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Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 27066

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Special Issue Editors

Prof. Dr. Giuseppe Trapani

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Guest Editor

Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, Italy
Interests: brain targeting; nasal route; mucoadhesion; nanoparticles from renewable polymers; self-emulsifying lipid based drug delivery system; polymer-small molecule drug conjugates; cyclodextrins
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Massimo Conese

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Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
Interests: nose-to-brain delivery; applications of nanoparticles to drug delivery; Parkinson’s disease; mucopenetration; mesenchymal stem cells; exosomes; airway diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Central Nervous System (CNS) is the most complex organ of the human body and, consequently, remarkable challenges must be tackled in the therapeutic treatment of neurological disorders, the most relevant being the crossing of the blood–brain barrier (BBB). At present, the treatment of CNS diseases is mainly symptomatic and there are no disease-modifying therapies for most of these disorders. In this context, it appears necessary not only to create more effective drugs but also to improve their corresponding delivery systems, particularly when complex drugs, including genes, antibodies, peptides, and proteins, as well as neurotrophic factors and stem cells for regenerative therapy, are to be administered. For this last purpose, in the last few decades several nanostructured biomaterials have been identified as tools for the preparation of advanced drug delivery systems that could potentially be useful for the treatment of neurological disorders. The main advantages of using such nanostructured biomaterials in the neurological field are the satisfactory overcoming of the BBB and their biocompatibility. Current research in this area is focused on slowing down disease progression to achieve the important goal of improving the quality of life of patients.

We are pleased to invite you to the Special Issue, which aims to serve as an overview of the current status, challenges, and recent advances in polymer- and lipid-based nanostructured formulations used for the treatment of neurological disorders.

For this Special Issue, in particular, we call to researchers involved in brain targeting, overcoming the BBB both by invasive (e.g., brain implants, BBB transient opening etc.), and non-invasive methods (prodrugs, intranasal administration route (i.e., nose-to-brain delivery) etc.) using different materials such as polymers and lipids from natural and renewable resources to participate. These raw materials can be used as such or in physical mixtures to provide advanced nanostructured drug delivery systems (DDS), including polymeric nanoparticles, micelles, hydrogels, and lipid nanocarriers (liposomes, solid lipid nanoparticles and nanostructured lipid carriers). Moreover, such nanostructured DDS can be appropriately functionalized with suitable molecules to provide particular properties such as brain targeting or stability in biological fluids. A relevant application of such functionalized nanostructured DDS is the treatment of the most aggressive brain tumors, which are characterized by an unfavourable prognosis. The mentioned materials can be also used as scaffolds for the transplantation of stem cells (neural, pluripotent, or mesenchymal) to induce and promote the regeneration of damaged neuronal cells in neurodegenerative diseases by secreting growth factors and the exosomes derived thereof. In this Special Issue, original research articles and reviews on the mentioned research areas are welcome, as well as scientific papers on the diagnostic applications of these nanosized DDS.

We look forward to receiving your contributions.

Prof. Dr. Giuseppe Trapani
Prof. Dr. Massimo Conese
Guest Editors

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Keywords

neurodegenerative diseases
neurological diseases
brain tumors
brain targeting
nose-to-brain delivery
polymers from natural and renewable resources
polymer/lipid nanoparticles
neurotrophic factors
stem cells
exosomes

Published Papers (8 papers)

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Research

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19 pages, 2751 KiB

Open AccessArticle

Combined Dopamine and Grape Seed Extract-Loaded Solid Lipid Nanoparticles: Nasal Mucosa Permeation, and Uptake by Olfactory Ensheathing Cells and Neuronal SH-SY5Y Cells

by Adriana Trapani, Stefano Castellani, Lorenzo Guerra, Elvira De Giglio, Giuseppe Fracchiolla, Filomena Corbo, Nicola Cioffi, Giuseppe Passantino, Maria Luana Poeta, Pasqualina Montemurro, Rosanna Mallamaci, Rosa Angela Cardone and Massimo Conese

Pharmaceutics 2023, 15(3), 881; https://doi.org/10.3390/pharmaceutics15030881 - 8 Mar 2023

