pH-Responsive Polyethylene Glycol Engagers for Enhanced Brain Delivery of PEGylated Nanomedicine to Treat Glioblastoma
Jun-Lun Meng, Zi-Xuan Dong, Yanru Chen, Meng-Hsuan Lin, Yu‐Ching Liu, Steve R. Roffler, Wen-Wei Lin, Chin‐Yuan Chang, Shey-Cherng Tzou, Tian-Lu Cheng, Hsiao-Chen Huang, Zhiqin Li, Yen-Cheng Lin, Yu-Cheng Su
Abstract
High Resolution Image Download MS PowerPoint Slide The blood–brain barrier (BBB) remains a major obstacle for effective delivery of therapeutics to treat central nervous system (CNS) disorders. Although transferrin receptor (TfR)-mediated transcytosis is widely employed for brain drug delivery, the inefficient release of therapeutic payload hinders their efficacy from crossing the BBB. Here, we developed a pH-responsive anti-polyethylene glycol (PEG) × anti-TfR bispecific antibody (pH-PEG engager TfR ) that can complex with PEGylated nanomedicine at physiological pH to trigger TfR-mediated transcytosis in the brain microvascular endothelial cells, while rapidly dissociating from PEGylated nanomedicine at acidic endosomes for efficient release of PEGylated nanomedicine to cross the BBB. The pH-PEG engager TfR significantly increased the accumulation of PEGylated nanomedicine in the mouse brain compared to wild-type PEG engager TfR (WT-PEG engager TfR ). pH-PEG engager TfR -decorated PEGylated liposomal doxorubicin exhibited an enhanced antitumor effect and extended survival in a human glioblastoma (GBM) orthotopic xenograft mice model. Conditional release of PEGylated nanomedicine during BBB-related receptor-mediated transcytosis by pH-PEG engager TfR is promising for enhanced brain drug delivery to treat CNS disorders.