Central Nervous System Delivery Research Articles

A Bioinspired Platform for Effective Delivery of Protein Therapeutics to the Central Nervous System.

Central nervous system (CNS) diseases are the leading cause of morbidity and mortality; their treatment, however, remains constrained by the blood-brain barrier (BBB) that impedes the access of most therapeutics to the brain. A CNS delivery platform for protein therapeutics, which is achieved by encapsulating the proteins within nanocapsules that contain choline and acetylcholine analogues, is reported herein. Mediated by nicotinic acetylcholine receptors and choline transporters, such nanocapsules can effectively penetrate the BBB and deliver the therapeutics to the CNS, as demonstrated in mice and non-human primates. This universal platform, in general, enables the delivery of any protein therapeutics of interest to the brain, opening a new avenue for the treatment of CNS diseases.

Direct CNS delivery of proteins using thermosensitive liposome-in-gel carrier by heterotopic mucosal engrafting.

Delivering therapeutics across the blood-brain barrier (BBB) for treating central nervous system (CNS) diseases is one of the biggest challenges today as the BBB limits the uptake of molecules greater than 500 Da into the CNS. Here we describe a novel trans-nasal mucosal drug delivery as an alternative to the intranasal drug delivery to overcome its limitations and deliver high molecular weight (HMW) therapeutics efficiently to the brain. This approach is based on human endoscopic skull base surgical techniques in which a surgical defect is repaired by engrafting semipermeable nasal mucosa over a skull base defect. Based on endoscopic skull based surgeries, our groups has developed a trans-nasal mucosal rodent model where we have evaluated the permeability of ovalbumin (45 kDa) as a model protein through the implanted mucosal graft for delivering HMW therapeutics to the brain. A thermo sensitive liposome-in-gel (LiG) system was developed for creating a drug depot allowing for a sustained release from the site of delivery to the brain through the implanted nasal graft. We would like to report this as an exploratory pilot study where we are using this novel surgical model to show that the implanted nasal mucosal graft and the LiG delivery system result in an efficient and a sustained brain delivery of HMW proteins. Hence, this study demonstrates that the trans-nasal mucosal engrafting technique could overcome the limitations for intranasal drug delivery and enable the uptake of HMW protein therapeutics into the CNS for the treatment of a wide range of neurodegenerative diseases.

An overview of the neuroprotective potential of rosmarinic acid and its association with nanotechnology-based delivery systems: A novel approach to treating neurodegenerative disorders

Neurodegenerative disorders (ND) are characterized by slow and progressive neuronal dysfunction induced by the degeneration of neuronal cells in the central nervous system (CNS). Recently, the neuroprotective effects of natural compounds with anti-inflammatory and antioxidant activities has been clearly demonstrated. This appears to be an attractive therapeutic approach for ND, particularly regarding the use of polyphenols. In this review, we present an overview of the neuroprotective potential of rosmarinic acid (RA) and discuss the use of nanotechnology as a novel approach to treating ND. RA presents a variety of biological important activities, i.e. the modulation of pro-inflammatory cytokine expression, prevention of neurodegeneration and damage reduction. However, its poor bioavailability represents a limitation in terms of pharmacodynamics. In this sense, nanotechnology-based carriers could allow for the administration of higher but still safe amounts of RA, aiming for CNS delivery. Nasal administration could be a pleasant route for delivery to the CNS, as this represents a direct route to the CNS. With these advantages, RA-loaded nanotechnology-based therapy through the nasal route could be promising approach for the treatment of ND.

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier.

Central nervous system (CNS) drug delivery can be achieved by targeting drug uptake transporters such as Oatp1a4. In fact, many drugs that can improve neurologic outcomes in CNS diseases [3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (i.e., statins)] are organic anion transporting polypeptide (OATP) transport substrates. To date, transport properties and regulatory mechanisms of Oatp1a4 at the blood-brain barrier (BBB) have not been rigorously studied. Such knowledge is critical to develop Oatp1a4 for optimization of CNS drug delivery and for improved treatment of neurological diseases. Our laboratory has demonstrated that the transforming growth factor-β (TGF-β)/activin receptor-like kinase 1 (ALK1) signaling agonist bone morphogenetic protein 9 (BMP-9) increases functional expression of Oatp1a4 in rat brain microvessels. Here, we expand on this work and show that BMP-9 treatment increases blood-to-brain transport and brain exposure of established OATP transport substrates (i.e., taurocholate, atorvastatin, and pravastatin). We also demonstrate that BMP-9 activates the TGF-β/ALK1 pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor (i.e., pSmad1/5/8). Furthermore, we report that an activated Smad protein complex comprised of phosphorylated Smad1/5/8 and Smad4 is formed following BMP-9 treatment and binds to the promoter of the Slco1a4 gene (i.e., the gene that encodes Oatp1a4). This signaling mechanism causes increased expression of Slco1a4 mRNA. Overall, this study provides evidence that Oatp1a4 transport activity at the BBB is directly regulated by TGF-β/ALK1 signaling and indicates that this pathway can be targeted for control of CNS delivery of OATP substrate drugs.

