A novel target LDL receptor-related protein 1 (LRP1) for opening the blood-labyrinth barrier (BLB)

Introduction 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) 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.

Materials and Methods C57BL/6J, BALB/c nude mice, Bama miniature pigs and HEI-OC1 cell line were used through the study. Western Blot and qPCR were used to study the expression of LRR1 receptor in cochlea and HEI-OC1 cell line. Immunostaining was used to locate LRP1 expression in cochlea and the colocalization of Cy5.5 injected intravenously and LRP1 receptor in both mice and porcine cochlea. LC–MS was used to detect the curcumin, IETP and IETP-curcumin in cochlear lymphatic fluid. ABR was used to assess the hearing ability of mice and pigs. Live animal imaging was used to screen the efficiency of IETPs. Results 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 lymph and targeting cells, indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB.

Conclusion  LRP1-IETP2 system will be a potential routine to realize inner ear targeted, systematic drug delivery for inner ear disorders.

Publication History

Article published online:
12 May 2023