Research

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16 pages, 1793 KiB

Open AccessArticle

Targeting Small Molecule Delivery to the Brain and Spinal Cord via Intranasal Administration of Rabies Virus Glycoprotein (RVG29)-Modified PLGA Nanoparticles

by Eugene P. Chung, Jennifer D. Cotter, Alesia V. Prakapenka, Rebecca L. Cook, Danielle M. DiPerna and Rachael W. Sirianni

Pharmaceutics 2020, 12(2), 93; https://doi.org/10.3390/pharmaceutics12020093 - 24 Jan 2020

Cited by 38 | Viewed by 4975

Abstract

Alternative routes of administration are one approach that could be used to bypass the blood–brain barrier (BBB) for effective drug delivery to the central nervous system (CNS). Here, we focused on intranasal delivery of polymer nanoparticles. We hypothesized that surface modification of poly(lactic- [...] Read more.

Alternative routes of administration are one approach that could be used to bypass the blood–brain barrier (BBB) for effective drug delivery to the central nervous system (CNS). Here, we focused on intranasal delivery of polymer nanoparticles. We hypothesized that surface modification of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with rabies virus glycoprotein (RVG29) would increase residence time and exposure of encapsulated payload to the CNS compared to non-targeted nanoparticles. Delivery kinetics and biodistribution were analyzed by administering nanoparticles loaded with the carbocyanine dye 1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindotricarbocyanine Iodide (DiR) to healthy mice. Intranasal administration yielded minimal exposure of nanoparticle payload to most peripheral organs and rapid, effective delivery to whole brain. Regional analysis of payload delivery within the CNS revealed higher delivery to tissues closest to the trigeminal nerve, including the olfactory bulb, striatum, midbrain, brainstem, and cervical spinal cord. RVG29 surface modifications presented modest targeting benefits to the striatum, midbrain, and brainstem 2 h after administration, although targeting was not observed 30 min or 6 h after administration. Payload delivery to the trigeminal nerve was 3.5× higher for targeted nanoparticles compared to control nanoparticles 2 h after nanoparticle administration. These data support a nose-to-brain mechanism of drug delivery that closely implicates the trigeminal nerve for payload delivery from nanoparticles via transport of intact nanoparticles and eventual diffusion of payload. Olfactory and CSF routes are also observed to play a role. These data advance the utility of targeted nanoparticles for nose-to-brain drug delivery of lipophilic payloads and provide mechanistic insight to engineer effective delivery vectors to treat disease in the CNS. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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11 pages, 3705 KiB

Open AccessArticle

PLGA-PEG-ANG-2 Nanoparticles for Blood–Brain Barrier Crossing: Proof-of-Concept Study

by Gina P. Hoyos-Ceballos, Barbara Ruozi, Ilaria Ottonelli, Federica Da Ros, Maria Angela Vandelli, Flavio Forni, Eleonora Daini, Antonietta Vilella, Michele Zoli, Giovanni Tosi, Jason T. Duskey and Betty L. López-Osorio

Pharmaceutics 2020, 12(1), 72; https://doi.org/10.3390/pharmaceutics12010072 - 17 Jan 2020

Cited by 44 | Viewed by 5570

Abstract

The treatment of diseases that affect the central nervous system (CNS) represents a great research challenge due to the restriction imposed by the blood–brain barrier (BBB) to allow the passage of drugs into the brain. However, the use of modified nanomedicines engineered with [...] Read more.

The treatment of diseases that affect the central nervous system (CNS) represents a great research challenge due to the restriction imposed by the blood–brain barrier (BBB) to allow the passage of drugs into the brain. However, the use of modified nanomedicines engineered with different ligands that can be recognized by receptors expressed in the BBB offers a favorable alternative for this purpose. In this work, a BBB-penetrating peptide, angiopep-2 (Ang–2), was conjugated to poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles through pre- and post-formulation strategies. Then, their ability to cross the BBB was qualitatively assessed on an animal model. Proof-of-concept studies with fluorescent and confocal microscopy studies highlighted that the brain-targeted PLGA nanoparticles were able to cross the BBB and accumulated in neuronal cells, thus showing a promising brain drug delivery system. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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19 pages, 12516 KiB

