School of Pharmacy, Naval Medical University, Shanghai 200433, P.R. China.
Center of Medical Research and Innovation, Shanghai Pudong Hospital & Department of Pharmacology, School of Basic Medical Sciences & State Key Laboratory of Molecular Engineering of Polymers, Fudan University Shanghai Engineering Research Center for Synthetic Immunology, Shanghai 201399, P.R. China.
Nano Lett. 2022 Aug 24;22(16):6516-6522. doi: 10.1021/acs.nanolett.2c01509. Epub 2022 Aug 9.
Folic acid (FA) is one of the most widely utilized small-molecule ligands for cancer targeted drug delivery. Natural IgM was recently found to avidly absorb on the surface of FA-functionalized liposomes (FA-sLip), negatively regulating the performance by efficiently activating complement. Herein, FA-functionalized lipodiscs (FA-Disc) were constructed to successfully circumvent IgM-mediated opsonization and retained binding activity with folate receptors . The FA moiety along with the bound IgM was restricted to the highly curved rim of lipodiscs, leading to IgM incapability of presenting the membrane-bound conformation to trigger complement activation. The C1q docking, C3 binding, and C5a release were blocked and accelerated blood clearance phenomenon was mitigated of FA-Disc. FA-Disc retained folate binding activity and could effectively target folate receptor positive tumors . The present study provides a useful solution to avoid the negative regulation by IgM and achieve FA-enabled targeting by exploring disc-shaped nanocarriers.
叶酸（FA）是最广泛应用于癌症靶向药物递送的小分子配体之一。最近发现天然 IgM 会强烈吸附在 FA 功能化脂质体（FA-sLip）表面，通过有效激活补体来负调控性能。在此，构建了 FA 功能化脂质盘（FA-Disc），成功规避了 IgM 介导的调理作用，并保留了与叶酸受体的结合活性。FA 部分以及结合的 IgM 被限制在脂质盘的高度弯曲边缘，导致 IgM 无法呈现膜结合构象以触发补体激活。C1q 对接、C3 结合和 C5a 释放被阻断，FA-Disc 的加速血液清除现象得到缓解。FA-Disc 保留了叶酸结合活性，能够有效靶向叶酸受体阳性肿瘤。本研究通过探索盘状纳米载体提供了一种有用的解决方案，可以避免 IgM 的负调控并实现 FA 介导的靶向作用。
