Department of Pharmacy, Peking University Third Hospital, Beijing, China.
Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou, China.
Signal Transduct Target Ther. 2022 Jun 10;7(1):175. doi: 10.1038/s41392-022-00995-z.
Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier (BLB) on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability, which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue. Here, we report the finding of a novel receptor, low-density lipoprotein receptor-related protein 1 (LRP1), that is expressed on the BLB, as a potential target for shuttling therapeutics across this barrier. As a proof-of-concept, we developed an LRP1-binding peptide, IETP2, and covalently conjugated a series of model small-molecule compounds to it, including potential drugs and imaging agents. All compounds were successfully delivered into the inner ear and inner ear lymph, indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB. The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.
内耳疾病是一组疾病，导致全球超过 15 亿人听力损失。然而，由于血迷路屏障（BLB）表面内耳毛细血管的低通透性，极大地阻碍了全身药物的有效性用于预防和干预，因为大多数药物化合物从血液进入内耳组织的通透性很低。在这里，我们报告了一种新的受体，即低密度脂蛋白受体相关蛋白 1（LRP1），它在内耳 BLB 上表达，作为穿过这种屏障的治疗药物的潜在靶点。作为概念验证，我们开发了一种 LRP1 结合肽，IETP2，并将一系列模型小分子化合物与之共价连接，包括潜在药物和成像剂。所有化合物都成功地递送到内耳和内耳淋巴中，表明靶向受体 LRP1 是增强 BLB 通透性的有前途的策略。受体 LRP1 的发现将为穿过 BLB 和改善内耳疾病的全身药物递送开辟新的策略。
