Department of Biomedical Engineering, University of California, Davis, CA 95616, USA.
J Control Release. 2011 Apr 10;151(1):28-34. doi: 10.1016/j.jconrel.2011.01.008. Epub 2011 Jan 15.
Changes in lipid acyl chain length can result in desorption of lipid from the liposomal anchorage and interaction with blood components. PET studies of the stability of such lipids have not been performed previously although such studies can map the pharmacokinetics of unstable lipids non-invasively in vivo. The purpose of this study was to characterize the in vivo clearance of (64)Cu-labeled distearoyl- and dipalmitoyl lipid included within long circulating liposomes. Distearoyl and dipalmitoyl maleimide lipids (1mol%) in liposomes were labeled with a (64)Cu-incorporated bifunctional chelator (TETA-PDP) after the activation of pyridine disulfide to thiol by TCEP. Long circulating liposomes containing HSPC:DSPE-PEG2k-OMe:cholesterol: x (55:5:39:1), where x was (64)Cu-DSPE or (64)Cu-DPPE, or HSPC:DSPE-PEG2k-OMe:cholesterol:(64)Cu-DSPE:DPPC (54:5:39:1:1) were evaluated in serum (in vitro) and via intravenous injection to FVB mice. The time-activity curves for the blood, liver, and kidney were measured from PET images and the biodistribution was performed at 48h. In vitro assays showed that (64)Cu-DPPE transferred from liposomes to serum with a 7.9h half-life but (64)Cu-DSPE remained associated with the liposomes. The half clearance of radioactivity from the blood pool was 18 and 5h for (64)Cu-DSPE- and (64)Cu-DPPE liposome-injected mice, respectively. The clearance of radioactivity from the liver and kidney was significantly greater following the injection of (64)Cu-DPPE-labeled liposomes than (64)Cu-DSPE-labeled liposomes at 6, 18 and 28h. Forty eight hours after injection, the whole body radioactivity was 57 and 17% ID/cc for (64)Cu-DSPE and (64)Cu-DPPE, respectively. These findings suggest that the acyl chain length of the radiolabel should be considered for liposomal PET studies and that PET is an effective tool for evaluating the stability of nanoformulations in vivo.
脂质酰链长度的变化可能导致脂质从脂质体锚定中解吸，并与血液成分相互作用。尽管此类研究可以无创地在体内描绘不稳定脂质的药代动力学，但以前尚未对这类脂质的 PET 稳定性进行研究。本研究旨在表征（64）Cu 标记的二硬脂酰基和二棕榈酰基脂质在长循环脂质体中的体内清除率。二硬脂酰基和二棕榈酰基马来酰亚胺脂质（1mol％）在脂质体中通过 TCEP 激活吡啶二硫代将巯基转化为硫醇后，用（64）Cu 掺入的双功能螯合剂（TETA-PDP）标记。含有 HSPC：DSPE-PEG2k-OMe：胆固醇：x（55：5：39：1）的长循环脂质体，其中 x 为（64）Cu-DSPE 或（64）Cu-DPPE，或 HSPC：DSPE-PEG2k-OMe：胆固醇：（64）Cu-DSPE：DPPC（54：5：39：1：1）在血清（体外）中和通过静脉内注射到 FVB 小鼠中进行评估。通过 PET 图像测量血液、肝脏和肾脏的时间-活性曲线，并在 48 小时时进行生物分布。体外测定表明，（64）Cu-DPPE 从脂质体转移到血清中的半衰期为 7.9 小时，但（64）Cu-DSPE 仍与脂质体结合。（64）Cu-DSPE 和（64）Cu-DPPE 脂质体注射小鼠的血液池放射性清除半衰期分别为 18 和 5 小时。与（64）Cu-DSPE 标记的脂质体相比，（64）Cu-DPPE 标记的脂质体在 6、18 和 28 小时时，放射性从肝脏和肾脏的清除率明显更高。注射后 48 小时，（64）Cu-DSPE 和（64）Cu-DPPE 的全身放射性分别为 57 和 17％ID/cc。这些发现表明，在脂质体 PET 研究中应考虑放射性标记的酰链长度，并且 PET 是评估纳米制剂体内稳定性的有效工具。
