Koning G A, Morselt H W, Gorter A, Allen T M, Zalipsky S, Kamps J A, Scherphof G L
Department of Cell Biology, Groningen University Institute for Drug Exploration, Faculty of Medical Sciences, University of Groningen, The Netherlands.
Pharm Res. 2001 Sep;18(9):1291-8. doi: 10.1023/a:1013085811044.
Compare pharmacokinetics of tumor-directed immunoliposomes in healthy and tumor-bearing rats (hepatic colon cancer metastases).
A tumor cell-specific monoclonal antibody was attached to polyethyleneglycol-stabilized liposomes, either in a random orientation via a lipid anchor (MPB-PEG-liposomes) or uniformly oriented at the distal end of the PEG chains (Hz-PEG-liposomes). Pharmacokinetics and tissue distribution were determined using [3H]cholesteryloleylether or bilayer-anchored 5-fluoro[3H]deoxyuridine-dipalmitate ([3H]FUdR-dP) as a marker.
In healthy animals clearance of PEG-(immuno)liposomes was almost log-linear and only slightly affected by antibody attachment; in tumor-bearing animals all liposomes displayed biphasic clearance. In normal and tumor animals blood elimination increased with increasing antibody density; particularly for the Hz-PEG-liposomes, and was accompanied by increased hepatic uptake, probably due to increased numbers of macrophages induced by tumor growth. The presence of antibodies on the liposomes enhanced tumor accumulation: uptake per gram tumor tissue (2-4% of dose) was similar to that of liver. Remarkably, this applied to tumor-specific and irrelevant antibody. Increased immunoliposome uptake by trypsin-treated Kupffer cells implicated involvement of high-affinity Fc-receptors on activated macrophages.
Tumor growth and immunoliposome characteristics (antibody density and orientation) determine immunoliposome pharmacokinetics. Although with a long-circulating immunoliposome formulation, efficiently retaining the prodrug FUdR-dP, we achieved enhanced uptake by hepatic metastases, this was probably not mediated by specific interaction with the tumor cells, but rather by tumor-associated macrophages.
比较肿瘤导向免疫脂质体在健康大鼠和荷瘤大鼠(肝结肠癌转移瘤)中的药代动力学。
将肿瘤细胞特异性单克隆抗体连接到聚乙二醇稳定的脂质体上,抗体通过脂质锚以随机方向连接(MPB - PEG - 脂质体),或者均匀地连接在聚乙二醇链的远端(Hz - PEG - 脂质体)。使用[3H]胆固醇油醚或双层锚定的5 - 氟[3H]脱氧尿苷 - 二棕榈酸酯([3H]FUdR - dP)作为标记物来测定药代动力学和组织分布。
在健康动物中,聚乙二醇(免疫)脂质体的清除几乎呈对数线性,且仅受抗体连接的轻微影响;在荷瘤动物中,所有脂质体均表现出双相清除。在正常和肿瘤动物中,血液清除率随抗体密度增加而增加;特别是对于Hz - PEG - 脂质体,同时肝脏摄取增加,这可能是由于肿瘤生长诱导的巨噬细胞数量增加所致。脂质体上抗体的存在增强了肿瘤蓄积:每克肿瘤组织的摄取量(剂量的2 - 4%)与肝脏相似。值得注意的是,这适用于肿瘤特异性抗体和无关抗体。经胰蛋白酶处理的库普弗细胞对免疫脂质体摄取增加,提示活化巨噬细胞上的高亲和力Fc受体参与其中。
肿瘤生长和免疫脂质体特性(抗体密度和方向)决定免疫脂质体的药代动力学。尽管使用了一种长效循环免疫脂质体制剂,能有效保留前药FUdR - dP,但我们发现肝转移瘤摄取增加,这可能不是由与肿瘤细胞的特异性相互作用介导的,而是由肿瘤相关巨噬细胞介导的。