Evidence for sex difference in the CSF/plasma albumin ratio in ~20 000 patients and 335 healthy volunteers.

Given sex‐related differences in brain disorders, it is of interest to study if there is a sex difference in the permeability of the blood‐cerebrospinal fluid barrier (BCSFB) and the blood‐brain barrier (BBB). The CSF/serum albumin ratio (QA lb) is a standardized biomarker that evaluates the function of these barriers. In previous studies, contradictory results have been reported with respect to sex difference using this quotient, possibly because of small population sizes and heterogeneity with respect to ages. QA lb measurements in more than 20 000 patients between 1 and 90 years visiting our hospitals revealed a significant sex difference in all age groups also when excluding patients with pathologically high CSF albumin > 400 mg/L. Similar pattern was found in 335 healthy volunteers in similar age intervals. Although also other factors are likely important, our observation is consistent with lower integrity of the brain barriers in males. If the difference in QA lb is caused mainly by a difference in barrier function, this may require different drug doses and strategies for efficient central nervous system (CNS) delivery in males and females, as well as it may indicate differences in brain metabolism. Moreover, our study emphasizes that different reference values should be used both for different ages and sexes.

Drug Delivery Through Blood Brain Barrier: Taming the Bottleneck in CNS Therapeutics

Although many agents have therapeutic potentials for Central Nervous System (CNS) diseases, few of these agents have been clinically used because of the brain barriers. Physiological barriers like the blood-brain barrier and blood-cerebrospinal fluid barrier as well as various efflux transporter proteins make the entry of drugs into the central nervous system very difficult. Different strategies for efficient CNS delivery have been studied. This review presents the current approaches to facilitate penetration across these barriers for enhanced drug delivery to the CNS.

Ligand-cascading nano-delivery devices to enable multiscale targeting of anti-neurodegenerative therapeutics

Neurodegenerative diseases are a debilitating set of conditions that affect a significant fraction of the world’s population, and this fraction is expected to increase as the population ages. Many therapeutic strategies have been explored to treat the pathological mechanisms of neurodegenerative diseases, but multiple sequential hurdles to central nervous system (CNS) delivery, including the blood–brain barrier (BBB), diseased neuronal membranes, and the organelle barrier, make drug delivery challenging and necessitate the use of innovative strategies to target and cross each barrier. Advances in drug delivery technology have the potential to improve the standard of treatment for neurodegenerative diseases by enhancing local drug concentration at the pathologically relevant cells and organelles. Furthermore, ligand-cascading nano-delivery devices could address these issues by sequentially presenting targeting ligands for crossing each of the aforementioned hurdles. In this review, we provide an overview of ligand technologies that enable BBB transcytosis, localization to or internalization in diseased neuronal cells, and localization at the organelle of interest. We summarize recent strategies for sequentially presenting pertinent ligands at each hurdle to CNS delivery. These ligand-cascade strategies will enable rational design of nano-delivery devices for multiscale targeting of anti-neurodegenerative therapeutics.

Intra-arterial Temozolomide, Osmotic Blood-brain Barrier Disruption and Radiotherapy in a Rat F98-Glioma Model

