Targeting CDK4/6 in glioblastoma via in situ injection of a cellulose-based hydrogel

Despite aggressive treatments, including surgery, chemotherapy and radiotherapy, the prognosis of glioblastoma (GBM) remains poor, and tumor recurrence is inevitable. The FDA-approved CDK4/6 inhibitor palbociclib (PB) showed interesting anti-GBM effects, but its brain penetration is limited by the blood-brain barrier. The aim of this project is to find whether the cellulose-based hydrogel via in situ injection could provide an alternative route to PB brain delivery and generate sufficient drug exposure in orthotopic GBM. In brief, PB was encapsulated in a cellulose nanocrystal network structure crosslinked by polydopamine via divalent Cu²⁺ and hexadecylamine. The formed hydrogel (PB@PH/Cu-CNCs) exhibited sustained drug retention and acid-responsive network de-polymerization for controlled release in vivo. Specifically, the released Cu²⁺ catalyzed a Fenton-like reaction to generate reactive oxygen species (ROS), which was further enhanced by PB, and consequently, irreversible senescence and apoptosis were induced in GBM cells. Finally, PB@PH/Cu-CNCs demonstrated a more potent anti-GBM effect than those treated with free PB or PH/Cu-CNCs (drug-free hydrogel) in cultured cells or in an orthotopic glioma model. These results prove that the injection of the PB-loaded hydrogel in situ is an effective strategy to deliver the CDK4/6 inhibitor into the brain and its anti-GBM effect can be further enhanced by combining Cu²⁺-mediated Fenton-like reaction.