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Nose to Brain Delivery (Volume II)

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (10 November 2021) | Viewed by 39107

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Prof. Dr. Paolo Giunchedi

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Department of Medicine, Surgery and Pharmacy, University of Sassari, Via Muroni 23/a, 07100 Sassari, Italy
Interests: drug delivery; nanomedicine; nanoparticles
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Prof. Dr. Elisabetta Gavini

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Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy
Interests: drug delivery; nanomedicine; nasal route
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Prof. Dr. Maria Cristina Bonferoni

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Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
Interests: amphiphilic polymers; bioactive polysaccharides; nanoemulsions; poorly soluble drug formulations; nanoparticles; theranostic
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Special Issue Information

Dear Colleagues,

The blood-brain barrier (BBB) separates the central nervous system (CNS) from general circulation. Drugs targeting the brain run into a remarkable problem owing to the BBB, which does not allow most drugs passage through it. The use of a nose-to-brain delivery route is an important and noninvasive method of drug delivery capable of solving this problem and bypass the BBB. Different strategies have been developed to enhance nose-to-brain drug delivery. In fact, it is well-known that an intranasal direct anatomical connection between the nasal cavity and the CNS exists, which suggests the development of nasal formulations for brain targeting of drugs. The design and preparation of nasal formulations involve the development of polymeric pharmaceutical platforms able to interact with nasal mucosa; bioadhesion and penetration enhancement through nasal mucosa layers are the first and most important characteristics that these systems must have. The development of new nasal systems represents a great challenge in the field of controlled drug targeting and delivery.

This Special Issue aims to highlight current progress in the use of the nasal route for brain targeting.

Prof. Paolo Giunchedi
Prof. Elisabetta Gavini
Prof. Maria Cristina Bonferoni
Guest Editors

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Keywords

Nasal route
Brain targeting
Mucoadhesion
Transmucosal delivery
Penetration enhancers
Nanoparticles
Microspheres

Published Papers (10 papers)

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Research

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13 pages, 2005 KiB

Open AccessArticle

Direct Delivery of ANA-TA9, a Peptide Capable of Aβ Hydrolysis, to the Brain by Intranasal Administration

by Yusuke Hatakawa, Akiko Tanaka, Tomoyuki Furubayashi, Rina Nakamura, Motomi Konishi, Toshifumi Akizawa and Toshiyasu Sakane

Pharmaceutics 2021, 13(10), 1673; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101673 - 13 Oct 2021

Cited by 3 | Viewed by 1714

Abstract

We have recently reported Catalytides (Catalytic peptides) JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMI), which are the first Catalytides found to cleave Aβ42. Although the Catalytides must be delivered to the brain parenchyma to treat Alzheimer’s disease, the blood–brain barrier (BBB) limits their entry into the brain from the systemic circulation. To avoid the BBB, the direct route from the nasal cavity to the brain was used in this study. The animal studies using rats and mice clarified that the plasma clearance of ANA-TA9 was more rapid than in vitro degradation in the plasma, whole blood, and the cerebrospinal fluid (CSF). The brain concentrations of ANA-TA9 were higher after nasal administration than those after intraperitoneal administration, despite a much lower plasma concentration after nasal administration, suggesting the direct delivery of ANA-TA9 to the brain from the nasal cavity. Similar findings were observed for its transport to CSF after nasal and intravenous administration. The concentration of ANA-TA9 in the olfactory bulb reached the peak at 5 min, whereas those in the frontal and occipital brains was 30 min, suggesting the sequential backward translocation of ANA-TA9 in the brain. In conclusion, ANA-TA9 was efficiently delivered to the brain by nasal application, as compared to other routes. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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12 pages, 2482 KiB

Open AccessArticle

Focused Ultrasound-Enhanced Delivery of Intranasally Administered Anti-Programmed Cell Death-Ligand 1 Antibody to an Intracranial Murine Glioma Model

by Dezhuang Ye, Jinyun Yuan, Yimei Yue, Joshua B. Rubin and Hong Chen

Pharmaceutics 2021, 13(2), 190; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020190 - 01 Feb 2021

