Brain delivery of Plk1 inhibitor via chimaeric polypeptide polymersomes for safe and superb treatment of orthotopic glioblastoma.

The chemotherapy toward glioblastoma (GBM) is severely challenged by blood-brain barrier and dose-limiting toxicity. Herein, we adopt brain delivery of Plk1 inhibitor volasertib (Vol), which is highly specific and presents low off-target toxicity, as a new means to treat GBM, for which angiopep-2-docked chimaeric polypeptide polymersome (ANG-CPP) was designed and prepared from poly(ethylene glycol)-b-poly(L-tyrosine)-b-poly(L-aspartic acid) for loading Vol to its watery interior via electrostatic interactions. ANG-CPP loaded with 13.9 wt% Vol (ANG-CPP-Vol) exhibited a small size of about 76 nm, superb colloidal stability (against dilution, serum and long-term storage), and enzyme-triggered drug release behavior (about 73% of Vol released within 8 h with proteinase K). In sharp contrast to free Vol, ANG-CPP-Vol induced complete G2/M cell cycle arrest in U-87 MG GBM cells giving 7.8-times better anti-tumor activity, prolonged circulation time and largely increased GBM enrichment. ANG-CPP-Vol effectively suppressed the growth of orthotopic U-87 MG GBM and significantly boosted mice survival rate. Importantly, ANG-CPP-Vol showed further reduced toxicity over free Vol. This great safety and remarkable efficacy of ANG-CPP-Vol renders it a high potential for treating GBM.