Surface-engineered dual drug-loaded tumor-targeted liposomal nanoparticles to overcome the therapeutic resistance in glioblastoma multiforme

Glioblastoma (GBM) is the most common high-grade primary malignant brain tumor, characterized by a notably poor prognosis. Current treatments for GBM have shown limited effectiveness in improving patient survival, highlighting the urgent need for effective therapeutic strategies. Combination therapy offers significant potential in overcoming resistance by targeting multiple signaling pathways; however, it often comes with increased toxicity compared to monotherapy. Co-encapsulating multiple therapeutic agents into a tumor-targeted drug delivery platform holds promise for overcoming these limitations and improving treatment outcomes. We developed a tumor-targeted liposomal nanoformulation (TTL) using phospholipids, cholesterol, DSPE-(PEG)2000-OMe, and a proprietary tumor-targeting peptide (TTP). The TTL was loaded with everolimus (TTL-E), vinorelbine (TTL-V), rapamycin (TTL-R), a combination (TTL-EV), or (TTL-RV). These formulations were tested in vivo on orthotopic GBM mice, combined with temozolomide and radiation. RNA sequencing was performed to identify molecular and transcriptome changes post-treatment. TTL demonstrated tumor-specific uptake, effectively delivering drugs to GBM tumors. TTL-EV and TTL-RV outperformed single-drug formulations. Radiation combined with TTL-EV/RV improved tumor growth inhibition and survival, while temozolomide provided minimal benefit. Transcriptome analysis revealed differentially expressed genes (DEGs) linked to DNA damage repair, cell cycle, metabolism, and extracellular matrix pathways. TTL crossed the blood-brain barrier, targeting tumors effectively. Radiation plus TTL-EV/RV enhanced tumor suppression and survival in GBM models. Gene expression analysis identified DEGs related to DNA damage and cell death. Mechanistic studies suggest TTL-EV plus radiation inhibits mTOR/MAPK pathways and sensitizes tumors to radiation. These findings offer a potential approach for improving GBM treatment. Glioblastoma (GBM) is the most aggressive type of brain cancer and is very hard to treat. Current treatments such as surgery, radiation, and chemotherapy often do not work well enough, and patients usually survive for only a short time. One reason is that GBM tumors can resist treatment. Using more than one drug together may help, but it often causes harmful side effects. In this study, we created a new way to deliver drugs directly to brain tumors. We designed very small carriers, called tumor-targeted liposomes (TTL), that can travel into the brain and release drugs inside the tumor. We tested TTL loaded with different combinations of two cancer drugs in mice with GBM, together with radiation therapy. We found that this new treatment reached the brain tumors and worked better than single drugs. The combination slowed tumor growth and helped the mice live longer. Importantly, the new therapy also made tumors more sensitive to radiation. These findings suggest that this drug delivery system could be a promising new approach for treating GBM and may lead to better outcomes for patients in the future. Angom, Rachamala et al. developed a tumor-targeted liposomal nanoformulation using phospholipids, cholesterol, DSPE-(PEG)2000-OMe, and tumor-targeting peptide. The nanoformulation combined with radiation improved survival in mouse models of glioblastoma.