Mitocytosis Mediated by an Enzyme-activable Mitochondrion-disturbing Polymer-drug Conjugate Enhances Active Penetration in Glioblastoma Therapy.

The application of nanomedicines for glioblastoma (GBM) therapy is hampered by the blood-brain barrier (BBB) and the dense glioblastoma tissue. To achieve efficient BBB crossing and deep GBM penetration, we demonstrated a strategy of active transcellular transport of a mitochondrion-disturbing nanomedicine, GBEPPT, in the GBM tissue through mitocytosis. GBEPPT was computer-aided designed and prepared by self-assembling a conjugate of an amphiphilic block polymer and a drug podophyllotoxin (PPT). When GBEPPT was delivered to the tumor site, overexpressed γ-glutamyl transpeptidase (GGT) on the brain-blood endothelial cell or the GBM cell triggered enzymatic hydrolysis of γ-glutamylamide on GBEPPT to reverse its charge. Positively-charged GBEPPT rapidly entered into the cell and targeted the mitochondria. These GBEPPT disturbed the homeostasis of mitochondria, inducing mitocytosis-mediated extracellular transport of GBEPPT to the neighboring cells via mitosomes. This intracellular-to-intercellular delivery cycle allowed GBEPPT to penetrate deeply into the GBM parenchyma, and exert sustainable action of PPT released from GBEPPT on the tumor cells along its penetration path at the tumor site, thus improving the anti-GBM effect. The process of mitocytosis mediated by the mitochondrion-disturbing nanomedicine may offer great potential in enhancing drug penetration through malignant tissues, especially poorly permeable solid tumors. This article is protected by copyright. All rights reserved.