Experimental use of Liposome-encapsulated hemoglobin to improve microcirculation and oxygenation

背景我们验证了一种具有高氧亲和力（P_ =10 mmHg）的超小（200 nm）脂质体包裹血红蛋白（莱赫<50>）可能限制循环功能不全的缺血性损伤如脑缺血（CI）、心肌缺血（MI）和增强肿瘤放疗的假设。在阻断大鼠右侧大脑中动脉前、后5分钟分别静脉注射1%体重的莱赫。24小时后，用MRI系统获得皮质1纹状体、海马和梨状叶的T2加权相对信号强度，比较脑水肿的严重程度与未治疗的CI大鼠。莱赫可有效减轻除梨状叶外的所有脑区脑水肿。莱赫能有效减轻大鼠脑缺血前后的脑水肿。分别于左前降支闭塞后10、40分钟及再灌注后20分钟，对莱赫或1%生理盐水预处理的大鼠进行压力-容积环分析。虽然舒张末期或收缩末期左心室容积没有差异，但每搏输出量、舒张末期压和射血分数在LEH治疗的大鼠中显著保留。放射治疗前30、60、90和120分钟分别静脉输注NRC（0.5%、1%、2%体重）。放疗前30 min输注1%NRC效果最好，肿瘤生长时间由未治疗的20 d延长至26 d，延长5倍。高O_2亲和力莱赫能有效改善脑缺血和心肌缺血，增强放射治疗抗肿瘤生长的作用。最佳剂量、时间和O_2亲和力有待进一步确定。

Background. We tested a hypothesis that an ultra-small (200 nm) liposome-encapsulated-hemoglobin (LEH) with a high oxygen affinity (P_<50>=10 mmHg) may limit ischemia damages in circulatory insufficiency such as cerebral ischemia (CI), myocardial ischemia (MI) and potentiate tumor radiotherapy.Cerabral Ischemia. LEH was intravenously infused 1% of body weight 5 minutes before and after occlusion of the right middle cerebral artery in rats. Severity of edema was compared with CI rats without treatment 24-hour later on T2 weighed relative signal strength obtained with MRI system at cortex1 striatum, hippocampus and pyriform lobe. LEH was effective in reducing brain edema in all areas except in pyriform lobe in LEH-treated rats. LEH was effective in reducing brain edema before as well as after CI in the rat.Myocardial Ischemia. Pressure-volume loops were analyzed 10 and 40 minutes after occlusion of the left anterior descending artery and 20 minutes after reperfusion in rats pretreated with LEH or saline of 1% body-weight. Although end-diastolic or end-systolic left ventricular volumes were not different, stroke volume, end-diastolic pressure and ejection fraction were significantly preserved in LEH-treated rats.Neoplasm. NRC (0.5%, 1%, 2% of body weight) was intravenously infused 30, 60, 90 and 120 minutes before radiation therapy on implanted squamous cell carcinoma in mice. NRC was most effective when 1% NRC infusion 30 minutes prior to radiation, which prolonged 5-times tumor -growth time from 20 days (no treatment) to 26 days.Conclusion. High-O_2-affinity LEH was effective to ameliorate cerebral and myocardial ischemia and potentiate radiation therapy against tumor growth. Optimal dose, timing and O_2-affinity need to be further defined.