Department of Radiation Oncology, City of Hope Medical Center, Duarte, California 91010, United States.
Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, Duarte, California 91010, United States.
Bioconjug Chem. 2020 Mar 18;31(3):743-753. doi: 10.1021/acs.bioconjchem.9b00854. Epub 2020 Jan 30.
Lipid nanodiscs (LNDs), comprising a phospholipid bilayer encircled by two molecules of a recombinant membrane scaffold protein, can be targeted to tumors with covalently attached antibodies (Abs) or their fragments. Antibody attachment to click chemistry based PEGylated lipids on LNDs including DOTA allowed PET imaging with the positron emitter Cu. Carcinoembryonic antigen (CEA) positive tumors in CEA transgenic mice were chosen as a tumor target. Fab' fragments, that otherwise are rapidly cleared by the kidney due to their small size, were retained in circulation when conjugated to LNDs. Untargeted PET imaging of Cu-DOTA-LNDs revealed low tumor uptake (4-5% ID/g) in the range expected for the enhanced permeability retention (EPR) effect with high liver uptake (17-21% ID/g) indicating gut clearance. Fab' targeted LNDs showed little improvement over untargeted LNDs, but intact IgG targeted LNDs gave high tumor uptake (40% ID/g) with low liver (8% ID/g), demonstrating that tumor targeting with antibody conjugated LNDs is feasible.
脂质纳米盘（LNDs）由磷脂双层组成，周围环绕着两种重组膜支架蛋白，可通过共价连接的抗体（Abs）或其片段靶向肿瘤。抗体连接到 LNDs 上的基于点击化学的聚乙二醇化脂质上，包括 DOTA，允许使用正电子发射体 Cu 进行 PET 成像。选择癌胚抗原（CEA）阳性转基因小鼠中的 CEA 阳性肿瘤作为肿瘤靶标。Fab'片段由于其体积小，否则会因肾脏快速清除，当与 LNDs 结合时，在循环中保留。未靶向的 Cu-DOTA-LNDs 的 PET 成像显示，在增强通透性保留（EPR）效应的范围内，肿瘤摄取量较低（4-5% ID/g），肝脏摄取量较高（17-21% ID/g），表明肠道清除。Fab'靶向 LNDs 与未靶向 LNDs 相比没有明显改善，但完整 IgG 靶向 LNDs 显示出高肿瘤摄取量（40% ID/g）和低肝脏摄取量（8% ID/g），表明抗体偶联 LNDs 的肿瘤靶向是可行的。
