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      Research progress in brain-targeted nasal drug delivery

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          Abstract

          The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood–brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract).

          Graphical Abstract

          According to the factors that affect the absorption of drugs into the brain through the nose, the bioavailability of drugs administered through the nasal brain pathway can be improved by changing the dosage form of the drug, adding mucosal adhesives, applying osmotic enhancers, adding vasoconstrictors, and using a new drug delivery system.

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          Most cited references104

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          A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity

          The blood–brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain’s metabolic activity as well as neuronal function. Thus, the functional and structural integrity of the BBB is pivotal to maintain the homeostasis of the brain microenvironment. The different cells and structures contributing to developing this barrier are summarized along with the different functions that BBB plays at the brain–blood interface. We also explained the role of shear stress in maintaining BBB integrity. Furthermore, we elaborated on the clinical aspects that correlate between BBB disruption and different neurological and pathological conditions. Finally, we discussed several biomarkers that can help to assess the BBB permeability and integrity in-vitro or in-vivo and briefly explain their advantages and disadvantages.
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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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              In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery.

              Stimuli-sensitive block copolymer hydrogels, which are reversible polymer networks formed by physical interactions and exhibit a sol-gel phase-transition in response to external stimuli, have great potential in biomedical and pharmaceutical applications, especially in site-specific controlled drug-delivery systems. The drug may be mixed with a polymer solution in vitro and the drug-loaded hydrogel can form in situ after the in vivo administration, such as injection; therefore, stimuli-sensitive block copolymer hydrogels have many advantages, such as simple drug formulation and administration procedures, no organic solvent, site-specificity, a sustained drug release behavior, less systemic toxicity and ability to deliver both hydrophilic and hydrophobic drugs. Among the stimuli in the biomedical applications, temperature and pH are the most popular physical and chemical stimuli, respectively. The temperature- and/or pH-sensitive block copolymer hydrogels for biomedical applications have been extensively developed in the past decade. This review focuses on recent development of the preparation and application for drug delivery of the block copolymer hydrogels that respond to temperature, pH or both stimuli, including poly(N-substituted acrylamide)-based block copolymers, poloxamers and their derivatives, poly(ethylene glycol)-polyester block copolymers, polyelectrolyte-based block copolymers and the polyelectrolyte-modified thermo-sensitive block copolymers. In addition, the hydrogels based on other stimuli-sensitive block copolymers are discussed.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                17 January 2024
                2023
                : 15
                : 1341295
                Affiliations
                [1] 1Department of Anesthesiology, The General Hospital of Western Theater Command , Chengdu, China
                [2] 2College of Medicine, Southwest Jiaotong University , Chengdu, China
                [3] 3Department of Neurosurgery, The General Hospital of Western Theater Command , Chengdu, China
                Author notes

                Edited by: Aurel Popa-Wagner, University of Medicine and Pharmacy of Craiova, Romania

                Reviewed by: Resham Chhabra, Independent Researcher, Toronto, ON, Canada

                Rashad Hussain, University of Rochester Medical Center, United States

                *Correspondence: Gu Gong, Gonggu68@ 123456163.com
                Article
                10.3389/fnagi.2023.1341295
                10828028
                38298925
                8386d11c-bfbd-42e6-9a24-bc7ec0e56cc4
                Copyright © 2024 Huang, Chen, Yu, Gong and Shu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 November 2023
                : 22 December 2023
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 104, Pages: 11, Words: 9802
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Joint key project (grant number 2019LH01), the Department of Science and Technology of Sichuan Province (grant numbers 2022JDRC0041 and 22CXRC0178), the Medical Innovation Project (grant number 21WQ040), and the Hospital Management Project of the General Hospital of the Western Theater Command (grant numbers 2021-XZYG-C25, 2021-XZYG-B22, and 2021-XZYG-B21).
                Categories
                Neuroscience
                Review
                Custom metadata
                Neuroinflammation and Neuropathy

                Neurosciences
                nasal administration,brain targeting,drug delivery,blood–brain barrier,biomaterials,research progress

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