pH-Responsive Polyethylene Glycol Engagers for Enhanced Brain Delivery of PEGylated Nanomedicine to Treat Glioblastoma.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39749925.
- Also identified by DOI 10.1021/acsnano.4c05906 and PMC identifier 11752499.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>TfR</sup>) 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<sup>TfR</sup> significantly increased the accumulation of PEGylated nanomedicine in the mouse brain compared to wild-type PEG engager<sup>TfR</sup> (WT-PEG engager<sup>TfR</sup>). pH-PEG engager<sup>TfR</sup>-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<sup>TfR</sup> is promising for enhanced brain drug delivery to treat CNS disorders.
Medical subject headings
- Polyethylene Glycols
- Glioblastoma
- Nanomedicine
- Brain Neoplasms
- Doxorubicin
- Drug Delivery Systems