Strategies to enhance the distribution of nanotherapeutics in the brain

Clark Zhang; Panagiotis Mastorakos; Miguel Sobral; Sneha Berry; Eric Song; Elizabeth Nance; Charles G Eberhart; Justin Hanes; Jung Soo Suk

doi:10.1016/j.jconrel.2017.07.028

Strategies to enhance the distribution of nanotherapeutics in the brain

J Control Release. 2017 Dec 10:267:232-239. doi: 10.1016/j.jconrel.2017.07.028. Epub 2017 Jul 21.

Authors

Clark Zhang¹, Panagiotis Mastorakos², Miguel Sobral³, Sneha Berry⁴, Eric Song⁴, Elizabeth Nance⁵, Charles G Eberhart⁶, Justin Hanes⁷, Jung Soo Suk⁸

Affiliations

¹ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
² Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
³ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
⁴ Zanvyl Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, United States.
⁵ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21218, United States.
⁶ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
⁷ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
⁸ Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States. Electronic address: jsuk@jhmi.edu.

Abstract

Convection enhanced delivery (CED) provides a powerful means to bypass the blood-brain barrier and drive widespread distribution of therapeutics in brain parenchyma away from the point of local administration. However, recent studies have detailed that the overall distribution of therapeutic nanoparticles (NP) following CED remains poor due to tissue inhomogeneity and anatomical barriers present in the brain, which has limited its translational applicability. Using probe NP, we first demonstrate that a significantly improved brain distribution is achieved by infusing small, non-adhesive NP via CED in a hyperosmolar infusate solution. This multimodal delivery strategy minimizes the hindrance of NP diffusion imposed by the brain extracellular matrix and reduces NP confinement within the perivascular spaces. We further recapitulate the distributions achieved by CED of this probe NP using a most widely explored biodegradable polymer-based drug delivery NP. These findings provide a strategy to overcome several key limitations of CED that have been previously observed in clinical trials.

Keywords: Brain extracellular matrix; Convection enhanced delivery; Drug delivery; Nanoparticle; Perivascular space.

MeSH terms

Animals
Brain / blood supply
Brain / metabolism*
Convection
Drug Delivery Systems*
Female
Male
Mice
Nanoparticles / administration & dosage*
Nanoparticles / chemistry
Polymers / administration & dosage
Polymers / chemistry
Rats, Sprague-Dawley

Substances

Polymers

Abstract

MeSH terms

Substances

Grants and funding