Angiopep2-Conjugated Star-Shaped Polyprodrug Amphiphiles for Simultaneous Glioma-Targeting Therapy and MR Imaging.

Development of valuable theranostic agents for overcoming blood-brain barrier (BBB) to achieve efficient imaging-guided glioma-targeting delivery of therapeutics remains of great challenges for personalized glioma therapy. We herein developed a novel functional star-shaped polyprodrug amphiphile (denoted as CPP-2) via a combination of successive reversible addition-fragmentation chain transfer (RAFT) polymerization and click functionalization. In a diluted solution, the star amphiphile existed as structurally stable unimolecular micelles, possessing hydrophobic cores conjugated with reduction-activatable camptothecin prodrugs CPTM and tertiary amine monomer (2-(diethylamine) ethyl methacrylate, DEA), and hydrophilic oligo-(ethylene glycol) monomethyl ether methacrylat (OEGMA) outer coronas covalently anchored with targeting moieties Angiopep-2 (ANG) and MRI contrast agents DOTA-Gd. In vitro and in vivo data in this study demonstrated that the ANG-modified micelles were capable of efficient penetrating BBB and delivering loaded cargoes such as CPT and Gd3+ contrast agents to glioma cells, leading to considerably enhanced t1 relaxivity as well as anti-glioma efficacy. Simultaneously, the targeted anti-glioma efficacy and non-invasive MR imaging for a visualized therapy was realized. These collective findings augured well for the star polyprodrug amphiphiles to be utilized as a novel theranostic platform for clinical application in glioma therapy.

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