Open AccessArticle

Hyaluronate Nanoparticles as a Delivery System to Carry Neuroglobin to the Brain after Stroke

by Santos Blanco, Sebastián Peralta, María Encarnación Morales, Esther Martínez-Lara, José Rafael Pedrajas, Herminia Castán, María Ángeles Peinado and María Adolfina Ruiz

Pharmaceutics 2020, 12(1), 40; https://doi.org/10.3390/pharmaceutics12010040 - 03 Jan 2020

Cited by 17 | Viewed by 4180

Abstract

Therapies against stroke can restore the blood supply but cannot prevent the ischemic damage nor stimulate the recovery of the infarcted zone. The neuroglobin protein plays an important role in the neuro-regeneration process after stroke; however, the method for its effective systemic application [...] Read more.

Therapies against stroke can restore the blood supply but cannot prevent the ischemic damage nor stimulate the recovery of the infarcted zone. The neuroglobin protein plays an important role in the neuro-regeneration process after stroke; however, the method for its effective systemic application has not been identified yet, as neuroglobin is unable to pass through the blood-brain barrier. Previously, we developed different types of sodium hyaluronate nanoparticles, which successfully cross the blood-brain barrier after stroke. In this work, these nanoparticles have been used to carry neuroglobin through the bloodstream to the nerve cells in rats submitted to stroke. We have biosynthesized rat-recombinant neuroglobin and determined the formulation of sodium hyaluronate nanoparticles loaded with neuroglobin, as well as its size and ζ-potential, encapsulation efficiently, in vitro release, and its kinetic of liberation. The results show that the formulation achieved is highly compatible with pharmaceutical use and may act as a delivery system to transport neuroglobin within the blood. We have found that this formulation injected intravenously immediately after stroke reached the damaged cerebral parenchyma at early stages (2 h). Neuroglobin colocalizes with its nanocarriers inside the nerve cells and remains after 24 h of reperfusion. In conclusion, the systemic administration of neuroglobin linked to nanoparticles is a potential neuroprotective drug-delivery strategy after stroke episodes. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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17 pages, 2362 KiB

Open AccessArticle

Muscle to Brain Partitioning as Measure of Transporter-Mediated Efflux at the Rat Blood–Brain Barrier and Its Implementation into Compound Optimization in Drug Discovery

by Yunhai Cui, Ralf Lotz, Hermann Rapp, Klaus Klinder, Anneke Himstedt and Achim Sauer

Pharmaceutics 2019, 11(11), 595; https://doi.org/10.3390/pharmaceutics11110595 - 11 Nov 2019

Cited by 10 | Viewed by 4428

Abstract

Movement of xenobiotic substances across the blood–brain barrier (BBB) is tightly regulated by various transporter proteins, especially the efflux transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). Avoiding drug efflux at the BBB is a unique challenge for the development of new [...] Read more.

Movement of xenobiotic substances across the blood–brain barrier (BBB) is tightly regulated by various transporter proteins, especially the efflux transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). Avoiding drug efflux at the BBB is a unique challenge for the development of new central nervous system (CNS) drugs. Drug efflux at the BBB is described by the partition coefficient of unbound drug between brain and plasma (K_p,uu,brain) which is typically obtained from in vivo and often additionally in vitro measurements. Here, we describe a new method for the rapid estimation of the in vivo drug efflux at the BBB of rats: the measurement of the partition coefficient of a drug between brain and skeletal muscle (K_{p,brain/muscle}). Assuming a closely similar distribution of drugs into the brain and muscle and that the efflux transporters are only expressed in the brain, K_{p,brain/muscle}, similar to K_p,uu,brain, reflects the efflux at the BBB. The new method requires a single in vivo experiment. For 64 compounds from different research programs, we show the comparability to other approaches used to obtain K_p,uu,brain. P-gp- and BCRP-overexpressing cell systems are valuable in vitro tools for prescreening. Drug efflux at the BBB can be most accurately predicted based on a simple algorithm incorporating data from both in vitro assays. In conclusion, the combined use of our new in vivo method and the in vitro tools allows an efficient screening method in drug discovery with respect to efflux at the BBB. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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22 pages, 1929 KiB

