior to radiation prolonged 5-fold tumor-growth time from 20.0days (radiation and EL) to 26.5days, P0.01, synergy ratio 1.42. While human hemoglobin (h-LEH) was detected in tumors 0.5 to 24h after administration, HIF-1α accumulation was sparse and became significantly reduced compared to controls 48 and 72h after h-LEH infusion. h-LEH (10mL/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.