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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Pages (from-to)	307-321
Number of pages	15
Journal	ACS Nano
Volume	19
Issue number	1
DOIs	https://doi.org/10.1021/acsnano.4c05906
State	Published - 14 Jan 2025

Keywords

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

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10.1021/acsnano.4c05906

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Meng, J. L., Dong, Z. X., Chen, Y. R., Lin, M. H., Liu, Y. C., Roffler, S. R., Lin, W. W., Chang, C. Y., Tzou, S. C., Cheng, T. L., Huang, H. C., Li, Z. Q., Lin, Y. C., & Su, Y. C. (2025). pH-Responsive Polyethylene Glycol Engagers for Enhanced Brain Delivery of PEGylated Nanomedicine to Treat Glioblastoma. ACS Nano, 19(1), 307-321. https://doi.org/10.1021/acsnano.4c05906

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

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 engagerTfR) 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 engagerTfR significantly increased the accumulation of PEGylated nanomedicine in the mouse brain compared to wild-type PEG engagerTfR (WT-PEG engagerTfR). pH-PEG engagerTfR-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 engagerTfR 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)",

author = "Meng, {Jun Lun} and Dong, {Zi Xuan} and Chen, {Yan Ru} and Lin, {Meng Hsuan} and Liu, {Yu Ching} and Roffler, {Steve R.} and Lin, {Wen Wei} and Chang, {Chin Yuan} and Tzou, {Shey Cherng} and Cheng, {Tian Lu} and Huang, {Hsiao Chen} and Li, {Zhi Qin} and Lin, {Yen Cheng} and Su, {Yu Cheng}",

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AU - Chen, Yan Ru

AU - Lin, Meng Hsuan

AU - Liu, Yu Ching

AU - Roffler, Steve R.

AU - Lin, Wen Wei

AU - Chang, Chin Yuan

AU - Tzou, Shey Cherng

AU - Cheng, Tian Lu

AU - Huang, Hsiao Chen

AU - Li, Zhi Qin

AU - Lin, Yen Cheng

AU - Su, Yu Cheng

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N2 - 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 engagerTfR) 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 engagerTfR significantly increased the accumulation of PEGylated nanomedicine in the mouse brain compared to wild-type PEG engagerTfR (WT-PEG engagerTfR). pH-PEG engagerTfR-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 engagerTfR is promising for enhanced brain drug delivery to treat CNS disorders.

AB - 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 engagerTfR) 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 engagerTfR significantly increased the accumulation of PEGylated nanomedicine in the mouse brain compared to wild-type PEG engagerTfR (WT-PEG engagerTfR). pH-PEG engagerTfR-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 engagerTfR is promising for enhanced brain drug delivery to treat CNS disorders.

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

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