Open AccessArticle

IVIVC Assessment of Two Mouse Brain Endothelial Cell Models for Drug Screening

by Ina Puscas, Florian Bernard-Patrzynski, Martin Jutras, Marc-André Lécuyer, Lyne Bourbonnière, Alexandre Prat, Grégoire Leclair and V. Gaëlle Roullin

Pharmaceutics 2019, 11(11), 587; https://doi.org/10.3390/pharmaceutics11110587 - 08 Nov 2019

Cited by 17 | Viewed by 4405

Abstract

Since most preclinical drug permeability assays across the blood-brain barrier (BBB) are still evaluated in rodents, we compared an in vitro mouse primary endothelial cell model to the mouse b.End3 and the acellular parallel artificial membrane permeability assay (PAMPA) models for drug screening [...] Read more.

Since most preclinical drug permeability assays across the blood-brain barrier (BBB) are still evaluated in rodents, we compared an in vitro mouse primary endothelial cell model to the mouse b.End3 and the acellular parallel artificial membrane permeability assay (PAMPA) models for drug screening purposes. The mRNA expression of key feature membrane proteins of primary and bEnd.3 mouse brain endothelial cells were compared. Transwell^® monolayer models were further characterized in terms of tightness and integrity. The in vitro in vivo correlation (IVIVC) was obtained by the correlation of the in vitro permeability data with log BB values obtained in mice for seven drugs. The mouse primary model showed higher monolayer integrity and levels of mRNA expression of BBB tight junction (TJ) proteins and membrane transporters (MBRT), especially for the efflux transporter Pgp. The IVIVC and drug ranking underlined the superiority of the primary model (r² = 0.765) when compared to the PAMPA-BBB (r² = 0.391) and bEnd.3 cell line (r² = 0.019) models. The primary monolayer mouse model came out as a simple and reliable candidate for the prediction of drug permeability across the BBB. This model encompasses a rapid set-up, a fair reproduction of BBB tissue characteristics, and an accurate drug screening. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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16 pages, 10515 KiB

Open AccessArticle

Nanomedicine against Aβ Aggregation by β–Sheet Breaker Peptide Delivery: In Vitro Evidence

by Francesca Pederzoli, Barbara Ruozi, Jason Duskey, Simone Hagmeyer, Ann Katrin Sauer, Stefanie Grabrucker, Romina Coelho, Natalia Oddone, Ilaria Ottonelli, Eleonora Daini, Michele Zoli, Maria Angela Vandelli, Giovanni Tosi and Andreas M. Grabrucker

Pharmaceutics 2019, 11(11), 572; https://doi.org/10.3390/pharmaceutics11110572 - 01 Nov 2019

Cited by 20 | Viewed by 3150

Abstract

The accumulation of amyloid β (Aβ) triggers a cascade of toxic events in Alzheimer’s disease (AD). The KLVFF peptide can interfere with Aβ aggregation. However, the peptide suffers from poor bioavailability and the inability to cross the blood–brain barrier. In this work, we [...] Read more.

The accumulation of amyloid β (Aβ) triggers a cascade of toxic events in Alzheimer’s disease (AD). The KLVFF peptide can interfere with Aβ aggregation. However, the peptide suffers from poor bioavailability and the inability to cross the blood–brain barrier. In this work, we study the possibility of adopting nanomedicine to overcome KLVFF limits in biodistribution. We produced new engineered polymeric nanoparticles (NPs), and we evaluated the cellular toxicity of these NPs and validated that KVLFF peptides released by NPs show the same promising effects on AD pathology. Our results revealed the successful generation of KVLFF loaded NPs that, without significant effects on cell heath, are even more potent in reversing Aβ-induced pathologies compared to the free peptide. Therefore, NPs will significantly advance KVLFF treatment as a therapeutic option for AD. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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15 pages, 2642 KiB

Open AccessArticle

Improving In Vivo Brain Delivery of Monoclonal Antibody Using Novel Cyclic Peptides

by Kavisha R. Ulapane, Brian M. Kopec and Teruna J. Siahaan

Pharmaceutics 2019, 11(11), 568; https://doi.org/10.3390/pharmaceutics11110568 - 31 Oct 2019

Cited by 14 | Viewed by 3424

Abstract

Many proteins can be used to treat brain diseases; however, the presence of the blood–brain barrier (BBB) creates an obstacle to delivering them into the brain. Previously, various molecules were delivered through the paracellular pathway of the BBB via its modulation, using ADTC5 [...] Read more.

