(133c) Dendrimer Based Systemic Therapies for the Treatment of Glioblastoma

Authors: 
Zhang, F., Fred Hutchinson Cancer Research Institute
Mishra, M. K., Johns Hopkins University School of Medicine
Mangraviti, A., Johns Hopkins School of Medicine
Hanes, J., Johns Hopkins University School of Medicine
Brem, H., Johns Hopkins University SOM
Olivi, A., Johns Hopkins School of Medicine
Mastorakos, P., Johns Hopkins University
Tyler, B., Johns Hopkins University SOM
Kannan, R., Johns Hopkins University School of Medicine

Malignant glioma is the most common and most aggressive primary brain tumor. Despite the advances in treatment, the median survival remains at 16.4 months. Recent advances in nanotechnology have offered multiple novel platforms for targeted, sustained and controlled delivery of therapeutics in order to overcome the limitations of traditional small molecule drugs. However, the small ‘cut off size’ of the brain tumor microvasculature pores, the relatively large and heterogeneous intervascular distances in combination with the tortuous and dense extracellular matrix, impose serious limitations in the ability of nanoparticles to reach target cells. Hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers, with their small size, near-neutral surface charge, and safety profile may offer new opportunities to address these challenges. In addition, dendrimers have demonstrated promising results in targeting neuroinflammation, promising their potential to be taken-up by tumor associated macrophage (TAM). In this study we show systemically delivered hydroxyl terminated PAMAM dendrimer uniformly and selectively distributed through the entire solid tumor and peritumoral area 15 min after injection with subsequent co-localization and retention in TAM even at 48 hours post injection. The rapid clearance of systemically administered dendrimers from major organs promises minimal off-target adverse effects of conjugated drugs. This comprehensive study of the pharmacokinetics and biodistribution of dendrimers in a rodent gliosarcoma model provides crucial information for the design and engineering of dendrimer-drug conjugates for effective treatment of glioblastoma.