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      Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances and Future Perspectives

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          Abstract

          Restricted drug entry to the brain that is closely associated with the existence of the blood brain barrier (BBB) has limited the accessibility of most potential active therapeutic compounds to the brain from the systemic circulation. Recently, evidences for the presence of direct nose-to-brain drug transport pathways have been accumulated by several studies and an intranasal drug administration route has gained attention as a promising way for providing direct access to the brain without the needs to cross to the BBB. Studies aiming for developing nanoparticles as an intranasal drug carrier have shown considerable promise in overcoming the challenges of intranasal drug delivery route. This review gives a comprehensive overview of works having investigated liposomes as a potential vehicle to deliver drugs to the brain through nose-to-brain route while considering the excellent biocompatibility and high potential of liposomes for clinical development. Herein, studies are reviewed with special emphasis on the impact of formulation factors, such as liposome composition and surface modification of liposomes with targeting moieties, in addition to intranasal environmental factors that may affect the extent/site of absorption of intranasally administered, liposome-encapsulated drugs.

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          Most cited references73

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          Intranasal delivery of biologics to the central nervous system.

          Treatment of central nervous system (CNS) diseases is very difficult due to the blood-brain barrier's (BBB) ability to severely restrict entry of all but small, non-polar compounds. Intranasal administration is a non-invasive method of drug delivery which may bypass the BBB to allow therapeutic substances direct access to the CNS. Intranasal delivery of large molecular weight biologics such as proteins, gene vectors, and stem cells is a potentially useful strategy to treat a variety of diseases/disorders of the CNS including stroke, Parkinson's disease, multiple sclerosis, Alzheimer's disease, epilepsy, and psychiatric disorders. Here we give an overview of relevant nasal anatomy and physiology and discuss the pathways and mechanisms likely involved in drug transport from the nasal epithelium to the CNS. Finally we review both pre-clinical and clinical studies involving intranasal delivery of biologics to the CNS. Copyright © 2011 Elsevier B.V. All rights reserved.
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            Blood-brain barrier delivery.

            Neuropharmaceutics is the largest potential growth sector of the pharmaceutical industry. However, this growth is blocked by the problem of the blood-brain barrier (BBB). Essentially 100% of large-molecule drugs and >98% of small-molecule drugs do not cross the BBB. The BBB can be traversed because there are multiple endogenous transporters within this barrier. Therefore, brain drug development programs of the future need to be re-configured so that drugs are formulated to enable transport into the brain via endogenous BBB transporters.
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              Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration.

              We investigated the CNS delivery of insulin-like growth factor-I (IGF-I), a 7.65 kDa protein neurotrophic factor, following intranasal administration and the possible pathways and mechanisms underlying transport from the nasal passages to the CNS. Anesthetized adult male Sprague-Dawley rats were given [125I]-IGF-I intranasally or intravenously and then killed by perfusion-fixation within 30 min. Other animals were killed following cisternal puncture and withdrawal of cerebrospinal fluid (CSF) or intranasal administration of unlabeled IGF-I or vehicle. Both gamma counting of microdissected tissue and high resolution phosphor imaging of tissue sections showed that the tissue concentrations and distribution following intranasal administration were consistent with two routes of rapid entry into the CNS: one associated with the peripheral olfactory system connecting the nasal passages with the olfactory bulbs and rostral brain regions (e.g. anterior olfactory nucleus and frontal cortex) and the other associated with the peripheral trigeminal system connecting the nasal passages with brainstem and spinal cord regions. Intranasal administration of [125I]-IGF-I also targeted the deep cervical lymph nodes, consistent with their possible role in lymphatic drainage of both the nasal passages and the CNS. Cisternal CSF did not contain [125I]-IGF-I following intranasal administration. Intravenous [125I]-IGF-I resulted in blood and peripheral tissue exposure similar to that seen following intranasal administration but CNS concentrations were significantly lower. Finally, delivery of IGF-I into the CNS activated IGF-I signaling pathways, confirming some portion of the IGF-I that reached CNS target sites was functionally intact. The results suggest intranasally delivered IGF-I can bypass the blood-brain barrier via olfactory- and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                17 October 2019
                October 2019
                : 11
                : 10
                : 540
                Affiliations
                [1 ]Department of Integrated Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 05006, Korea; kekeman1004@ 123456naver.com
                [2 ]College of Pharmacy, Chung-ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea; kyungoh@ 123456cau.ac.kr
                [3 ]College of Pharmacy, Hangang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Korea; hangon@ 123456hanyang.ac.kr
                Author notes
                [* ]Correspondence: sjlim@ 123456sejong.ac.kr ; Tel.: +82-2-3408-3767; Fax: +82-2-3408-4334
                Author information
                https://orcid.org/0000-0002-2318-387X
                Article
                pharmaceutics-11-00540
                10.3390/pharmaceutics11100540
                6835450
                31627301
                d8b88558-afb1-4062-97a6-32e297c0dbc9
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 August 2019
                : 14 October 2019
                Categories
                Review

                liposomes,intranasal,formulation,brain delivery,nanoparticle

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