Many proteins can be used to treat brain diseases; however, the presence of the blood–brain barrier (BBB) creates an obstacle to delivering them into the brain. Previously, various molecules were delivered through the paracellular pathway of the BBB via its modulation, using ADTC5 and HAV6 peptides. This study goal was to design new cyclic peptides with N-to-C terminal cyclization for better plasma stability and modulation of the BBB. Cyclic HAVN1 and HAVN2 peptides were derived from a linear HAV6 peptide. Linear and N-to-C terminal cyclic ADTHAV peptides were designed by combining the sequences of ADTC5 and HAV6. These novel cyclic peptides were used to deliver an IRdye800CW-labeled IgG monoclonal antibody into the brain. Cyclic HAVN1 and HAVN2 peptides deliver IgG into the brain, while the parent linear HAV6 peptide does not. Cyclic and linear ADTHAV and ADTC5 peptides enhanced brain delivery of IgG mAb, in which cyclic ADTHAV peptide was better than linear ADTHAV (p = 0.07). Cyclic ADTHAV and ADTC5 influenced the distribution of IgG mAb in other organs while HAV6, HAVN1 and HAVN2 did not. In summary, the novel cyclic peptides are generally better BBB modulators than their linear counterparts for delivering IgG mAb into the brain. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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16 pages, 1899 KiB

Open AccessArticle

Brain Delivery of a Potent Opioid Receptor Agonist, Biphalin during Ischemic Stroke: Role of Organic Anion Transporting Polypeptide (OATP)

by Thamer H Albekairi, Bhuvaneshwar Vaidya, Ronak Patel, Saeideh Nozohouri, Heidi Villalba, Yong Zhang, Yeon Sun Lee, Abraham Al-Ahmad and Thomas J Abbruscato

Pharmaceutics 2019, 11(9), 467; https://doi.org/10.3390/pharmaceutics11090467 - 10 Sep 2019

Cited by 27 | Viewed by 4489

Abstract

Transporters (expressed) at the blood-brain barrier (BBB) can play an essential role in the treatment of brain injury by transporting neuroprotective substance to the central nervous system. The goal of this study was to understand the role of organic anion transporting polypeptide (OATP1; [...] Read more.

Transporters (expressed) at the blood-brain barrier (BBB) can play an essential role in the treatment of brain injury by transporting neuroprotective substance to the central nervous system. The goal of this study was to understand the role of organic anion transporting polypeptide (OATP1; OATP1A2 in humans and oatp1a4 in rodents) in the transport of a potent opioid receptor agonist, biphalin, across the BBB during ischemic stroke. Brain microvascular endothelial cells (BMECs) that were differentiated from human induced pluripotent stem cells (iPSCs) were used in the present study. The effect of oxygen-glucose deprivation (OGD) and reperfusion on the OATP1 expression, uptake, and transport of biphalin was measured in induced pluripotent stem cells differentiated brain microvascular endothelial cells (iPSC–BMECs) in the presence and absence of an OATP1 substrate, estrone-3-sulfate (E3S). Biphalin brain permeability was quantified while using a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. It was found that iPSC-BMECs expressed OATP1. In vitro studies showed that biphalin BBB uptake and transport decreased in the presence of an OATP1 specific substrate. It was also observed that OGD and reperfusion modulate the expression and function of OATP1 in BMECs. This study strongly demonstrates that OATP1 contributes to the transport of biphalin across the BBB and increased expression of OATP1 during OGD-reperfusion could provide a novel target for improving ischemic brain drug delivery of biphalin or other potential neurotherapeutics that have affinity to this BBB transporter. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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12 pages, 1388 KiB

Open AccessCommunication

Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach

by Katalin Prokai-Tatrai, Daniel L. De La Cruz, Vien Nguyen, Benjamin P. Ross, Istvan Toth and Laszlo Prokai

Pharmaceutics 2019, 11(7), 349; https://doi.org/10.3390/pharmaceutics11070349 - 18 Jul 2019

Cited by 7 | Viewed by 3878

Abstract

Using thyrotropin-releasing hormone (TRH) as a model, we explored whether synergistic combination of lipoamino acid(s) and a linker cleaved by prolyl oligopeptidase (POP) can be used as a promoiety for prodrug design for the preferential brain delivery of the peptide. A representative prodrug [...] Read more.

