Gene and doxorubicin co-delivery system for targeting therapy of glioma

Abstract

The combination of gene therapy and chemotherapy is a promising treatment strategy for brain gliomas. In this paper, we designed a co-delivery system (DGDPT/pORF-hTRAIL) loading chemotherapeutic drug doxorubicin and gene agent pORF-hTRAIL, and with functions of pH-trigger and cancer targeting. Peptide HAIYPRH (T7), a transferrin receptor-specific peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. T7-modified co-delivery system showed higher efficiency in cellular uptake and gene expression than unmodified co-delivery system in U87 MG cells, and accumulated in tumor more efficiently in vivo. DOX was covalently conjugated to carrier though pH-trigged hydrazone bond. In vitro incubation of the conjugates in buffers led to a fast DOX release at pH 5.0 (intracellular environment) while at pH 7.4 (blood) the conjugates are relatively stable. The combination treatment resulted in a synergistic growth inhibition (combination index, CI < 1) in U87 MG cells. The synergism effect of DGDPT/pORF-hTRAIL was verified in vitro and in vivo. In vivo anti-glioma efficacy study confirmed that DGDPT/pORF-hTRAIL displayed anti-glioma activity but was less toxic.