Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers

Fan Zhang; Panagiotis Mastorakos; Manoj K Mishra; Antonella Mangraviti; Lee Hwang; Jinyuan Zhou; Justin Hanes; Henry Brem; Alessandro Olivi; Betty Tyler; Rangaramanujam M Kannan

doi:10.1016/j.biomaterials.2015.02.053

Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers

Biomaterials. 2015 Jun:52:507-16. doi: 10.1016/j.biomaterials.2015.02.053. Epub 2015 Mar 18.

Authors

Affiliations

¹ Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, United States.
² Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
³ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
⁴ F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, United States.
⁵ Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, United States.
⁶ Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
⁷ Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, United States; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, United States. Electronic address: krangar1@jhmi.edu.

Abstract

Effective blood-brain tumor barrier penetration and uniform solid tumor distribution can significantly enhance therapeutic delivery to brain tumors. Hydroxyl-functionalized, generation-4 poly(amidoamine) (PAMAM) dendrimers, with their small size, near-neutral surface charge, and the ability to selectively localize in cells associated with neuroinflammation may offer new opportunities to address these challenges. In this study we characterized the intracranial tumor biodistribution of systemically delivered PAMAM dendrimers in an intracranial rodent gliosarcoma model using fluorescence-based quantification methods and high resolution confocal microscopy. We observed selective and homogeneous distribution of dendrimer throughout the solid tumor (∼6 mm) and peritumoral area within fifteen minutes after systemic administration, with subsequent accumulation and retention in tumor associated microglia/macrophages (TAMs). Neuroinflammation and TAMs have important growth promoting and pro-invasive effects in brain tumors. The rapid clearance of systemically administered dendrimers from major organs promises minimal off-target adverse effects of conjugated drugs. Therefore, selective delivery of immunomodulatory molecules to TAM, using hydroxyl PAMAM dendrimers, may hold promise for therapy of glioblastoma.

Keywords: Biodistribution; Blood-brain barrier; Glioblastoma; PAMAM dendrimer; Tumor associated macrophages; Tumor penetration.

MeSH terms

Animals
Blood-Brain Barrier / drug effects
Brain Neoplasms / drug therapy
Brain Neoplasms / pathology*
Carbocyanines / chemistry
Dendrimers / chemistry*
Drug Carriers / pharmacology
Drug Delivery Systems / methods
Female
Glioblastoma / drug therapy
Glioblastoma / pathology
Gliosarcoma / pathology
Inflammation / pathology
Macrophages / cytology*
Microscopy, Confocal
Microscopy, Fluorescence
Rats
Rats, Inbred F344
Tissue Distribution

Substances

Carbocyanines
Dendrimers
Drug Carriers
PAMAM Starburst
cyanine dye 5

Grants and funding

P30 CA006973/CA/NCI NIH HHS/United States