Using thyrotropin-releasing hormone (TRH) as a model, we explored whether synergistic combination of lipoamino acid(s) and a linker cleaved by prolyl oligopeptidase (POP) can be used as a promoiety for prodrug design for the preferential brain delivery of the peptide. A representative prodrug based on this design principle was synthesized, and its membrane affinity and in vitro metabolic stability, with or without the presence of a POP inhibitor, were studied. The in vivo formation of TRH from the prodrug construct was probed by utilizing the antidepressant effect of the peptide, as well as its ability to increase acetylcholine (ACh) synthesis and release. We found that the prototype prodrug showed excellent membrane affinity and greatly increased metabolic stability in mouse blood and brain homogenate compared to the parent peptide, yet a POP inhibitor completely prevented prodrug metabolism in brain homogenate. In vivo, administration of the prodrug triggered antidepressant-like effect, and microdialysis sampling showed greatly increased ACh release that was also antagonized upon a POP inhibitor treatment. Altogether, the obtained promising exploratory data warrant further investigations on the utility of the prodrug approach introduced here for brain-enhanced delivery of small peptides with neurotherapeutic potential. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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Review

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15 pages, 642 KiB

Open AccessReview

Cannabinoids, Blood–Brain Barrier, and Brain Disposition

by Fabrizio Calapai, Luigi Cardia, Emanuela Elisa Sorbara, Michele Navarra, Sebastiano Gangemi, Gioacchino Calapai and Carmen Mannucci

Pharmaceutics 2020, 12(3), 265; https://doi.org/10.3390/pharmaceutics12030265 - 15 Mar 2020

Cited by 68 | Viewed by 10113

Abstract

Potential therapeutic actions of the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are based on their activity as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds. THC and CBD lipophilicity and their neurological actions makes them candidates as new medicinal approaches to treat central nervous system [...] Read more.

Potential therapeutic actions of the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are based on their activity as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds. THC and CBD lipophilicity and their neurological actions makes them candidates as new medicinal approaches to treat central nervous system (CNS) diseases. However, they show differences about penetrability and disposition in the brain. The present article is an overview about THC and CBD crossing the blood–brain barrier (BBB) and their brain disposition. Several findings indicate that CBD can modify the deleterious effects on BBB caused by inflammatory cytokines and may play a pivotal role in ameliorating BBB dysfunction consequent to ischemia. Thus supporting the therapeutic potential of CBD for the treatment of ischemic and inflammatory diseases of CNS. Cannabinoids positive effects on cognitive function could be also considered through the aspect of protection of BBB cerebrovascular structure and function, indicating that they may purchase substantial benefits through the protection of BBB integrity. Delivery of these cannabinoids in the brain following different routes of administration (subcutaneous, oral, and pulmonary) is illustrated and commented. Finally, the potential role of cannabinoids in drug-resistance in the clinical management of neurological or psychiatric diseases such as epilepsy and schizophrenia is discussed on the light of their crossing the BBB. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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18 pages, 1941 KiB

Open AccessReview

Transporter-Mediated Delivery of Small Molecule Drugs to the Brain: A Critical Mechanism That Can Advance Therapeutic Development for Ischemic Stroke

by Erica I. Williams, Robert D. Betterton, Thomas P. Davis and Patrick T. Ronaldson

Pharmaceutics 2020, 12(2), 154; https://doi.org/10.3390/pharmaceutics12020154 - 14 Feb 2020

Cited by 26 | Viewed by 3775

Abstract

Ischemic stroke is the 5th leading cause of death in the United States. Despite significant improvements in reperfusion therapies, stroke patients still suffer from debilitating neurocognitive deficits. This indicates an essential need to develop novel stroke treatment paradigms. Endogenous uptake transporters expressed at [...] Read more.

