Abstract
Glioblastoma multiforme (GBM) is an aggressive and difficult to treat form of brain cancer. In this work, we report on a novel chronotherapeutic polymeric drug, PEAMOtecan, for GBM therapy. PEAMOtecan was synthesized by conjugating camptothecin, a topoisomerase I inhibitor, to our proprietary, 'clickable' and modular polyoxetane polymer platform consisting of acetylene-functionalized 3-ethyl-3-(hydroxymethyl)oxetane (EAMO) repeat units (Patent No.: US 9,421,276) via the linker 3,3'-dithiodipropionic acid (DDPA) with a disulfide bond (SS) extended by short-chain polyethylene glycol (PEG). We show that PEAMOtecan is a highly modular polymer nanoformulation that protects covalently bound CPT until slowly being released over extended periods of time dependent on the cleavage of the disulfide and ester linkages. PEAMOtecan kills glioma cells by mitotic catastrophe with p53 mutant/knockdown cells being more sensitive than matched wild type cells potentially providing cancer-specific targeting. To establish proof-of-principle therapeutic effects, we tested PEAMOtecan as monotherapy for efficacy in a mouse orthotopic glioma model. PEAMOtecan was administered by one-time, convection-enhanced delivery (CED) intra-tumorally to achieve superior distribution and extended drug release over time. In addition, the near-infrared (NIR) dye Cy5.5 was coupled to the polymer providing live-animal imaging capability to track tissue distribution and clearance of the injected polymer over time. We show that PEAMOtecan significantly improves the survival of mice harboring intra-cranial tumors (p = .0074 compared to untreated group). Altogether, these results support further development and testing of our nanoconjugate platform.