Bioinspired Lipoproteins of Furoxans–Gemcitabine Preferentially Targets Glioblastoma and Overcomes Radiotherapy Resistance

Abstract

AbstractRadiotherapy (RT) resistance is an enormous challenge in glioblastoma multiforme (GBM) treatment, which is largely associated with DNA repair, poor distribution of reactive radicals in tumors, and limited delivery of radiosensitizers to the tumor sites. Inspired by the aberrant upregulation of RAD51 (a critical protein of DNA repair), scavenger receptor B type 1 (SR‐B1), and C‐C motif chemokine ligand 5 (CCL5) in GBM patients, a reduction‐sensitive nitric oxide (NO) donor conjugate of gemcitabine (RAD51 inhibitor) (NG) is synthesized as radio‐sensitizer and a CCL5 peptide‐modified bioinspired lipoprotein system of NG (C‐LNG) is rationally designed, aiming to preferentially target the tumor sites and overcome the RT resistance. C‐LNG can preferentially accumulate at the orthotopic GBM tumor sites with considerable intratumor permeation, responsively release the gemcitabine and NO, and then generate abundant peroxynitrite (ONOO−) upon X‐ray radiation, thereby producing a 99.64% inhibition of tumor growth and a 71.44% survival rate at 120 days in GL261‐induced orthotopic GBM tumor model. Therefore, the rationally designed bioinspired lipoprotein of NG provides an essential strategy to target GBM and overcome RT resistance.