Cited by 23 | Viewed by 4369

Abstract

Immune checkpoint inhibitors have great potential for the treatment of gliomas; however, their therapeutic efficacy has been partially limited by their inability to efficiently cross the blood–brain barrier (BBB). The objective of this study was to evaluate the capability of focused-ultrasound-mediated intranasal brain drug delivery (FUSIN) in achieving the locally enhanced delivery of anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain. Both non-tumor mice and mice transcranially implanted with GL261 glioma cells at the brainstem were used in this study. aPD-L1 was labeled with a near-infrared fluorescence dye (IRDye 800CW) and administered to mice through the nasal route to the brain, followed by focused ultrasound sonication in the presence of systemically injected microbubbles. FUSIN enhanced the accumulation of aPD-L1 at the FUS-targeted brainstem by an average of 4.03- and 3.74-fold compared with intranasal (IN) administration alone in the non-tumor mice and glioma mice, respectively. Immunohistochemistry staining found that aPD-L1 was mainly located within the perivascular spaces after IN delivery, while FUSIN further enhanced the penetration depth and delivery efficiency of aPD-L1 to the brain parenchyma. The delivered aPD-L1 was found to be colocalized with the tumor cells after FUSIN delivery to the brainstem glioma. These findings suggest that FUSIN is a promising technique to enhance the delivery of immune checkpoint inhibitors to gliomas. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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8 pages, 12707 KiB

Open AccessCommunication

Brain and Nasal Cavity Anatomy of the Cynomolgus Monkey: Species Differences from the Viewpoint of Direct Delivery from the Nose to the Brain

by Toshiyasu Sakane, Sachi Okabayashi, Shunsuke Kimura, Daisuke Inoue, Akiko Tanaka and Tomoyuki Furubayashi

Pharmaceutics 2020, 12(12), 1227; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121227 - 18 Dec 2020

Cited by 8 | Viewed by 3546

Abstract

Based on structural data on the nasal cavity and brain of the cynomolgus monkey, species differences in the olfactory bulb and cribriform plate were discussed from the viewpoint of direct delivery from the nose to the brain. Structural 3D data on the cynomolgus monkey skull were obtained using X-ray computed tomography. The dimensions of the nasal cavity of the cynomolgus monkey were 5 mm width × 20 mm height × 60 mm depth. The nasal cavity was very narrow and the olfactory region was far from the nostrils, similar to rats and humans. The weight and size of the monkey brain were 70 g and 55 mm width × 40 mm height × 70 mm depth. The olfactory bulb of monkeys is plate-like, while that of humans and rats is bulbar, suggesting that the olfactory area connected with the brain of monkeys is narrow. Although the structure of the monkey nasal cavity is similar to that of humans, the size and shape of the olfactory bulb are different, which is likely to result in low estimation of direct delivery from the nose to the brain in monkeys. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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22 pages, 3440 KiB

Open AccessArticle

Intranasal 17β-Estradiol Modulates Spatial Learning and Memory in a Rat Model of Surgical Menopause

by Alesia V. Prakapenka, Veronica L. Peña, Isabel Strouse, Steven Northup-Smith, Ally Schrier, Kinza Ahmed, Heather A. Bimonte-Nelson and Rachael W. Sirianni

Pharmaceutics 2020, 12(12), 1225; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121225 - 17 Dec 2020

Cited by 5 | Viewed by 2520

Abstract

Exogenously administered 17β-estradiol (E2) can improve spatial learning and memory, although E2 also exerts undesired effects on peripheral organs. Clinically, E2 has been solubilized in cyclodextrin for intranasal administration, which enhances brain-specific delivery. Prior work shows that the cyclodextrin structure impacts region-specific brain distribution of intranasally administered small molecules. Here, we investigated (1) cyclodextrin type-specific modulation of intranasal E2 brain distribution, and (2) cognitive and peripheral tissue effects of intranasal E2 in middle-aged ovariectomized rats. First, brain and peripheral organ distribution of intranasally administered, tritiated E2 was measured for E2 solubilized freely or in one of four cyclodextrin formulations. The E2-cyclodextrin formulation with greatest E2 uptake in cognitive brain regions versus uterine horns was then compared to free E2 on learning, memory, and uterine measures. Free E2 improved spatial reference memory, whereas E2-cyclodextrin impaired spatial working memory compared to their respective controls. Both E2 formulations increased uterine horn weights relative to controls, with E2-cyclodextrin resulting in the greatest uterine horn weight, suggesting increased uterine stimulation. Thus, intranasal administration of freely solubilized E2 is a strategic delivery tool that can yield a cognitively beneficial impact of the hormone alongside decreased peripheral effects compared to intranasal administration of cyclodextrin solubilized E2. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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13 pages, 3888 KiB

Open AccessArticle

Investigation of Cytotoxicity and Cell Uptake of Cationic Beta-Cyclodextrins as Valid Tools in Nasal Delivery

by Giovanna Rassu, Silvia Fancello, Marta Roldo, Milo Malanga, Lajos Szente, Rossana Migheli, Elisabetta Gavini and Paolo Giunchedi