Background: The blood-brain barrier (BBB) is a major obstacle in the treatment of brain tumors. Intra-arterial (IA) administration with osmotic BBB disruption (BBBD) allows greater drug delivery to the central nervous system (CNS). Its use with temozolomide (TMZ), the first-line agent in the treatment of glioblastoma, has never been reported in an animal glioma model. Objective: This study was designed to investigate whether increased TMZ delivery would improve survival in the Fischer-F98 glioma model. Methods: Alternative methods of administration for TMZ (200 mg/m2) were tested, comparing intravenous infusions (IV, n=13) to IA (n=13) or BBBD with IA (n=13). IA normal saline (NS) was used as a control group (n=13). Five rats per group also underwent radiotherapy. Survival and adverse effects were measured. TMZ was quantified in plasma, CSF and brain at three time-points post-TMZ infusion (IV, IA or IA+BBBD) by LC-MS\MS. Results: Compared to IV, higher peak TMZ concentrations were observed in brain tumor (BT) tissues with IA and IA+BBBD infusions (4-fold and 5-fold, respectively). No difference in survival was observed between the IA with/without BBBD vs. IV/control groups. Radiotherapy increased survival independently of the method of TMZ delivery. Conclusion: We show that the enhanced delivery of TMZ by IA infusion (with/without BBBD) does not improve survival in this resistant model. However, the method of TMZ administration has a significant impact on CNS delivery. Bypassing the BBB with judicious use of local delivery approaches and appropriate therapeutic agents has potential for the treatment of glioblastomas. Keywords: Blood-brain barrier, Blood-brain barrier disruption, Drug delivery, F98 cells, Glioblastoma multiforme, Temozolomide.

GLUT1 -mediated venlafaxine-thiamine disulfide system-glucose conjugates with "lock-in" function for central nervous system delivery.

Venlafaxine, a novel third-generation antidepressant drug, has been described as a reference treatment for major depression, owing to its ability of inhibiting both noradrenalin and serotonin neuronal reuptake, and inhibiting dopamine reuptake slightly. However, its clinical application is hampered by a limited brain distribution. Glucosylation is an effective way to enhance the brain targeting ability of drugs, but the bidirectional transport of glucose transporter 1 (GLUT1 ) might decrease the concentrations of venlafaxine-glucose (V-G) in brain before the release of parent drug venlafaxine. To conquer this drawback of GLUT1 , "lock-in" thiamine disulfide system (TDS) was introduced to modify the V-G conjugate. Both conjugates could release venlafaxine when incubated with the various buffers, mice plasma, and brain homogenate. The evaluation in vivo demonstrated that venlafaxine-TDS-glucose (V-TDS-G) had an improved targeting ability and significantly increased the level of venlafaxine in brain compared to the naked venlafaxine and V-G. The relative uptake efficiency (RE) and concentration efficiency (CE) were enhanced to 5.69 and 5.70 times higher than that of naked venlafaxine, respectively. The results of this study suggest that the conjugate strategy based on the glucose-TDS (G-TDS) is available to enhance the delivery of central nervous system (CNS) drugs into brain.

Design, Synthesis and Evaluation of Dual-targeting Prodrug Co-modified by Organic Amine and L-ascorbic Acid for CNS Delivery

Background: L-ascorbic acid and organic amine showed a good brain targeting ability. However, there was no report on the combination of L-ascorbic acid and organic amine as a carrier for central nervous system (CNS) drug delivery. Keywords: Dual-brain targeting, drug delivery, organic amine, L-ascorbic acid, prodrug, CNS.

Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy.

Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood–brain barrier (BBB) to reach targets in the central nervous system (CNS). For SMA application, we have investigated the ability of various BBB-crossing peptides for CNS delivery of a splice-switching phosphorodiamidate morpholino oligonucleotide (PMO) targeting survival motor neuron 2 (SMN2) exon 7 inclusion. We identified a branched derivative of the well-known ApoE (141–150) peptide, which as a PMO conjugate was capable of exon inclusion in the CNS following systemic administration, leading to an increase in the level of full-length SMN2 transcript. Treatment of newborn SMA mice with this peptide-PMO (P-PMO) conjugate resulted in a significant increase in the average lifespan and gains in weight, muscle strength, and righting reflexes. Systemic treatment of adult SMA mice with this newly identified P-PMO also resulted in small but significant increases in the levels of SMN2 pre-messenger RNA (mRNA) exon inclusion in the CNS and peripheral tissues. This work provides proof of principle for the ability to select new peptide paradigms to enhance CNS delivery and activity of a PMO SSO through use of a peptide-based delivery platform for the treatment of SMA potentially extending to other neuromuscular and neurodegenerative diseases.

