Wong J P, Yang H, Nagata L, Kende M, Levy H, Schnell G, Blasetti K
Medical Countermeasures Section, Defence Research Establishment Suffield, Medicine Hat., Ralston, Alta., Canada.
Vaccine. 1999 Mar 26;17(13-14):1788-95. doi: 10.1016/s0264-410x(98)00439-3.
The use of liposome delivery technology to enhance the antiviral activity of poly ICLC (an immunomodulating dsRNA) while decreasing its intrinsic toxicity is evaluated in this study. The antiviral efficacies of free and liposome-encapsulated poly ICLC were evaluated and compared using a lethal respiratory influenza A virus infection in mice. The toxicity profiles of free and liposome-encapsulated poly ICLC were compared by determining the extent of hypothermia and loss in body weights in mice pretreated with these drugs. Poly ICLC was encapsulated in cationic liposomes prepared by the freeze drying method. To determine the antiviral efficacies of free and liposome-encapsulated poly ICLC, mice were intranasally pretreated with two doses of poly ICLC (free or liposomal, 1 mg/kg/dose) given 48 h apart. At various times post pretreatment, mice were intranasally challenged with 10 LD50 mouse-adapted influenza A/PR/8 (H1N1) virus. The survival rates of the mice were determined at day 14 post infected and compared to the untreated control mice. Results indicate mice pretreated with liposome-encapsulated poly ICLC within 3 weeks prior to virus challenge were completely protected (100% survival compared to 0% for the untreated control group, p < 0.001), while window of protection provided by free unencapsulated poly ICLC was 12 days. When the toxicity profiles of free and liposome-encapsulated poly ICLC were compared, it was found that hypothermia and body weight loss induced by poly ICLC were either completely mitigated or significantly reduced in mice given equivalent doses of poly ICLC in the liposome-encapsulated form. These results suggest that liposomes are an excellent drug carrier for poly ICLC, that liposome-encapsulated poly ICLC may provide a safe and effective immunotherapeutic approach for the prevention of respiratory influenza virus infections.
本研究评估了使用脂质体递送技术增强聚肌胞苷酸（一种免疫调节双链RNA）的抗病毒活性，同时降低其内在毒性。使用致死性甲型流感病毒感染小鼠，评估并比较了游离型和脂质体包裹型聚肌胞苷酸的抗病毒效力。通过测定用这些药物预处理的小鼠的体温过低程度和体重减轻情况，比较了游离型和脂质体包裹型聚肌胞苷酸的毒性特征。聚肌胞苷酸被包裹在通过冷冻干燥法制备的阳离子脂质体中。为了确定游离型和脂质体包裹型聚肌胞苷酸的抗病毒效力，小鼠经鼻预处理两剂聚肌胞苷酸（游离型或脂质体包裹型，1mg/kg/剂），间隔48小时给药。在预处理后的不同时间，小鼠经鼻接种10倍半数致死量的小鼠适应株甲型流感病毒A/PR/8（H1N1）。在感染后第14天测定小鼠的存活率，并与未处理的对照小鼠进行比较。结果表明，在病毒攻击前3周内用脂质体包裹型聚肌胞苷酸预处理的小鼠得到了完全保护（存活率100%，未处理对照组为0%，p<0.001），而游离未包裹的聚肌胞苷酸提供的保护窗口为12天。当比较游离型和脂质体包裹型聚肌胞苷酸的毒性特征时，发现给予等量脂质体包裹形式聚肌胞苷酸的小鼠中，聚肌胞苷酸诱导的体温过低和体重减轻要么完全减轻，要么显著降低。这些结果表明，脂质体是聚肌胞苷酸的优良药物载体，脂质体包裹型聚肌胞苷酸可能为预防呼吸道流感病毒感染提供一种安全有效的免疫治疗方法。