Cited by 3 | Viewed by 1447

Abstract

We have already formulated solid lipid nanoparticles (SLNs) in which the combination of the neurotransmitter dopamine (DA) and the antioxidant grape-seed-derived proanthocyanidins (grape seed extract, GSE) was supposed to be favorable for Parkinson’s disease (PD) treatment. In fact, GSE supply would reduce the PD-related oxidative stress in a synergic effect with DA. Herein, two different methods of DA/GSE loading were studied, namely, coadministration in the aqueous phase of DA and GSE, and the other approach consisting of a physical adsorption of GSE onto preformed DA containing SLNs. Mean diameter of DA coencapsulating GSE SLNs was 187 ± 4 nm vs. 287 ± 15 nm of GSE adsorbing DA-SLNs. TEM microphotographs evidenced low-contrast spheroidal particles, irrespective of the SLN type. Moreover, Franz diffusion cell experiments confirmed the permeation of DA from both SLNs through the porcine nasal mucosa. Furthermore, fluorescent SLNs also underwent cell-uptake studies by using flow cytometry in olfactory ensheathing cells and neuronal SH-SY5Y cells, evidencing higher uptake when GSE was coencapsulated rather than adsorbed onto the particles. Full article

(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application)

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18 pages, 6089 KiB

Open AccessArticle

Optimization of an Injectable Hydrogel Depot System for the Controlled Release of Retinal-Targeted Hybrid Nanoparticles

by Ilaria Ottonelli, Andrea Bighinati, Elisa Adani, François Loll, Riccardo Caraffi, Maria Angela Vandelli, Frank Boury, Giovanni Tosi, Jason Thomas Duskey, Valeria Marigo and Barbara Ruozi

Pharmaceutics 2023, 15(1), 25; https://doi.org/10.3390/pharmaceutics15010025 - 21 Dec 2022

Cited by 12 | Viewed by 2312

Abstract

A drawback in the development of treatments that can reach the retina is the presence of barriers in the eye that restrain compounds from reaching the target. Intravitreal injections hold promise for retinal delivery, but the natural defenses in the vitreous can rapidly degrade or eliminate therapeutic molecules. Injectable hydrogel implants, which act as a reservoir, can allow for long-term drug delivery with a single injection into the eye, but still suffer due to the fast clearance of the released drugs when traversing the vitreous and random diffusion that leads to lower pharmaceutic efficacy. A combination with HA-covered nanoparticles, which can be released from the gel and more readily pass through the vitreous to increase the delivery of therapeutic agents to the retina, represents an advanced and elegant way to overcome some of the limitations in eye drug delivery. In this article, we developed hybrid PLGA-Dotap NPs that, due to their hyaluronic acid coating, can improve in vivo distribution throughout the vitreous and delivery to retinal cells. Moreover, a hydrogel implant was developed to act as a depot for the hybrid NPs to better control and slow their release. These results are a first step to improve the treatment of retinal diseases by protecting and transporting the therapeutic treatment across the vitreous and to improve treatment options by creating a depot system for long-term treatments. Full article

(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application)

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16 pages, 2883 KiB

Open AccessArticle

The Encapsulation of Citicoline within Solid Lipid Nanoparticles Enhances Its Capability to Counteract the 6-Hydroxydopamine-Induced Cytotoxicity in Human Neuroblastoma SH-SY5Y Cells

by Andrea Margari, Anna Grazia Monteduro, Silvia Rizzato, Loredana Capobianco, Alessio Crestini, Roberto Rivabene, Paola Piscopo, Mara D’Onofrio, Valeria Manzini, Giuseppe Trapani, Alessandra Quarta, Giuseppe Maruccio, Carmelo Ventra, Luigi Lieto and Adriana Trapani

Pharmaceutics 2022, 14(9), 1827; https://doi.org/10.3390/pharmaceutics14091827 - 30 Aug 2022

Cited by 5 | Viewed by 1937

Abstract

(1) Backgrond: Considering the positive effects of citicoline (CIT) in the management of some neurodegenerative diseases, the aim of this work was to develop CIT-Loaded Solid Lipid Nanoparticles (CIT-SLNs) for enhancing the therapeutic use of CIT in parkinsonian syndrome; (2) Methods: CIT-SLNs were prepared by the melt homogenization method using the self-emulsifying lipid Gelucire^® 50/13 as lipid matrix. Solid-state features on CIT-SLNs were obtained with FT-IR, thermal analysis (DSC) and X-ray powder diffraction (XRPD) studies. (3) Results: CIT-SLNs showed a mean diameter of 201 nm, −2.20 mV as zeta potential and a high percentage of entrapped CIT. DSC and XRPD analyses evidenced a greater amorphous state of CIT in CIT-SLNs. On confocal microscopy, fluorescent SLNs replacing unlabeled CIT-SLNs released the dye selectively in the cytoplasm. Biological evaluation showed that pre-treatment of SH-SY5Y dopaminergic cells with CIT-SLNs (50 µM) before the addition of 40 µM 6-hydroxydopamine (6-OHDA) to mimic Parkinson’s disease’s degenerative pathways counteracts the cytotoxic effects induced by the neurotoxin, increasing cell viability with the consistent maintenance of both nuclear and cell morphology. In contrast, pre-treatment with CIT 50 and 60 µM or plain SLNs for 2 h followed by 6-OHDA (40 µM) did not significantly influence cell viability. (4) Conclusions: These data suggest an enhanced protection exerted by CIT-SLNs with respect to free CIT and prompt further investigation of possible molecular mechanisms that underlie this difference. Full article