Development of rhenacarborane complexes as central nervous system (CNS) drug delivery agents

The search for non-invasive neural therapeutics is a problematic pursuit often hindered by the blood-brain barrier (BBB), a gatekeeper of endothelial cells and tight junctions closely regulating exchange between the bloodstream and brain tissue. A recent study of the complex [3-NO-3,3-κ2-(2,2′-N2C10H6(Me)((CH2)7131I)-4,4′)-closo-3,1,2-ReC2B9H11] demonstrated its ability to not only safely pass through the BBB but also cleanly efflux out of neural tissue, suggesting potential use as a drug-delivery vehicle for central nervous system (CNS) delivery. However, due to the practical difficulty of asymmetric modification of the bipyridyl ligand, a more direct synthetic approach of carborane cage vertex adaptation has been investigated with the hope of utilizing such species for CNS therapeutics. A second prototype of [3,3-(CO)2-3-NO-closo-Re(8-O(CH2)2O(CH2)2125I-3,1,2-C2B9H10)] was rapidly absorbed into the bloodstream from the subcutaneous site of injection and displayed a 1.1%Inj/g for peak brain uptake, which rapidly stabilized to 0.10% while the previous complex merely peaked at 0.10%Inj/g in initial studies. It was also determined that peak brain uptake of 15mL/g was higher than lung and liver tissues, suggesting that the brain is somehow specifically targeted, although the exact rationale for selectivity remains to be explored.

Zebrafish as a visual and dynamic model to study the transport of nanosized drug delivery systems across the biological barriers

With the wide application of nanotechnology to drug delivery systems, a simple, dynamic and visual in vivo model for high-throughput screening of novel formulations with fluorescence markers across biological barriers is desperately needed. In vitro cell culture models have been widely used, although they are far from a complimentary in vivo system. Mammalian animal models are common predictive models to study transport, but they are costly and time consuming. Zebrafish (Danio rerio), a small vertebrate model, have the potential to be developed as an “intermediate” model for quick evaluations. Based on our previously established coumarin 6 nanocrystals (C6-NCs), which have two different sizes, the present study investigates the transportation of C6-NCs across four biological barriers, including the chorion, blood brain barrier (BBB), blood retinal barrier (BRB) and gastrointestinal (GI) barrier, using zebrafish embryos and larvae as in vivo models. The biodistribution and elimination of C6 from different organs were quantified in adult zebrafish. The results showed that compared to 200nm C6-NCs, 70nm C6-NCs showed better permeability across these biological barriers. A FRET study suggested that intact C6-NCs together with the free dissolved form of C6 were absorbed into the larval zebrafish. More C6 was accumulated in different organs after incubation with small sized NCs via lipid raft-mediated endocytosis in adult zebrafish, which is consistent with the findings from in vitro cell monolayers and the zebrafish larvae model. C6-NCs could be gradually eliminated in each organ over time. This study demonstrated the successful application of zebrafish as a simple and dynamic model to simultaneously assess the transport of nanosized drug delivery systems across several biological barriers and biodistribution in different organs, especially in the brain, which could be used for central nervous system (CNS) drug and delivery system screening.

Synthesis and Evaluation of Parenchymal Retention and Efficacy of a Metabolically Stable O-Phosphocholine-N-docosahexaenoyl-l-serine siRNA Conjugate in Mouse Brain.

Ligand-conjugated siRNAs have the potential to achieve targeted delivery and efficient silencing in neurons following local administration in the central nervous system (CNS). We recently described the activity and safety profile of a docosahexaenoic acid (DHA)-conjugated, hydrophobic siRNA (DHA-hsiRNA) targeting Huntingtin (Htt) mRNA in mouse brain. Here, we report the synthesis of an amide-modified, phosphocholine-containing DHA-hsiRNA conjugate (PC-DHA-hsiRNA), which closely resembles the endogenously esterified biological structure of DHA. We hypothesized that this modification may enhance neuronal delivery in vivo. We demonstrate that PC-DHA-hsiRNA silences Htt in mouse primary cortical neurons and astrocytes. After intrastriatal delivery, Htt-targeting PC-DHA-hsiRNA induces ∼80% mRNA silencing and 71% protein silencing after 1 week. However, PC-DHA-hsiRNA did not substantially outperform DHA-hsiRNA under the conditions tested. Moreover, at the highest locally administered dose (4 nmol, 50 μg), we observe evidence of PC-DHA-hsiRNA-mediated reactive astrogliosis. Lipophilic ligand conjugation enables siRNA delivery to neural tissues, but rational design of functional, nontoxic siRNA conjugates for CNS delivery remains challenging.

Mouse Microsurgery Infusion Technique for Targeted Substance Delivery into the CNS via the Internal Carotid Artery.

