Blume G, Cevc G
Medizinische Biophysik-Forschungslaboratorien, Urologische Klinik und Poliklinik, Technischen Universität München, Germany.
Biochim Biophys Acta. 1993 Mar 14;1146(2):157-68. doi: 10.1016/0005-2736(93)90351-y.
An important, if not the chief, condition for the prolongation of the circulation times of lipid vesicles in vivo is the suppression of macromolecular adsorption onto the surface of such vesicles. This adsorption can be prevented very efficiently by a zone of suitably designed and mobile steric hindrances near the lipid layer surface. Lipid vesicles with such a surface coat, cryptosomes, thus circulate in blood for very long periods of time after systemic applications. Lipid vesicles composed of phosphatidylcholine molecules and of suitable polyoxyethylene (PEG) derivatives of phosphatidylethanolamine, for example, remain in the blood circulation 8-10-times longer than standard liposomes made of phosphatidylcholine only: in mice the half-lives of the former and latter vesicles, after an i.v. administration, are approx. 0.6 h and between 5.9 and 13.8 h, respectively. Vesicle longevity is not destroyed by the phosphatidylcholine chains fluidity. Vesicles consisting of a mixture of distearoylphosphatidylethanolamine-PEG (DSPE-PEG) with distearoylphosphatidylcholine or cryptosomes made of DSPE-PEG and soy-bean phosphatidylcholine, consequently, have a very similar fate in vivo. Furthermore, the cryptosome longevity is not affected directly by the presence of the net charges on the lipid membranes and is little sensitive to the details of the group coupling the PEG-headgroups and the lipidic (hydrophobic) anchor. However, the life-time and the distribution of the stabilized lipid vesicles in vivo depend quite sensitively on the surface density of the sterically active headgroups; often (if not always) the resistance to plasma components adsorption as well as the resulting longevity in vivo both show a maximum near the same lipid/stabilizer molar ratio. Optimum bilayer composition may differ for the different combinations of the main and sterically active membrane components. Its position is probably determined by the variations in the molecular mobility and the effective surface-coverage effects: both must be sufficiently high for the vesicle phagocytosis and accumulation in the reticulohystiocytic system to be suppressed. On the contrary, the bilayer surface hydrophilicity, which hitherto has been believed to be of paramount importance for the liposome longevity in vivo, is per se not relevant for the biological fate of the lipid vesicles, provided that this hydrophilicity exceeds some minimum value.
脂质囊泡在体内循环时间延长的一个重要条件（即便不是首要条件）是抑制大分子吸附到此类囊泡表面。通过在脂质层表面附近设置一个设计合理且可移动的空间位阻区域，能非常有效地防止这种吸附。具有这种表面涂层的脂质囊泡，即隐窝脂质体，在全身给药后能在血液中循环很长时间。例如，由磷脂酰胆碱分子和合适的磷脂酰乙醇胺聚氧乙烯（PEG）衍生物组成的脂质囊泡，在血液循环中的停留时间比仅由磷脂酰胆碱制成的标准脂质体长8 - 10倍：在小鼠体内，静脉注射后，前者和后者囊泡的半衰期分别约为0.6小时和5.9至13.8小时。囊泡的寿命不会因磷脂酰胆碱链的流动性而受到破坏。因此，由二硬脂酰磷脂酰乙醇胺 - PEG（DSPE - PEG）与二硬脂酰磷脂酰胆碱的混合物组成的囊泡或由DSPE - PEG和大豆磷脂酰胆碱制成的隐窝脂质体在体内具有非常相似的命运。此外，隐窝脂质体的寿命不受脂质膜上净电荷的直接影响，并且对连接PEG头基和脂质（疏水）锚的基团细节不太敏感。然而，稳定化脂质囊泡在体内的寿命和分布相当敏感地取决于空间活性头基的表面密度；通常（如果不是总是如此），对血浆成分吸附的抗性以及由此产生的体内寿命在接近相同的脂质/稳定剂摩尔比时都显示出最大值。对于主要膜成分和空间活性膜成分的不同组合，最佳双层组成可能会有所不同。其位置可能由分子流动性的变化和有效的表面覆盖效应决定：两者都必须足够高，才能抑制囊泡在网状组织细胞系统中的吞噬作用和积累。相反，迄今为止一直被认为对脂质体在体内的寿命至关重要的双层表面亲水性，就脂质囊泡的生物学命运而言，本身并不相关，前提是这种亲水性超过某个最小值。
