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J Control Release. 2018 Aug 28;284:152-159. doi: 10.1016/j.jconrel.2018.06.021. Epub 2018 Jun 15.

Nootropic nanocomplex with enhanced blood-brain barrier permeability for treatment of traumatic brain injury-associated neurodegeneration.

Author information

1
Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
2
Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
3
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
4
Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
5
Laboratory Animal Center, Osong Medical Innovation Foundation, 123 Osongsaengmyeong-ro, Chungbuk 28160, Republic of Korea.
6
Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: jkeunsoo1@gmail.com.
7
Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
8
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea. Electronic address: yunkyungkim@kist.re.kr.
9
Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea. Electronic address: sehoonkim@kist.re.kr.

Abstract

Traumatic brain injury (TBI) is an intracranial injury which can induce immediate neuroinflammation and long-term neurological deficits. Methylene blue (MB) as a nootropic has a great potential to treat neurodegeneration after TBI because of its anti-inflmmatory and neuroprotective functions. However, its limited accumulation to the brain across the blood-brain barrier (BBB) remains a major hurdle to be overcome. In this paper, we present a polymer surfactant-encapsulated nanocomplex of MB as a delivery system with high BBB permeability for efficacious treatment of TBI-induced neurodegeneration. MB was formulated via electrostatically/hydrophobically directed assembly with fatty acid and Pluronic surfactant (F-127 or F-68) to construct nanocomplexes of two different colloidal sizes (<10 nm and ~108 nm in hydrodynamic diameter for NanoMB-127 and NanoMB-68, respectively). Compared to uncomplexed free MB, formulation into the ultrasmall nanocomplex (NanoMB-127) significantly enhanced the uptake of MB by blood-brain vascular endothelial bEnd3 cells in vitro, and indeed improved its BBB penetration upon systemic administration to normal mice in vivo. However, large-size NanoMB-68 showed negligible BBB crossing despite the efficient bEnd3 cell internalization in vitro, probably due to the unfavorable pharmacokinetic profile associated with its large particle size. By virtue of the efficient BBB penetration and cellular uptake, ultrasmall NanoMB-127 was shown to distinctively reduce the expression level of an inflammatory cytokine with no notable toxicity in vitro and also considerably prevent the neurodegeneration after TBI in mice at much lower doses than free MB. Overall, the Pluronic-supported nanocomplexation method allows efficient brain delivery of MB, offering a novel way of enhancing the efficacy of neurotherapeutics to treat brain diseases.

KEYWORDS:

Blood-brain barrier; Methylene blue; Neuroprotection; Pluronic block copolymer; Traumatic brain injury

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