Engineering Blood-Brain Barrier-Permeable and Tumor Cell-Ingestible Pro-Proteins for Glioblastoma Treatment
Science China Chemistry(2023)
摘要
Intracellular protein therapeutics holds great potentials for the treatment of glioblastoma, which however, is greatly challenged by the unmet demands to concomitantly penetrate the blood-brain barrier (BBB) and glioblastoma cell membrane barrier with high efficiency and selectivity. Herein, a unique pro-protein platform was developed via facile green synthesis, which allowed efficient and selective delivery into glioblastoma cells in a carrier-free manner. Pro-proteins were engineered via reversible modification of native proteins in the aqueous buffer with 3,4-dihydroxy-phenylalanine, the substrate of L-type amino acid transporter (LAT1), bridged with a phenylboronic acid-containing linker. By harnessing the LAT1-mediated direct transport mechanism, the optimized pro-protein, named protein-M2-D, can efficiently penetrate BBB after i.v. injection, and subsequently enable selective and endocytosis-free delivery of various proteins including enzymes, toxins, and antibodies into glioblastoma cells, wherein intracellular H2O2 triggered traceless restoration of the native protein structure. Systemic administration of saporin-M2-D provoked potent anti-tumor efficacy against orthotopic U87 glioblastoma in mice, without inducing systemic toxicity. Such a facile, versatile, and robust platform renders a promising paradigm for cytosolic protein delivery and glioblastoma treatment.
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关键词
blood-brain barrier,cytosolic protein delivery,pro-protein,L-type amino acid transporter 1 (LAT1),glioblastoma treatment
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