Ischemic stroke is the 5th leading cause of death in the United States. Despite significant improvements in reperfusion therapies, stroke patients still suffer from debilitating neurocognitive deficits. This indicates an essential need to develop novel stroke treatment paradigms. Endogenous uptake transporters expressed at the blood-brain barrier (BBB) provide an excellent opportunity to advance stroke therapy via optimization of small molecule neuroprotective drug delivery to the brain. Examples of such uptake transporters include organic anion transporting polypeptides (OATPs in humans; Oatps in rodents) and organic cation transporters (OCTs in humans; Octs in rodents). Of particular note, small molecule drugs that have neuroprotective properties are known substrates for these transporters and include 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) for OATPs/Oatps and 1-amino-3,5-dimethyladamantane (i.e., memantine) for OCTs/Octs. Here, we review current knowledge on specific BBB transporters that can be targeted for improvement of ischemic stroke treatment and provide state-of-the-art perspectives on the rationale for considering BBB transport properties during discovery/development of stroke therapeutics. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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54 pages, 2885 KiB

Open AccessReview

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

by David Gomez-Zepeda, Méryam Taghi, Jean-Michel Scherrmann, Xavier Decleves and Marie-Claude Menet

Pharmaceutics 2020, 12(1), 20; https://doi.org/10.3390/pharmaceutics12010020 - 23 Dec 2019

Cited by 73 | Viewed by 9465

Abstract

Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability [...] Read more.

Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood–brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood–brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood–brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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10 pages, 3816 KiB

Open AccessReview

Perivascular and Perineural Pathways Involved in Brain Delivery and Distribution of Drugs after Intranasal Administration

by Jeffrey J. Lochhead and Thomas P. Davis

Pharmaceutics 2019, 11(11), 598; https://doi.org/10.3390/pharmaceutics11110598 - 12 Nov 2019

Cited by 49 | Viewed by 5821

Abstract

One of the most challenging aspects of treating disorders of the central nervous system (CNS) is the efficient delivery of drugs to their targets within the brain. Only a small fraction of drugs is able to cross the blood–brain barrier (BBB) under physiological [...] Read more.

One of the most challenging aspects of treating disorders of the central nervous system (CNS) is the efficient delivery of drugs to their targets within the brain. Only a small fraction of drugs is able to cross the blood–brain barrier (BBB) under physiological conditions, and this observation has prompted investigation into the routes of administration that may potentially bypass the BBB and deliver drugs directly to the CNS. One such route is the intranasal (IN) route. Increasing evidence has suggested that intranasally-administered drugs are able to bypass the BBB and access the brain through anatomical pathways connecting the nasal cavity to the CNS. Though the exact mechanisms regulating the delivery of therapeutics following IN administration are not fully understood, current evidence suggests that the perineural and perivascular spaces of the olfactory and trigeminal nerves are involved in brain delivery and cerebral perivascular spaces are involved in widespread brain distribution. Here, we review evidence for these delivery and distribution pathways, and we address questions that should be resolved in order to optimize the IN route of administration as a viable strategy to treat CNS disease states. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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23 pages, 1148 KiB

Open AccessReview

Neuronanomedicine: An Up-to-Date Overview

by Daniel Mihai Teleanu, Cristina Chircov, Alexandru Mihai Grumezescu and Raluca Ioana Teleanu

Pharmaceutics 2019, 11(3), 101; https://doi.org/10.3390/pharmaceutics11030101 - 26 Feb 2019

Cited by 59 | Viewed by 4761

Abstract

The field of neuronanomedicine has recently emerged as the bridge between neurological sciences and nanotechnology. The possibilities of this novel perspective are promising for the diagnosis and treatment strategies of severe central nervous system disorders. Therefore, the development of nano-vehicles capable of permeating [...] Read more.

The field of neuronanomedicine has recently emerged as the bridge between neurological sciences and nanotechnology. The possibilities of this novel perspective are promising for the diagnosis and treatment strategies of severe central nervous system disorders. Therefore, the development of nano-vehicles capable of permeating the blood–brain barrier (BBB) and reaching the brain parenchyma may lead to breakthrough therapies that could improve life expectancy and quality of the patients diagnosed with brain disorders. The aim of this review is to summarize the recently developed organic, inorganic, and biological nanocarriers that could be used for the delivery of imaging and therapeutic agents to the brain, as well as the latest studies on the use of nanomaterials in brain cancer, neurodegenerative diseases, and stroke. Additionally, the main challenges and limitations associated with the use of these nanocarriers are briefly presented. Full article

(This article belongs to the Special Issue Drug Delivery to the Brain)

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