Brain-tumor-seeking and serpin-inhibiting outer membrane vesicles restore plasmin-mediated attacks against brain metastases.
J Control Release
; 375: 116-126, 2024 Sep 06.
Article
in En
| MEDLINE
| ID: mdl-39236899
ABSTRACT
Many chemotherapeutic and molecular targeted drugs have been used to treat brain metastases, e.g., anti-angiogenic vandetanib. However, the blood-brain barrier and brain-specific resistance mechanisms make these systemic therapeutic approaches inefficacious. Brain metastatic cancer cells could mimic neurons to upregulate multiple serpins and secrete them into the extracellular environment to reduce local plasmin production to promote L1CAM-mediated vessel co-option and resist anti-angiogenesis therapy. Here, we developed brain-tumor-seeking and serpin-inhibiting outer membrane vesicles (DE@OMVs) to traverse across the blood-brain barrier, bypass neurons, and specially enter metastatic cancer cells via targeting GRP94 and vimentin. Through specific delivery of dexamethasone and embelin, reduced serpin secretion, restored plasmin production, significant L1CAM inactivation and tumor cell apoptosis were specially found in intracranial metastatic regions, leading to delayed tumor growth and prolonged survival in mice with brain metastases. By combining the brain-tumor-seeking properties with the regulation of the serpin/plasminogen activator/plasmin/L1CAM axis, this study provides a potent and highly-selective systemic therapeutic option for brain metastases.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
J Control Release
Journal subject:
FARMACOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Países Bajos