(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application)

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18 pages, 1869 KiB

Open AccessArticle

Trehalose-Based Nucleolipids as Nanocarriers for Autophagy Modulation: An In Vitro Study

by Anthony Cunha, Alexandra Gaubert, Julien Verget, Marie-Laure Thiolat, Philippe Barthélémy, Laurent Latxague and Benjamin Dehay

Pharmaceutics 2022, 14(4), 857; https://doi.org/10.3390/pharmaceutics14040857 - 13 Apr 2022

Cited by 8 | Viewed by 2163

Abstract

The Autophagy Lysosomal Pathway is one of the most important mechanisms for removing dysfunctional cellular components. Increasing evidence suggests that alterations in this pathway play a pathogenic role in Parkinson’s disease, making it a point of particular vulnerability. Numerous studies have proposed nanotechnologies as a promising approach for delivering active substances within the central nervous system to treat and diagnose neurodegenerative diseases. In this context, the aim was to propose the development of a new pharmaceutical technology for the treatment of neurodegenerative diseases. We designed a trehalose-based nanosystem by combining both a small natural autophagy enhancer molecule named trehalose and an amphiphilic nucleolipid conjugate. To improve nucleolipid protection and cellular uptake, these conjugates were formulated by rapid mixing in either solid lipid nanoparticles (Ø = 120.4 ± 1.4 nm) or incorporated into poly(lactic-co-glycolic acid) nanoparticles (Ø = 167.2 ± 2.4 nm). In vitro biological assays demonstrated a safe and an efficient cellular uptake associated with autophagy induction. Overall, these nucleolipid-based formulations represent a promising new pharmaceutical tool to deliver trehalose and restore the autophagy impaired function. Full article

(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application)

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Review

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28 pages, 2049 KiB

Open AccessReview

Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery

by Rebecca Maher, Almudena Moreno-Borrallo, Dhruvi Jindal, Binh T. Mai, Eduardo Ruiz-Hernandez and Andrew Harkin

Pharmaceutics 2023, 15(3), 746; https://doi.org/10.3390/pharmaceutics15030746 - 23 Feb 2023

Cited by 11 | Viewed by 4383

Abstract

Nanomedicine is currently focused on the design and development of nanocarriers that enhance drug delivery to the brain to address unmet clinical needs for treating neuropsychiatric disorders and neurological diseases. Polymer and lipid-based drug carriers are advantageous for delivery to the central nervous system (CNS) due to their safety profiles, drug-loading capacity, and controlled-release properties. Polymer and lipid-based nanoparticles (NPs) are reported to penetrate the blood–brain barrier (BBB) and have been extensively assessed in in vitro and animal models of glioblastoma, epilepsy, and neurodegenerative disease. Since approval by the Food and Drug Administration (FDA) of intranasal esketamine for treatment of major depressive disorder, intranasal administration has emerged as an attractive route to bypass the BBB for drug delivery to the CNS. NPs can be specifically designed for intranasal administration by tailoring their size and coating with mucoadhesive agents or other moieties that promote transport across the nasal mucosa. In this review, unique characteristics of polymeric and lipid-based nanocarriers desirable for drug delivery to the brain are explored in addition to their potential for drug repurposing for the treatment of CNS disorders. Progress in intranasal drug delivery using polymeric and lipid-based nanostructures for the development of treatments of various neurological diseases are also described. Full article

(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application)

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22 pages, 2043 KiB

Open AccessReview

Nanoparticles for Drug and Gene Delivery in Pediatric Brain Tumors’ Cancer Stem Cells: Current Knowledge and Future Perspectives

by Luana Abballe, Zaira Spinello, Celeste Antonacci, Lucia Coppola, Ermanno Miele, Giuseppina Catanzaro and Evelina Miele

