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 tumor-associated 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 poly-temozolomide (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.