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

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

Author information

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

[Indexed for MEDLINE]
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