433835 Dendrimer Based Systemic Therapies for the Treatment of Glioblastoma

Monday, November 9, 2015: 1:10 PM
151D/E (Salt Palace Convention Center)
Fan Zhang1,2, Panagiotis Mastorakos1, Manoj K. Mishra1, Antonella Mangraviti3, Jinyuan Zhou4, Justin Hanes1, Henry Brem3, Alessandro Olivi3, Betty Tyler3 and Rangaramanujam Kannan1, (1)Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD, (2)Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, (3)Neurosurgery, Johns Hopkins University SOM, Baltimore, MD, (4)F.M. Kirby Research Center for Functional Brain Imaging/Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD

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.

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See more of this Session: Drug Delivery II
See more of this Group/Topical: Food, Pharmaceutical & Bioengineering Division