Animal models of central nervous system (CNS) diseases and, consequently, blood-brain barrier disruption diseases, require the delivery of exogenous substances into the brain. These exogenous substances may induce injurious impact or constitute therapeutic strategy. The most common delivery methods of exogenous substances into the brain are based on systemic deliveries, such as subcutaneous or intravenous routes. Although commonly used, these approaches have several limitations, including low delivery efficacy into the brain. In contrast, surgical methods that locally deliver substances into the CNS are more specific and prevent the uptake of the exogenous substances by other organs. Several surgical methods for CNS delivery are available; however, they tend to be very traumatic. Here, we describe a mouse infusion microsurgery technique, which effectively delivers substances into the brain via the internal carotid artery, with minimal trauma and no interference with normal CNS functionality.

Mouse Microsurgery Infusion Technique for Targeted Substance Delivery into the CNS <i>via</i> the Internal Carotid Artery

Animal models of central nervous system (CNS) diseases and, consequently, blood-brain barrier disruption diseases, require the delivery of exogenous substances into the brain. These exogenous substances may induce injurious impact or constitute therapeutic strategy. The most common delivery methods of exogenous substances into the brain are based on systemic deliveries, such as subcutaneous or intravenous routes. Although commonly used, these approaches have several limitations, including low delivery efficacy into the brain. In contrast, surgical methods that locally deliver substances into the CNS are more specific and prevent the uptake of the exogenous substances by other organs. Several surgical methods for CNS delivery are available; however, they tend to be very traumatic. Here, we describe a mouse infusion microsurgery technique, which effectively delivers substances into the brain via the internal carotid artery, with minimal trauma and no interference with normal CNS functionality.

The phospholipase A2 signaling as a new therapeutic biomarker of Alzheimer’s disease: modulation through phage display-derived peptides able to cross the blood-brain barrier

Event Abstract Back to Event The phospholipase A2 signaling as a new therapeutic biomarker of Alzheimer’s disease: modulation through phage display-derived peptides able to cross the blood-brain barrier Séverine André1*, Fatima Daldal1, Marine Lecomte1, Robert Muller1, 2, Luce Vander Elst1, Sophie Laurent1, 2 and Carmen Burtea1 1 University of Mons, General, Organic and Biomedical Chemistry, Belgium 2 Center for Microscopy and Molecular Imaging, Belgium Introduction The treatment of Alzheimer’s disease (AD) is a real challenge up to now. Phospholipase A2 (PLA2) signaling pathway was recently revealed to be involved in this pathology [1], its inhibition already showing neuron protection against apoptosis induced by amyloid beta (Aβ) [2]. Using the phage-display technology, we have identified a PLA2-targeted peptide (PLP25) aiming to limit the activation of PLA2. Furthermore, the blood-brain barrier (BBB) is a restrictive barrier protecting the brain against xenobiotics and limiting the access of most molecules, including potential therapeutic agents. Non-invasive crossing strategies are thus indispensable to deliver therapeutic agents to the central nervous system (CNS) without BBB disruption. Because of its involvement in LDL transcytosis [3], LDL receptor (LDLR) was targeted by phage display and the peptide LRP2 was identified as a new vector able to facilitate the crossing of this barrier. LRP2 will be thus used as vector of our therapeutic peptide aiming to improve its CNS delivery. Methods The specificity of both peptides PLP25 and LRP2 to their respective target was validated by immunofluorescence. The inhibitory potential of PLP25 targeting PLA2 was evaluated by the dosage of arachidonic acid (AA) released by human astrocytes (1321N1) and mouse neurons (N18) induced by H2O2 and glutamate respectively, known as PLA2 activators. The localization of PLA2 after its activation was evaluated on these same cells by immunofluorescence. The endocytosis mechanism of LDLR-targeted LRP2 was investigated in human brain endothelial cells ACBRI376, human astrocytes 1321N1 and mouse neurons N18(H) by immunofluorescence. The ability of LRP2 to accede the brain was assessed in vivo on NMRI mice by Magnetic Resonance Imaging (MRI) using LRP2-grafted Ultrasmall Superparamagnetic Particles of Iron Oxide (USPIO-LRP2). After brain collection, USPIO derivatives were detected by Perls’-DAB. Results and Prospects The AA released by 1321N1 and N18(H) cells was increased after PLA2 induction with H2O2 or glutamate respectively. On 1321N1, the pre-incubation with PLP25 before PLA2 stimulation allowed to decrease AA levels released by these cells, ranging from 20% to 60% as compared to induced cells, with a more potent effect at low concentration. On differentiated N18(H) cells, PLP25 produced the same effects. Generally, PLP25 restored PLA2 activity in the range of negative control both in astrocytes and neurons. In order to observe the effect of PLP25 on cellular localization of PLA2, this last one was detected in a first stage on 1321N1 by immunofluorescence. H2O2 stimulation resulted in the concentration of PLA2 at the plasma membrane and its processes, showed by a higher fluorescent labeling. A similar experiment performed on glutamate-induced N18(H) revealed the migration of PLA2 in filopodia of neuronal growth cones. These results agree with the known translocation of the induced PLA2 from the cytoplasm to cellular membranes, where it binds via its C2 domain to the enzymatic substrate, the phosphatidylcholine [4]. PLA2 is involved in the dynamics of actin cytoskeleton and filipodia formation in astrocytes and neurons, playing a key role in neuronal plasticity [5,6]. Being specific to the C2 domain of PLA2, PLP25 prevented the migration of PLA2 to cell membrane and filopodia, as suggested by the decreased fluorescent labeling of these structures. This effect was moreover facilitated when PLP25 was combined to LRP2. Concerning the crossing of the BBB, the peptide LRP2 is endocytosed via a caveolae-mediated non-degradation pathway in ACBRI376 cells, which compose the BBB, whereas the lysosome degradation is bypassed. Interestingly, LRP2 is also able to penetrate 1321N1 and N18(H) cells mostly via the caveolae pathway, even if a small proportion seems to taken by lysosomes. These results confirm that LRP2 could be used as vector through the BBB for the therapeutic agent. In vivo MRI experiments showed that USPIO-LRP2 (a negative contrast agent) induces a darkening of brains as compared to USPIO-NSP (nonspecific). These observations were confirmed by the increased negative contrast (%SNR) obtained by the analysis of signal intensity. The Perls’-DAB staining performed on brain slices of the injected mice, highlighting iron contained in USPIO, revealed an important brown staining for USPIO-LRP2, as opposed to USPIO-NSP or PBS that do not show any staining. The evaluation of peptide LRP2 coupled to the therapeutic peptide PLP25 is currently in progress. Acknowledgements This work is supported by the Rotary Foundation – Hope in Head campaign 2015, the FRMH (Fond pour la Recherche Médicale en Hainaut) and the grant “Actions de Recherche Concertée” financed by the Fédération Wallonie-Bruxelles, the Waloon Region, Feder, Interreg and COST actions.

Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke.

Ischemic stroke is a leading cause of morbidity and mortality in the United States. The only approved pharmacologic treatment for ischemic stroke is thrombolysis via recombinant tissue plasminogen activator (r-tPA). A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity) greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms. Transporters expressed at the blood-brain barrier (BBB) provide a significant opportunity to advance stroke therapy via central nervous system delivery of drugs that have neuroprotective properties. Examples of such transporters include organic anion–transporting polypeptides (Oatps) and organic cation transporters (Octs). In addition, multidrug resistance proteins (Mrps) are transporter targets in brain microvascular endothelial cells that can be exploited to preserve BBB integrity in the setting of stroke. Here, we review current knowledge on stroke pharmacotherapy and demonstrate how endogenous BBB transporters can be targeted for improvement of ischemic stroke treatment.

Photocrosslinked poly(amidoamine) nanoparticles for central nervous system targeting

This study presents an innovative method for the synthesis of polymeric nanoparticles (NPs) for central nervous system (CNS) targeting. The method is based on Ultraviolet light (UV)-induced crosslinking of diacrylamide-terminated oligomers of poly(amidoamine)s (PAAs), a widely used class of synthetic polymers in biomedical field research, especially in drug delivery thanks to their excellent biocompatibility and controlled biodegradability. Previous attempts aiming at preparing PAA-based NPs by self-assembly were challenged by lack of structural stability and consequently their early degradation and premature drug release. Here, the UV-induced crosslinked PAA NPs demonstrated to overcome main disadvantages of the self-assembled ones, as they showed improved stability and controlled release properties. Besides the remarkable efficiency to produce monodisperse and stable PAA NPs, the UV-induced crosslinking method is featured by great versatility and low environmental impact, since it does not require use of organic solvents and multiple purification steps. The capability of PAA NPs to encapsulate a fluorescently labelled model protein was experimentally demonstrated in this study. Cell culture experiments showed that PAA NPs were biocompatible and highly permeable across an in vitro blood-brain barrier model, thus highlighting their great potential as drug delivery vectors for CNS delivery.

Focused Ultrasound Enhances Central Nervous System Delivery of Bevacizumab for Malignant Glioma Treatment.

Focused Ultrasound Enhances Central Nervous System Delivery of Bevacizumab for Malignant Glioma Treatment.