Torchilin V P
Department of Radiology, Massachusetts General Hospital, Charlestown, USA.
J Mol Recognit. 1996 Sep-Dec;9(5-6):335-46. doi: 10.1002/(sici)1099-1352(199634/12)9:5/6<335::aid-jmr309>3.0.co;2-0.
To make universal and efficient liposome-based drug carriers, liposomes should be able to recognize and bind other targets beyond their natural targets, the cells of the reticuloendothial system. To make liposomes targeted, numerous methods to couple active substances, primarily, monoclonal antibodies, to the liposome surface have been developed. Resulting immunoliposomes (or affinity liposomes) demonstrate good targeting to cells and organs both in vitro and in vivo. However, the short circulation time of immunoliposomes prevented them from accumulating in targets with diminished blood flow or low antigen concentration. Long-circulating liposomes were prepared by coupling soluble and flexible polymers, such as polyethylene glycol, to the liposome surface. The mechanism of liposome steric protection with flexible polymers is based on the formation of dense "conformational cloud' by a grafted polymer over the liposome surface, and might be analyzed in terms of a statistical model of polymer solutions. By co-immobilization of specific antibodies and protecting polymers on the liposome surface, liposomes can be prepared combining both targetability and prolonged circulation in vivo. A biological model (experimental myocardial infarction in rabbit) was used to estimate the relative importance of different factors (liposome size and coating with protective polymer and/or specific antibody) for effective accumulation of liposomes in the target. Statistical analysis demonstrated that different types of liposomes have to be used in order to reach maximum absolute delivery of liposomes to the target, or maximum target-to-non-target ratio (relative delivery). Therefore, different liposomes should be used as carriers of diagnostic and therapeutic agents.
为了制备通用且高效的基于脂质体的药物载体，脂质体应能够识别并结合除其天然靶标（即网状内皮系统细胞）之外的其他靶标。为了使脂质体具有靶向性，人们已开发出多种将活性物质（主要是单克隆抗体）偶联到脂质体表面的方法。由此产生的免疫脂质体（或亲和脂质体）在体外和体内均表现出对细胞和器官的良好靶向性。然而，免疫脂质体的短循环时间使其无法在血流减少或抗原浓度低的靶标中蓄积。通过将可溶性柔性聚合物（如聚乙二醇）偶联到脂质体表面来制备长循环脂质体。柔性聚合物对脂质体的空间保护机制基于接枝聚合物在脂质体表面形成致密的“构象云”，并且可以根据聚合物溶液的统计模型进行分析。通过将特异性抗体和保护性聚合物共同固定在脂质体表面，可以制备出兼具靶向性和体内延长循环时间的脂质体。使用生物模型（兔实验性心肌梗死）来评估不同因素（脂质体大小以及用保护性聚合物和/或特异性抗体包被）对脂质体在靶标中有效蓄积的相对重要性。统计分析表明，为了实现脂质体向靶标的最大绝对递送或最大靶标与非靶标比率（相对递送），必须使用不同类型的脂质体。因此，应使用不同的脂质体作为诊断和治疗剂的载体。
