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

Authors

• Fan Zhang, 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.
• Panagiotis Mastorakos, Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
• Manoj K. Mishra, Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
• Antonella Mangraviti, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
• Lee Hwang, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
• Jinyuan Zhou, F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, United States.
• Justin Hanes, 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.
• Henry Brem, 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.
• Alessandro Olivi, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
• Betty Tyler, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
• Rangaramanujam M. Kannan, 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.

Document Type

Article

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.

Medical Subject Headings

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

Publication Date

6-1-2015

Publication Title

Biomaterials

E-ISSN

1878-5905

Volume

52

First Page

507

Last Page

16

PubMed ID

25818456

Digital Object Identifier (DOI)

10.1016/j.biomaterials.2015.02.053

Recommended Citation

Zhang, Fan; Mastorakos, Panagiotis; Mishra, Manoj K.; Mangraviti, Antonella; Hwang, Lee; Zhou, Jinyuan; Hanes, Justin; Brem, Henry; Olivi, Alessandro; Tyler, Betty; and Kannan, Rangaramanujam M., "Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers" (2015). Neurosurgery. 2322.
https://scholar.barrowneuro.org/neurosurgery/2322