Moghimi S M, Muir I S, Illum L, Davis S S, Kolb-Bachofen V
Department of Pharmaceutical Sciences, University of Nottingham, UK.
Biochim Biophys Acta. 1993 Nov 7;1179(2):157-65. doi: 10.1016/0167-4889(93)90137-e.
The surfaces of polystyrene microspheres (60 nm in diameter) and colloidal gold particles (17 nm in diameter) were coated with a polyoxyethylene (POE)/polyoxypropylene (POP) block co-polymer; poloxamine-908. The polymer adsorb strongly to the microspheres via its relatively hydrophobic POP segments. This leaves the POE chains in a mobile state as they extend outward from the surface and thereby provide stability to the particle suspension by suppressing aggregation. The blood clearance and biodistribution of uncoated vs. poloxamine-908-coated 125I-labelled polystyrene microspheres were compared 1 h after intravenous administration into rats. Poloxamine coating dramatically reduced liver accumulation of microspheres and kept them within the systemic circulation. These observations were further confirmed by electron microscopy, demonstrating that Kupffer cells were loaded with uncoated latex but had ingested few if any of the poloxamine-908-coated particles. The interaction of uncoated and poloxamine-coated gold particles with freshly isolated rat liver sinusoidal cells was examined by electron microscopy. The accumulation in Kupffer cells of gold particles after opsonization with autologous plasma was in accordance with previous observations where the dominant opsonizing activity had been identified as fibronectin. In contrast, coating of gold particles with poloxamine-908 prior to plasma opsonization prevented the adsorption of fibronectin onto their surface. Simultaneously, Kupffer cells failed to recognize poloxamine-908-coated gold particles before and after opsonization. Unlike Kupffer cells, liver endothelial cells endocytosed poloxamine-908-coated gold particles prior to opsonization but failed to recognize them after the opsonization process. This was taken as an indication of the presence of dysopsonic activity in plasma. This dysopsonic activity was studied using polystyrene latex microspheres, where the uptake of such particles by phagocytes is known to be independent of opsonization. The coating of 125I-labelled polystyrene microspheres with poloxamine-908 dramatically reduced their interaction with liver sinusoidal cells. This interaction was further reduced in the presence of either autologous plasma or serum. A heat-stable (60 degrees C for 15 min) serum component of molecular mass > 100 kDa was found to mediate this suppressive effect. Thus, we demonstrate that organ-specific receptors, opsonin activities and plasma dysopsonins regulate the in vivo clearance of particulate materials from the circulation. Poloxamine-908 coating modulates particle clearance by effectively blocking opsonization but still allowing for dysopsonization.
聚苯乙烯微球（直径60纳米）和胶体金颗粒（直径17纳米）的表面用聚氧乙烯（POE）/聚氧丙烯（POP）嵌段共聚物泊洛沙明-908进行了包被。该聚合物通过其相对疏水的POP链段强烈吸附在微球上。这使得POE链处于可移动状态，因为它们从表面向外延伸，从而通过抑制聚集为颗粒悬浮液提供稳定性。将未包被与泊洛沙明-908包被的125I标记聚苯乙烯微球静脉注射到大鼠体内1小时后，比较了它们的血液清除率和生物分布。泊洛沙明包被显著降低了微球在肝脏中的蓄积，并使其保持在体循环中。电子显微镜进一步证实了这些观察结果，表明库普弗细胞摄取了未包被的乳胶，但几乎没有摄取泊洛沙明-908包被的颗粒。通过电子显微镜检查了未包被和泊洛沙明包被的金颗粒与新鲜分离的大鼠肝窦细胞的相互作用。用自体血浆调理后，金颗粒在库普弗细胞中的蓄积与先前的观察结果一致，在先前的观察中已确定主要的调理活性物质为纤连蛋白。相反，在血浆调理之前用泊洛沙明-908包被金颗粒可防止纤连蛋白吸附到其表面。同时，库普弗细胞在调理前后均无法识别泊洛沙明-908包被的金颗粒。与库普弗细胞不同，肝内皮细胞在调理之前会内吞泊洛沙明-908包被的金颗粒，但在调理过程之后无法识别它们。这被视为血浆中存在抗调理活性的一个指标。使用聚苯乙烯乳胶微球对这种抗调理活性进行了研究，已知吞噬细胞对这类颗粒的摄取与调理无关。用泊洛沙明-908包被125I标记的聚苯乙烯微球可显著降低它们与肝窦细胞的相互作用。在存在自体血浆或血清的情况下，这种相互作用会进一步降低。发现一种分子量>100 kDa的热稳定（60℃，15分钟）血清成分介导了这种抑制作用。因此，我们证明器官特异性受体、调理素活性和血浆抗调理素调节循环中颗粒物质的体内清除。泊洛沙明-908包被通过有效阻断调理作用但仍允许抗调理作用来调节颗粒清除。
