PRO-DRUG NANOPARTICLES AS SYNERGISTIC DRUG COMBINATION CARRIERS FOR IDH1-WT GLIOBLASTOMA

Abstract

Abstract AIMS Synergistic combinations of doxorubicin and gemcitabine have been assessed for post-surgical treatment of IDH1 wild-type glioblastoma (GBM). As a complementary drug carrier, hyperbranched and micellar nanoparticles are being investigated to enable enhanced drug loading and sustained drug release. METHOD 2D and 3D spheroid in vitro models have been generated from patient-derived glioblastoma cells resected from tumour core and invasive margin. Drug combinations were screened using synergy quantification from the Chou and Talalay method and synergy mechanisms investigated using measures of caspase 3/6-mediated apoptosis and γH2AX-mediated DNA damage. Polymeric nanoparticles (PEG-PCL) loaded with Cy5 were tested for internalisation and subsequent endocytosis pathway determination. Both single drug and drug combinations are currently being incorporated into PEG-PCL nanoparticles for in vitro assessment of biocompatibility, cellular uptake and cytotoxicity. RESULTS Data demonstrate synergism with doxorubicin and gemcitabine combinations is obtained in a molar ratio de- pendent manner. Consistent with this, enhanced apoptosis and DNA damage is observed in a synergistic manner. PEG-PCL nanoparticles demonstrate effcient cellular uptake and are internalised via dynamin-dependent caveolae and clathrin endocytotic pathways. Interestingly, nanoparticle internalisation is substantially in- creased (approx. 50%) in invasive GBM cells relative to proliferative core cells. CONCLUSIONS Doxorubicin and gemcitabine has been identified as a synergistic drug combination with the potential for sustained drug release when combined with PEG-PCL nanoparticle formulations. Together, the data has provided a platform of knowledge that will enable translation to pre-clinical in vivo models.