Targeted Regulation of Blood-Brain Barrier for Enhanced Therapeutic Efficiency of Hypoxia-Modifier Nanoparticles and Immune Checkpoint Blockade Antibodies for Glioblastoma.

Abstract

Glioblastoma is the most destructive type of brain cancer. The blood-brain barrier (BBB) is a tremendous obstacle that hinders therapeutic agents, such as chemical drugs and antibodies, from reaching glioblastoma tissues. Meanwhile, the abnormal microenvironment of glioblastoma extremely restricts the expected therapeutic effects of accumulated drugs. Therefore, in the present study, BBB-regulating nanovesicles (BRN) are developed to achieve targeted and controlled BBB regulation, carrying adenosine 2A receptor (A2AR) agonists and perfluorocarbon (PF). The red-blood-cell membrane (RBCM) is included on the outside to avoid the premature release of therapeutic agents. In the presence of ultrasonication (US), A2AR agonists are released and induce effects on both F-actin and tight junctions of endothelial cells. Subsequently, BBB permeability is temporarily increased and enables small molecules and nanoparticles to enter brain parenchymal tissues. The high affinity between manganese dioxide and temozolomide (TMZ) is utilized to form multifunctional nanoparticles to ameliorate the hypoxic microenvironment, which yields improved glioblastoma inhibition combined with radiotherapy. Moreover, with the aid of targeted BBB regulation, programmed death ligand-1 (PD-L1) antibody induces a tumor-specific immune response. Taken together, the findings suggest that synergistic combination may have the potential in amplifying the therapeutic efficacies of clinical drugs and immune checkpoint blockade antibodies to overcome the therapeutic resistance of glioblastoma.

• Authors: Lingtong Meng, Cuirong Wang, Yaping Lu, Gang Sheng, Lin Yang, Zhouyue Wu, Hang Xu, Chao Han, Yingmei Lu, Feng Han
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 13 Issue 10 Pg. 11657-11671 (Mar 17 2021) ISSN: 1944-8252 [Electronic] United States
• PMID: 33684289 (Publication Type: Journal Article)

Chemical References

• Immune Checkpoint Inhibitors
• Purinergic P1 Receptor Agonists

Topics

• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Brain Neoplasms (drug therapy, metabolism)
• Drug Delivery Systems
• Glioblastoma (drug therapy, metabolism)
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Male
• Mice
• Mice, Inbred BALB C
• Nanoparticles (administration & dosage, therapeutic use)
• Purinergic P1 Receptor Agonists (administration & dosage, therapeutic use)
• Tumor Hypoxia (drug effects)