Engineering Prodrug Nanoparticles for Targeted Therapy in Heterogeneous Glioblastoma

Glioblastoma (GBM) microenvironment heterogeneity poses a major challenge to GBM therapy. Glioma stem cells (GSCs) and tumorassociated macrophages (TAMs) are important elements in the GBM microenvironment and are crucial for malignant progression. Here, we constructed prodrug nanoparticles (A-PER-p(TMZ)29/Clo) containing perifosine (Akt inhibitors), an ester bond-linked polytemozolomide (poly(TMZ)29) prodrug, and clodronate (Clo) for combined approach to TAMs depletion, GSCs eradication, and activation inhibition of GBM. A-PER-p(TMZ)29/Clo treatment in a mouse model of intracranial GBM significantly inhibited tumor growth and markedly extended survival. These findings suggest that A-PER-p(TMZ)29/Clo provides a new strategy for therapeutic targeting of the heterogeneous glioma microenvironment.