Nanomodulators targeting endothelial WNT and pericytes to reversibly open the blood-tumor barrier for boosted brain tumor therapy

Rui Mu; Hang Sun; Yuteng Zeng; Yang Tong; Puxian Tang; Mei Zhao; Ziyan Lv; Ju Yu; Yanming Chen; Qing Lan; Xuechu Zhen; Liang Han

doi:10.1016/j.jconrel.2024.03.047

Nanomodulators targeting endothelial WNT and pericytes to reversibly open the blood-tumor barrier for boosted brain tumor therapy

J Control Release. 2024 Apr 5:369:458-474. doi: 10.1016/j.jconrel.2024.03.047. Online ahead of print.

Authors

Rui Mu¹, Hang Sun¹, Yuteng Zeng¹, Yang Tong¹, Puxian Tang¹, Mei Zhao¹, Ziyan Lv¹, Ju Yu², Yanming Chen², Qing Lan², Xuechu Zhen³, Liang Han⁴

Affiliations

¹ Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China.
² Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, Jiangsu, China.
³ Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: zhenxuechu@suda.edu.cn.
⁴ Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China. Electronic address: hanliang@suda.edu.cn.

PMID: 38575077
DOI: 10.1016/j.jconrel.2024.03.047

Abstract

The blood-brain barrier (BBB)/blood-tumor barrier (BTB) impedes brain entry of most brain-targeted drugs, whether they are water-soluble or hydrophobic. Endothelial WNT signaling and neoplastic pericytes maintain BTB low permeability by regulating tight junctions. Here, we proposed nitazoxanide (NTZ) and ibrutinib (IBR) co-loaded ICAM-1-targeting nanoparticles (NI@I-NPs) to disrupt the BTB in a time-dependent, reversible, and size-selective manner by targeting specific ICAM-1, inactivating WNT signaling and depleting pericytes in tumor-associated blood vessels in breast cancer brain metastases. At the optimal NTZ/IBR mass ratio (1:2), BTB opening reached the optimum effect at 48-72 h without any sign of intracranial edema and cognitive impairment. The combination of NI@I-NPs and chemotherapeutic drugs (doxorubicin and etoposide) extended the median survival of mice with breast cancer brain metastases. Targeting BTB endothelial WNT signaling and tumor pericytes via NI@I-NPs could open the BTB to improve chemotherapeutic efficiency against brain metastases.

Keywords: Blood–brain barrier; Blood–tumor barrier; Brain metastases; Drug delivery; Nanoparticles; Tumor pericytes; WNT signaling.