Pharmaceutics 2023, 15(2), 505; https://doi.org/10.3390/pharmaceutics15020505 - 2 Feb 2023

Cited by 7 | Viewed by 2949

Abstract

Primary malignant brain tumors are the most common solid neoplasm in childhood. Despite recent advances, many children affected by aggressive or metastatic brain tumors still present poor prognosis, therefore the development of more effective therapies is urgent. Cancer stem cells (CSCs) have been discovered and isolated in both pediatric and adult patients with brain tumors (e.g., medulloblastoma, gliomas and ependymoma). CSCs are a small clonal population of cancer cells responsible for brain tumor initiation, maintenance and progression, displaying resistance to conventional anticancer therapies. CSCs are characterized by a specific repertoire of surface markers and intracellular specific pathways. These unique features of CSCs biology offer the opportunity to build therapeutic approaches to specifically target these cells in the complex tumor bulk. Treatment of pediatric brain tumors with classical chemotherapeutic regimen poses challenges both for tumor location and for the presence of the blood–brain barrier (BBB). Lastly, the application of chemotherapy to a developing brain is followed by long-term sequelae, especially on cognitive abilities. Novel avenues are emerging in the therapeutic panorama taking advantage of nanomedicine. In this review we will summarize nanoparticle-based approaches and the efficacy that NPs have intrinsically demonstrated and how they are also decorated by biomolecules. Furthermore, we propose novel cargoes together with recent advances in nanoparticle design/synthesis with the final aim to specifically target the insidious CSCs population in the tumor bulk. Full article

(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application)

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18 pages, 1108 KiB

Open AccessReview

Exploring the Potential of Cannabinoid Nanodelivery Systems for CNS Disorders

by Mariana Kolesarova, Patrik Simko, Nicol Urbanska and Terezia Kiskova

Pharmaceutics 2023, 15(1), 204; https://doi.org/10.3390/pharmaceutics15010204 - 6 Jan 2023

Cited by 2 | Viewed by 4233

Abstract

Cannabinoids have a major therapeutic value in a variety of disorders. The concepts of cannabinoids are difficult to develop, but they can be used and are advantageous for a number of diseases that are not sufficiently managed by existing treatments. Nanoconjugation and encapsulation techniques have been shown to be effective in improving the delivery and the therapeutic effectiveness of drugs that are poorly soluble in water. Because the bioavailability of cannabinoids is low, the challenge is to explore different administration methods to improve their effectiveness. Because cannabinoids cross the blood-brain-barrier (BBB), they modify the negative effects of inflammatory processes on the BBB and may be a key factor in the improvement of BBB function after ischemic disease or other conditions. This review discusses various types of cannabinoid administration, as well as nanotechnologies used to improve the bioavailability of these compounds in CNS diseases. Full article

(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application)

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38 pages, 2824 KiB

Open AccessEditor’s ChoiceReview

Pharmacokinetics and Pharmacodynamics of Intranasal Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Nose-to-Brain Delivery

by Thi-Thao-Linh Nguyen and Han-Joo Maeng

Pharmaceutics 2022, 14(3), 572; https://doi.org/10.3390/pharmaceutics14030572 - 5 Mar 2022

Cited by 39 | Viewed by 6226

Abstract

Nose-to-brain drug delivery has been of great interest for the treatment of many central nervous system (CNS) diseases and psychiatric disorders over past decades. Several nasally administered formulations have been developed to circumvent the blood-brain barrier and directly deliver drugs to the CNS through the olfactory and trigeminal pathways. However, the nasal mucosa’s drug absorption is insufficient and the volume of the nasal cavity is small, which, in combination, make nose-to-brain drug delivery challenging. These problems could be minimized using formulations based on solid lipid nanoparticles (SLNs) or nanostructured lipid carriers (NLCs), which are effective nose-to-brain drug delivery systems that improve drug bioavailability by increasing drug solubility and permeation, extending drug action, and reducing enzymatic degradation. Various research groups have reported in vivo pharmacokinetics and pharmacodynamics of SLNs and NLCs nose-to-brain delivery systems. This review was undertaken to provide an overview of these studies and highlight research performed on SLN and NLC-based formulations aimed at improving the treatment of CNS diseases such neurodegenerative diseases, epilepsy, and schizophrenia. We discuss the efficacies and brain targeting efficiencies of these formulations based on considerations of their pharmacokinetic parameters and toxicities, point out some gaps in current knowledge, and propose future developmental targets. Full article

(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application)

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