title: Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers.
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.
authors.affiliation: 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.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Mastorakos
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mangraviti
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Lee
authors.initials: L
authors.lastname: Hwang
authors.affiliation: F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, United States.
authors.forename: Jinyuan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.affiliation: 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.
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Olivi
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.affiliation: 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.
authors.forename: Rangaramanujam M
authors.initials: RM
authors.lastname: Kannan
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002232:Carbocyanines / Q000737:chemistry; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D018316:Gliosarcoma / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D008264:Macrophages / Q000166:cytology*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D002232:Carbocyanines; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; C085321:cyanine dye 5
keywords: Biodistribution; Blood-brain barrier; Glioblastoma; PAMAM dendrimer; Tumor associated macrophages; Tumor penetration
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