Pharmaceutics 2020, 12(7), 658; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12070658 - 12 Jul 2020

Cited by 19 | Viewed by 2909

Abstract

Cyclodextrin polymers have high applicability in pharmaceutical formulations due to better biocompatibility, solubility enhancement, loading capacity and controlled drug release than their parent, cyclodextrins. The cytotoxicity and cell uptake of new cationic beta-cyclodextrin monomers and polymers were evaluated as suitable materials for nasal formulations and their protective effects on cells exposed to hydrogen peroxide were studied. PC12 and CACO-2 cells were selected as the neuronal- and epithelial-type cells, respectively, to mimic the structure of respiratory and olfactory epithelia of the nasal cavity. All cationic beta-cyclodextrin polymers tested showed dose- and time-dependent toxicity; nevertheless, at 5 µM concentration and 60 min of exposure, the quaternary-ammonium-beta-cyclodextrin soluble polymer could be recognized as nontoxic. Based on these results, a fluorescently labelled quaternary-ammonium-beta-cyclodextrin monomer and polymer were selected for uptake studies in CACO-2 cells. The monomeric and polymeric beta-cyclodextrins were internalized in the cytoplasm of CACO-2 cells; the cationic monomer showed higher permeability than the hydroxypropyl-beta-cyclodextrin, employed as comparison. Therefore, these cationic beta-cyclodextrins showed potential as excipients able to improve the nasal absorption of drugs. Furthermore, amino-beta-cyclodextrin and beta-cyclodextrin soluble polymers were able to reduce oxidative damage in PC12 and CACO-2 cells and thus could be studied as bioactive carriers or potential drugs for cell protection against oxidative stress. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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0 pages, 6452 KiB

Open AccessArticle

RETRACTED: Intranasal Niosomal In Situ Gel as a Promising Approach for Enhancing Flibanserin Bioavailability and Brain Delivery: In Vitro Optimization and Ex Vivo/In Vivo Evaluation

by Usama A. Fahmy, Shaimaa M. Badr-Eldin, Osama A. A. Ahmed, Hibah M. Aldawsari, Singkome Tima, Hani Z. Asfour, Mohammed W. Al-Rabia, Aya A. Negm, Muhammad H. Sultan, Osama A. A. Madkhali and Nabil A. Alhakamy

Pharmaceutics 2020, 12(6), 485; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12060485 - 27 May 2020

Cited by 43 | Viewed by 4257 | Retraction

Abstract

Flibanserin (FLB) is a multifunctional serotonergic agent that was recently approved by the FDA for the oral treatment of premenopausal women with hypoactive sexual desire disorder. FLB is a centrally acting drug that has a low oral bioavailability of 33% owing to its exposure to the hepatic first-pass effect, as well as its pH-dependent solubility, which could be an obstacle hindering the drug dissolution and absorption via mucosal barriers. Thus, this work aimed at overcoming the aforementioned drawbacks and promoting the nose-to-brain delivery of FLB via the formulation of an intra-nasal in situ niosomal gel. The Box–Behnken design was employed to study the impact of Span^® 85 concentration (X₁), hydration time (X₂), and pH of the hydrating buffer (X₃) on the vesicle size and drug entrapment. The optimized formulation exhibited a spherical shape with a vesicular size of 46.35 nm and entrapment efficiency of 92.48%. The optimized FLB niosomes integrated into gellan gum-based in situ gel exhibited enhanced ex vivo permeation and improved plasma and brain concentrations after nasal administration in rats compared to raw FLB. These findings highlight the capability of the proposed intra-nasal FLB niosomal in situ gel to boost the drug bioavailability and to promote its direct delivery to the brain. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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27 pages, 4268 KiB

Open AccessArticle

Optimization of Curcumin Nanocrystals as Promising Strategy for Nose-to-Brain Delivery Application

by Angela Bonaccorso, Maria Rosa Gigliobianco, Rosalia Pellitteri, Debora Santonocito, Claudia Carbone, Piera Di Martino, Giovanni Puglisi and Teresa Musumeci

Pharmaceutics 2020, 12(5), 476; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12050476 - 23 May 2020

