pH-Responsive Polyethylene Glycol Engagers for Enhanced Brain Delivery of PEGylated Nanomedicine to Treat Glioblastoma

Jun-Lun Meng; Zi-Xuan Dong; Yan-Ru 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; Zhi-Qin Li; Yen-Cheng Lin; Yu-Cheng Su

doi:10.1021/acsnano.4c05906

pH-Responsive Polyethylene Glycol Engagers for Enhanced Brain Delivery of PEGylated Nanomedicine to Treat Glioblastoma

ACS Nano. 2025 Jan 3. doi: 10.1021/acsnano.4c05906. Online ahead of print.

Authors

Jun-Lun Meng¹, Zi-Xuan Dong¹, Yan-Ru Chen¹, Meng-Hsuan Lin¹, Yu-Ching Liu¹, Steve R Roffler^{2

3}, Wen-Wei Lin⁴, Chin-Yuan Chang¹, Shey-Cherng Tzou^{1

5}, Tian-Lu Cheng⁵, Hsiao-Chen Huang¹, Zhi-Qin Li¹, Yen-Cheng Lin¹, Yu-Cheng Su^{1

5}

Affiliations

¹ Department of Biological Science and Technology, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan.
² Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
³ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁴ School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁵ Department of Biomedical Science and Environmental Biology, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

PMID: 39749925
DOI: 10.1021/acsnano.4c05906

Abstract

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.

Keywords: PEGylated nanomedicine; blood–brain barrier (BBB); glioblastoma (GBM); pH-responsive PEG engager; poly(ethylene glycol) (PEG); transferrin receptor (TfR).