LAT1 targeted brain delivery of temozolomide and sorafenib for effective glioma therapy

Glioma is the most common primary craniocerebral tumor caused by the cancerous growth of glial cells in the brain and spinal cord.Currently,standard treatment is the surgical resection followed by concurrent radiation and chemotherapy.However,the blood-brain barrier(BBB)prevents most antitumor drugs from entering the brain and reduces their efficacy,especially in lowgrade glioma.Since L-type amino acid transporter 1(LAT1)is highly expressed in glioma cells and mediates drug transport across the BBB,it is a promising target for drug delivery and treatment of glioma.Temozolomide(TMZ)is the first-line treatment for glioma,however,patients often exhibit drug resistance at advanced stage.A multikinase inhibitor and inducer of ferroptosis,sorafenib can improve the therapeutic effects of TMZ.Therefore,to optimize the glioma treatment and cross the BBB,we designed LAT1-targeting nanoparticles co-loaded with TMZ and sorafenib.Our results from both in vitro and in vivo studies confirmed that LAT1-targeting nanoparticles significantly increased the cellular uptake,cytotoxicity,accumulation at tumor site,and the anti-tumor efficacy compared to the non-target nanoparticles.Therefore,LAT1 can be used as a potential target for braintargeted drug delivery,and sorafenib-induced ferroptosis can aid the anti-glioma efficacy of TMZ.