Development of an LDL Receptor-Targeted Peptide Susceptible to Facilitate the Brain Access of Diagnostic or Therapeutic Agents
Development of an LDL Receptor-Targeted Peptide Susceptible to Facilitate the Brain Access of Diagnostic or Therapeutic Agents
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DOI：
10.3390/biology9070161
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发表时间：
2020-07-01
期刊：
影响因子：
4.2
通讯作者：
Burtea, Carmen
中科院分区：
文献类型：
--
作者：
Andre, Severine;Larbanoix, Lionel;Burtea, Carmen
血脑屏障（BBB）的穿越和脑穿透对于治疗药物和成像探针的递送确实具有挑战性。需要开发新的交叉策略，迄今为止已经提出了广泛的方法（侵入性或非侵入性）。受体介导的转胞吞作用是一种有吸引力的机制，允许非侵入性穿透BBB。在可用的靶点中，低密度脂蛋白（LDL）受体（LDLR）显示出有利的特性，主要是因为溶酶体绕过LDL递送到大脑的途径，允许所携带的配体完整地释放到大脑靶点。利用噬菌体展示技术筛选出一个针对LDLR胞外区的十二肽（ED-LDLR）。该肽能够在天然配体存在下结合ED-LDLR，并在酸性pH和不存在钙的情况下解离，其方式与LDL相似。在体外，我们的肽通过小窝依赖性途径被内皮细胞内吞，适合于BBB中的LDLR途径，这表明其溶酶体降解的预防。通过磁共振成像和荧光寿命成像进行的体内研究表明这种ED-LDLR靶向肽的脑渗透。
Blood-brain barrier (BBB) crossing and brain penetration are really challenging for the delivery of therapeutic agents and imaging probes. The development of new crossing strategies is needed, and a wide range of approaches (invasive or not) have been proposed so far. The receptor-mediated transcytosis is an attractive mechanism, allowing the non-invasive penetration of the BBB. Among available targets, the low-density lipoprotein (LDL) receptor (LDLR) shows favorable characteristics mainly because of the lysosome-bypassed pathway of LDL delivery to the brain, allowing an intact discharge of the carried ligand to the brain targets. The phage display technology was employed to identify a dodecapeptide targeted to the extracellular domain of LDLR (ED-LDLR). This peptide was able to bind the ED-LDLR in the presence of natural ligands and dissociated at acidic pH and in the absence of calcium, in a similar manner as the LDL. In vitro, our peptide was endocytosed by endothelial cells through the caveolae-dependent pathway, proper to the LDLR route in BBB, suggesting the prevention of its lysosomal degradation. The in vivo studies performed by magnetic resonance imaging and fluorescent lifetime imaging suggested the brain penetration of this ED-LDLR-targeted peptide.