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A Highly Translatable Dual-arm Local Delivery Strategy To Achieve Widespread Therapeutic Coverage in Healthy and Tumor-bearing Brain Tissues |
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| Authors: | Karina Negron Gijung Kwak Heng Wang Haolin Li Yi-Ting Huang Shun-Wen Chen Betty Tyler Charles G Eberhart Justin Hanes Jung Soo Suk |
| Affiliation: | 1. Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231 USA
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA;2. Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231 USA;3. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218 USA;4. Department of Neuroscience and Behavioral Biology, Johns Hopkins University, Baltimore, MD, 21218 USA;5. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21231 USA;6. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231 USA;7. Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231 USA Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231 USA Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218 USA |
| Abstract: | Drug delivery nanoparticles (NPs) based entirely on materials generally recognized as safe that provide widespread parenchymal distribution following intracranial administration via convection-enhanced delivery (CED) are introduced. Poly(lactic-co-glycolic acid) (PLGA) NPs are coated with various poloxamers, including F68, F98, or F127, via physical adsorption to render particle surfaces non-adhesive, thereby resisting interactions with brain extracellular matrix. F127-coated PLGA (F127/PLGA) NPs provide markedly greater distribution in healthy rat brains compared to uncoated NPs and widespread coverage in orthotopically-established brain tumors. Distribution analysis of variously-sized F127/PLGA NPs determines the average rat brain tissue porosity to be between 135 and 170 nm while revealing unprecedented brain coverage of larger F127/PLGA NPs with an aid of hydraulic pressure provided by CED. Importantly, F127/PLGA NPs can be lyophilized for long-term storage without compromising their ability to penetrate the brain tissue. Further, 65- and 200-nm F127/PLGA NPs lyophilized-reconstituted and administered in a moderately hyperosmolar infusate solution show further enhance particle dissemination in the brain via osmotically-driven enlargement of the brain tissue porosity. Combination of F127/PLGA NPs and osmotic tissue modulation provides a means with a clear regulatory path to maximize the brain distribution of large NPs that enable greater drug loading and prolong drug release. |
| Keywords: | brain extracellular space drug delivery nanoparticles extracellular matrix (ECM) modulation infusate osmolality local infusion |