Presentation Information
[P04-583]pH-Sensitive Bispecific PEG Engagers for Enhanced Brain Delivery of PEGylated Nanotherapeutics in Glioblastoma
○Yu-Cheng Su1, Jun-Lun Meng1 (1. National Yang Ming Chiao Tung University (Taiwan))
Keywords:
Polyethylene glycol (PEG),Bispecific PEG Engager,Blood–brain barrier (BBB),Glioblastoma,Nanomedicine,Transferrin receptor (TfR)
[Purpose]
The blood–brain barrier (BBB) represents a critical challenge for therapeutic delivery to the central nervous system (CNS). While transferrin receptor (TfR)-mediated transcytosis has been widely exploited for brain drug transport, inefficient release of therapeutic cargos in endothelial endosomes restricts their efficacy. To address this limitation, we engineered a pH-responsive bispecific antibody, termed pH-PEG engagerTfR, that simultaneously binds polyethylene glycol (PEG) and TfR. [Method]
physiological pH, pH-PEG engagerTfR forms stable complexes with PEGylated nanomedicines, enabling their uptake via TfR-mediated transcytosis in brain microvascular endothelial cells (BMECs). In acidic endosomal compartments, the engager rapidly dissociates, releasing PEGylated nanomedicines for efficient transport across the BBB.
[Results]
Compared with the wild-type engager (WT-PEG engagerTfR), pH-PEG engagerTfR markedly enhanced brain accumulation of PEGylated nanomedicines in mice. Moreover, PEGylated liposomal doxorubicin decorated with pH-PEG engagerTfR achieved superior antitumor efficacy and significantly prolonged survival in an orthotopic glioblastoma (GBM) xenograft mouse model.
[Consideration]
Conditional release of PEGylated nanomedicine during receptor-mediated transcytosis is critical for overcoming limitations associated with endosomal trapping and inefficient drug delivery, emphasizing the importance of pH-responsiveness in therapeutic design.
[Conclusion]
These findings highlight conditional release of PEGylated nanomedicine during receptor-mediated transcytosis as an effective strategy to overcome BBB-associated limitations, offering a promising platform for improved brain drug delivery and treatment of CNS disorders.
The blood–brain barrier (BBB) represents a critical challenge for therapeutic delivery to the central nervous system (CNS). While transferrin receptor (TfR)-mediated transcytosis has been widely exploited for brain drug transport, inefficient release of therapeutic cargos in endothelial endosomes restricts their efficacy. To address this limitation, we engineered a pH-responsive bispecific antibody, termed pH-PEG engagerTfR, that simultaneously binds polyethylene glycol (PEG) and TfR. [Method]
physiological pH, pH-PEG engagerTfR forms stable complexes with PEGylated nanomedicines, enabling their uptake via TfR-mediated transcytosis in brain microvascular endothelial cells (BMECs). In acidic endosomal compartments, the engager rapidly dissociates, releasing PEGylated nanomedicines for efficient transport across the BBB.
[Results]
Compared with the wild-type engager (WT-PEG engagerTfR), pH-PEG engagerTfR markedly enhanced brain accumulation of PEGylated nanomedicines in mice. Moreover, PEGylated liposomal doxorubicin decorated with pH-PEG engagerTfR achieved superior antitumor efficacy and significantly prolonged survival in an orthotopic glioblastoma (GBM) xenograft mouse model.
[Consideration]
Conditional release of PEGylated nanomedicine during receptor-mediated transcytosis is critical for overcoming limitations associated with endosomal trapping and inefficient drug delivery, emphasizing the importance of pH-responsiveness in therapeutic design.
[Conclusion]
These findings highlight conditional release of PEGylated nanomedicine during receptor-mediated transcytosis as an effective strategy to overcome BBB-associated limitations, offering a promising platform for improved brain drug delivery and treatment of CNS disorders.
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