LDL receptor-related protein 1 (LRP1), a novel target for opening the blood-labyrinth barrier (BLB) PMID: 35680846

ADC Targets in Oncology

2026-04-10

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

Signal Transduct Target Ther. 2022 Jun 10;7(1):175. doi: 10.1038/s41392-022-00995-z.

Xi Shi ^# ¹ ² , Zihao Wang ^# ³ , Wei Ren ^# ⁴ ⁵ ⁶ ⁷ , Long Chen ^# ¹ ⁸ , Cong Xu ⁴ ⁵ ⁶ ⁷ , Menghua Li ² , Shiyong Fan ³ , Yuru Xu ³ , Mengbing Chen ⁴ ⁵ ⁶ ⁷ , Fanjun Zheng ⁴ ⁵ ⁶ ⁷ , Wenyuan Zhang ⁸ , Xinbo Zhou ³ , Yue Zhang ⁴ ⁵ ⁶ ⁷ , Shiwei Qiu ² , Liyuan Wu ² , Peng Zhou ⁸ , Xinze Lv ² , Tianyu Cui ² , Yuehua Qiao ² , Hui Zhao ⁴ ⁵ ⁶ ⁷ , Weiwei Guo ⁴ ⁵ ⁶ ⁷ , Wei Chen ⁴ ⁵ ⁶ ⁷ , Song Li ³ , Wu Zhong ⁹ , Jian Lin ¹⁰ ¹¹ , Shiming Yang ¹² ¹³ ¹⁴ ¹⁵

Affiliations

1. Department of Pharmacy, Peking University Third Hospital, Beijing, China.
2. Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou, China.
3. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
4. College of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Beijing, China.
5. National Clinical Research Center for Otolaryngologic Diseases, Beijing, China.
6. Key Lab of Hearing Science, Ministry of Education, Beijing, China.
7. Beijing Key Lab of Hearing Impairment for Prevention and Treatment, Beijing, China.
8. Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Innovation Center for Genomics, Peking University, Beijing, China.
9. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China. [email protected].
10. Department of Pharmacy, Peking University Third Hospital, Beijing, China. [email protected].
11. Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Innovation Center for Genomics, Peking University, Beijing, China. [email protected].
12. College of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Beijing, China. [email protected].
13. National Clinical Research Center for Otolaryngologic Diseases, Beijing, China. [email protected].
14. Key Lab of Hearing Science, Ministry of Education, Beijing, China. [email protected].
15. Beijing Key Lab of Hearing Impairment for Prevention and Treatment, Beijing, China. [email protected].
# Contributed equally.

Abstract

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.