Cited by 37 | Viewed by 4006

Abstract

Intranasal (IN) drug delivery is recognized to be an innovative strategy to deliver drugs to the Central Nervous System. One of the main limitations of IN dosing is the low volume of drug that can be administered. Accordingly, two requirements are necessary: the drug should be active at a low dosage, and the drug solubility in water must be high enough to accommodate the required dose. Drug nanocrystals may overcome these limitations; thus, curcumin was selected as a model drug to prepare nanocrystals for potential IN administration. With this aim, we designed curcumin nanocrystals (NCs) by using Box Behnken design. A total of 51 formulations were prepared by the sonoprecipitation method. Once we assessed the influence of the independent variables on nanocrystals’ mean diameter, the formulation was optimized based on the desirability function. The optimized formulation was characterized from a physico-chemical point of view to evaluate the mean size, zeta potential, polidispersity index, pH, osmolarity, morphology, thermotropic behavior and the degree of crystallinity. Finally, the cellular uptake of curcumin and curcumin NCs was evaluated on Olfactory Ensheathing Cells (OECs). Our results showed that the OECs efficiently took up the NCs compared to the free curcumin, showing that NCs can ameliorate drug permeability. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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Review

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21 pages, 2112 KiB

Open AccessReview

Nose-to-Brain Delivery of Antioxidants as a Potential Tool for the Therapy of Neurological Diseases

by Maria Cristina Bonferoni, Giovanna Rassu, Elisabetta Gavini, Milena Sorrenti, Laura Catenacci and Paolo Giunchedi

Pharmaceutics 2020, 12(12), 1246; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121246 - 21 Dec 2020

Cited by 16 | Viewed by 3263

Abstract

Oxidative stress has a key role in the pathogenesis of neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and can be an important cause of the damages in cerebral ischemia. Oxidative stress arises from high levels of reactive oxygen species (ROS). Consequently, on this rational base, antioxidants (many of natural origin) are proposed as potential drugs to prevent ROS noxious actions because they can protect the target tissues from the oxidative stress. However, the potential of antioxidants is limited, owing to the presence of the blood–brain barrier (BBB), which is difficult to cross with a consequent low bioavailability of the drug into the brain after systemic (intravenous, intraperitoneal, oral) administrations. One strategy to improve the delivery of antioxidants to the brain involves the use of the so-called nose-to-brain route, with the administration of the antioxidant in specific nasal formulations and its passage to the central nervous system (CNS) mainly through the olfactory nerve way. In the current literature, many examples show encouraging results in studies carried out in cell cultures and in animal models about the potential neuroprotective effects of antioxidants when administered through the nose. This review concerns the nose-to-brain route for the brain targeting of antioxidants as a potential tool for the therapy of neurological diseases. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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17 pages, 688 KiB

Open AccessReview

A Short Review on the Intranasal Delivery of Diazepam for Treating Acute Repetitive Seizures

by Sai H. S. Boddu and Sneha Kumari

Pharmaceutics 2020, 12(12), 1167; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121167 - 30 Nov 2020

Cited by 21 | Viewed by 7641

Abstract

Benzodiazepines such as diazepam, lorazepam and midazolam remained the mainstay of treatment for acute repetitive seizures (ARS). The immediate care for ARS should often begin at home by a caregiver. This prevents the progression of ARS to prolonged seizures or status epilepticus. For a long time and despite social objections rectal diazepam gel remained only FDA-approved rescue medication. Intranasal administration of benzodiazepines is considered attractive and safe compared with rectal, buccal and sublingual routes. Intranasal delivery offers numerous advantages such as large absorptive surface area, bypass the first-pass metabolism and good patient acceptance as it is needle free and painless. Recent clinical studies have demonstrated that diazepam nasal spray (NRL-1; Valtoco^®, Neurelis Inc.,San Diego, CA, USA) showed less pharmacokinetic variability and reliable bioavailability compared with the diazepam rectal gel. Diazepam nasal spray could be considered as a suitable alternative for treating seizure emergencies outside the hospital. This review summarizes the treatment options for ARS and findings from clinical studies involving intranasal diazepam for treating seizure emergencies. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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26 pages, 693 KiB

Open AccessReview

Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation

by Elizabeth M. Rhea, Aric F. Logsdon, William A. Banks and Michelle E. Erickson

Pharmaceutics 2020, 12(11), 1120; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12111120 - 20 Nov 2020

Cited by 8 | Viewed by 3777

Abstract

This review highlights the pre-clinical and clinical work performed to use intranasal delivery of various compounds from growth factors to stem cells to reduce neuroimmune interactions. We introduce the concept of intranasal (IN) delivery and the variations of this delivery method based on the model used (i.e., rodents, non-human primates, and humans). We summarize the literature available on IN delivery of growth factors, vitamins and metabolites, cytokines, immunosuppressants, exosomes, and lastly stem cells. We focus on the improvement of neuroimmune interactions, such as the activation of resident central nervous system (CNS) immune cells, expression or release of cytokines, and detrimental effects of signaling processes. We highlight common diseases that are linked to dysregulations in neuroimmune interactions, such as Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, and traumatic brain injury. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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