Integrin receptor-targeted, doxorubicin-loaded cerium oxide nanoparticles delivery to combat glioblastoma.

Aim: To assess the chemo-immunomodulatory effects of doxorubicin-loaded cerium oxide nanoparticles coated with oleyl amine-linked cyclic RGDfK peptide (CeNP+Dox+RGD) to target both gliomas and its tumor microenvironment (TME) via integrin receptors. Materials & methods: CeNP+Dox+RGD nanoparticles are synthesized by the sequential addition of cerium III chloride heptahydrate, beta-cyclodextrin, oleic acid, and F127 micelle (CeNP). Doxorubicin was then loaded into CeNPs and coated with oleyl amine-linked cyclic RGDfK peptide to form stable CeNP+Dox+RGD nanoparticles. Results: CeNP+Dox+RGD nanoparticles crossed blood–brain barrier (BBB) effectively and demonstrated threefold enhanced survivability in glioma-bearing mice. The IHC profiling of glial tumor cross-sections showed increased CD80 expression (M1 TAMs) and decreased arginase-1 expression (M2 TAMs). Conclusion: CeNP+Dox+RGD can be an immunotherapeutic treatment option to combat glioblastoma. Article highlights The complexity of the brain's blood–brain barrier and the cross-talk between gliomas with their surrounding tumor microenvironment (TME) often impact the effectiveness of conventional regimens for glioblastoma (GBM) treatment. Doxorubicin (Dox) loaded cerium oxide nanoparticles (CeNPs) coated with oleyl amine-linked cyclic RGDfK peptide (CeNP+Dox+RGD) were synthesized to target both the gliomas and its TME. The first study was to evaluate both the anticancer properties and immunomodulatory effects of CeNP+Dox+RGD nanoparticles via integrin receptors in the orthotopic glioma model in mice. The functionalization of nanoparticles with RGD peptide facilitated their translocation across the blood–brain barrier successfully. A three-fold increase in the survivability of mice with CeNP+Dox+RGD treatment was observed compared with control and other treated groups in the orthotopic mice glioma models. Increased expression of CD80 marker associated with anticancer M1 phenotype of tumor-associated macrophages (TAMs) with CeNP+Dox+RGD treatment. Decreased expression of Arginase-1 marker associated with recruitment of immunosuppressive M2 phenotype TAMs in orthotopic glioma model in mice. CeNP+Dox+RGD treatment can enhance the current immunotherapeutic strategies to combat gliomas via integrin receptors. [ABSTRACT FROM AUTHOR]