Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance

Nanoparticles releasing an oxaliplatin prodrug and a cationic DNA intercalator within temozolomide-resistant gliomas in mice after convection-enhanced delivery inhibit the growth of the tumours without causing any detectable toxicity. In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.

Automated summary

Nanoparticles releasing an oxaliplatin prodrug and a cationic DNA intercalator within temozolomide-resistant gliomas inhibit tumor growth without causing detectable toxicity. Combining anticancer drugs with distinct mechanisms of action, selective drug release, and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.