Search Results (11)

The blood–brain barrier (BBB) controls the flow of substances to maintain a homeostatic environment in the brain, which is highly regulated and crucial for the normal function of the central nervous system (CNS). Brain endothelial cells (bECs), which are directly exposed to blood, play the most important role in maintaining the integrity of the BBB. Unlike endothelial cells in other tissues, bECs have two unique features: specialized endothelial tight junctions and actively suppressed transcellular vesicle trafficking (transcytosis). These features help to maintain the relatively low permeability of the CNS barrier. In addition to the predominant role of tight junctions in the BBB, caveolae-mediated adsorptive transcytosis has attracted much interest in recent years. The active suppression of transcytosis is dynamically regulated during development and in response to diseases. Altered caveolae-mediated transcytosis of bECs has been reported in several neurological diseases, but the understanding of this process in bECs is limited. Here, we review the process of caveolae-mediated transcytosis based on previous studies and discuss its function in the breakdown of the BBB in neurological disorders. Full article

Neutral/negatively charged nanoparticles are beneficial to reduce plasma protein adsorption and prolong their blood circulation time, while positively charged nanoparticles easily transverse the blood vessel endothelium into a tumor and easily penetrate the depth of the tumor via transcytosis. Γ-Glutamyl transpeptidase (GGT) is overexpressed on the external surface of endothelial cells of tumor blood vessels and metabolically active tumor cells. Nanocarriers modified by molecules containing γ-glutamyl moieties (such as glutathione, G-SH) can maintain a neutral/negative charge in the blood, as well as can be easily hydrolyzed by the GGT enzymes to expose the cationic surface at the tumor site, thus achieving good tumor accumulation via charge reversal. In this study, DSPE-PEG2000-GSH (DPG) was synthesized and used as a stabilizer to generate paclitaxel (PTX) nanosuspensions for the treatment of Hela cervical cancer (GGT-positive). The obtained drug-delivery system (PTX-DPG nanoparticles) was 164.6 ± 3.1 nm in diameter with a zeta potential of −9.85 ± 1.03 mV and a high drug-loaded content of 41.45 ± 0.7%. PTX-DPG NPs maintained their negative surface charge in a low concentration of GGT enzyme (0.05 U/mL), whereas they showed a significant charge-reversal property in the high-concentration solution of GGT enzyme (10 U/mL). After intravenous administration, PTX-DPG NPs mainly accumulated more in the tumor than in the liver, achieved good tumor-targetability, and significantly improved anti-tumor efficacy (68.48% vs. 24.07%, tumor inhibition rate, p < 0.05 in contrast to free PTX). This kind of GGT-triggered charge-reversal nanoparticle is promising to be a novel anti-tumor agent for the effective treatment of such GGT-positive cancers as cervical cancer. Full article

The blood-brain barrier (BBB) constitutes a microvascular network responsible for excluding most drugs from the brain. Treatment of brain tumors is limited by the impermeability of the BBB and, consequently, survival outcomes for malignant brain tumors remain poor. Nanoparticles (NPs) represent a potential solution to improve drug transport to brain tumors, given their small size and capacity to target tumor cells. Here, we review the unique physical and chemical properties of NPs that aid in BBB transport and discuss mechanisms of NP transport across the BBB, including paracellular transport, carrier-mediated transport, and adsorptive- and receptor-mediated transcytosis. The major types of NPs investigated for treatment of brain tumors are detailed, including polymeric NPs, liposomes, solid lipid NPs, dendrimers, metals, quantum dots, and nanogels. In addition to their role in drug delivery, NPs can be used as imaging contrast agents and can be conjugated with imaging probes to assist in visualizing tumors, demarcating lesion boundaries and margins, and monitoring drug delivery and treatment response. Multifunctional NPs can be designed that are capable of targeting tumors for both imaging and therapeutic purposes. Finally, limitations of NPs for brain tumor treatment are discussed. Full article

Central nervous system (CNS) diseases are the leading causes of death and disabilities in the world. It is quite challenging to treat CNS diseases efficiently because of the blood–brain barrier (BBB). It is a physical barrier with tight junction proteins and high selectivity to limit the substance transportation between the blood and neural tissues. Thus, it is important to understand BBB transport mechanisms for developing novel drug carriers to overcome the BBB. This paper introduces the structure of the BBB and its physiological transport mechanisms. Meanwhile, different strategies for crossing the BBB by using nanomaterial-based drug carriers are reviewed, including carrier-mediated, adsorptive-mediated, and receptor-mediated transcytosis. Since the viral-induced CNS diseases are associated with BBB breakdown, various neurotropic viruses and their mechanisms on BBB disruption are reviewed and discussed, which are considered as an alternative solution to overcome the BBB. Therefore, most recent studies on virus-mimicking nanocarriers for drug delivery to cross the BBB are also reviewed and discussed. On the other hand, the routes of administration of drug-loaded nanocarriers to the CNS have been reviewed. In sum, this paper reviews and discusses various strategies and routes of nano-formulated drug delivery systems across the BBB to the brain, which will contribute to the advanced diagnosis and treatment of CNS diseases. Full article

Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-mediated transcytosis, somatic gene transfer, and the use of carriers/shuttles such as cell-penetrating peptides, liposomes, extracellular vesicles, and nanoparticles. Approaches based on single-domain antibodies are reaching the clinic for other diseases. Several tailoring methods can be followed to favor the transport of nanobodies and VNARs to the CNS, avoiding the limitations imposed by the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies. Full article

The major impediment to the delivery of therapeutics to the brain is the presence of the blood-brain barrier (BBB). The BBB allows for the entrance of essential nutrients while excluding harmful substances, including most therapeutic agents; hence, brain disorders, especially tumours, are very difficult to treat. Chitosan is a well-researched polymer that offers advantageous biological and chemical properties, such as mucoadhesion and the ease of functionalisation. Chitosan-based nanocarriers (CsNCs) establish ionic interactions with the endothelial cells, facilitating the crossing of drugs through the BBB by adsorptive mediated transcytosis. This process is further enhanced by modifications of the structure of chitosan, owing to the presence of reactive amino and hydroxyl groups. Finally, by permanently binding ligands or molecules, such as antibodies or lipids, CsNCs have showed a boosted passage through the BBB, in both in vivo and in vitro studies which will be discussed in this review. Full article

Neurological disorders are the most devastating and challenging diseases associated with the central nervous system (CNS). The blood-brain barrier (BBB) maintains homeostasis of the brain and contributes towards the maintenance of a very delicate microenvironment, impairing the transport of many therapeutics into the CNS and making the management of common neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), cerebrovascular diseases (CVDs) and traumatic brain injury (TBI), exceptionally complicated. Nanoparticle (NP) technology offers a platform for the design of tissue-specific drug carrying systems owing to its versatile and modifiable nature. The prospect of being able to design NPs capable of successfully crossing the BBB, and maintaining a high drug bioavailability in neural parenchyma, has spurred much interest in the field of nanomedicine. NPs, which also come in an array of forms including polymeric NPs, solid lipid nanoparticles (SLNs), quantum dots and liposomes, have the flexibility of being conjugated with various macromolecules, such as surfactants to confer the physical or chemical property desired. These nanodelivery strategies represent potential novel and minimally invasive approaches to the treatment and diagnosis of these neurological disorders. Most of the strategies revolve around the ability of the NPs to cross the BBB via various influx mechanisms, such as adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT), targeting specific biomarkers or lesions unique to that pathological condition, thereby ensuring high tissue-specific targeting and minimizing off-target side effects. In this article, insights into common neurological disorders and challenges of delivering CNS drugs due to the presence of BBB is provided, before an in-depth review of nanoparticle-based theranostic strategies. Full article

Alzheimer’s disease (AD) is an age-related disease caused by abnormal accumulation of amyloid-β in the brain leading to progressive tissue degeneration. Flurbiprofen (FP), a drug used to mitigate the disease progression, has low efficacy due to its limited permeability across the blood–brain barrier (BBB). In a previous work, FP was coupled at the uppermost branching of an ε-lysine-based branched carrier, its root presenting a phenylalanine moiety able to increase the hydrophobicity of the complex and enhance the transport across the BBB by adsorptive-mediated transcytosis (AMT). The present study explores a different molecular design of the FP-peptide delivery system, whereby its root presents an ApoE-mimicking peptide, a targeting ligand that could enhance transport across the BBB by receptor-mediated transcytosis (RMT). The functionalised complex was synthesised using a solid-phase peptide synthesis and characterised by mass spectrometry and FTIR. Cytotoxicity and permeability of this complex across an in vitro BBB model were analysed. Moreover, its activity and degradation to release the drug were investigated. The results revealed successful synthesis and grafting of FP molecules at the uppermost molecular branches of the lysine terminal without observed cytotoxicity. When covalently linked to the nanocarrier, FP was still active on target cells, albeit with a reduced activity, and was released as a free drug upon hydrolysis in a lysosome-mimicking medium. Noticeably, this work shows the high efficiency of RMT-driven FP delivery over delivery systems relying on AMT. Full article

Extracellular vesicles can cross the blood–brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system. Full article

The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells. Full article

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been demonstrated to effectively treat the patients of extracranial non-small cell lung cancer (NSCLC). However, these patients often develop brain metastasis (BM) during their disease course. The major obstacle to treat BM is the limited penetration of anticancer drugs across the blood–brain barrier (BBB). In the present study, we utilized gefitinib-loaded liposomes with different modifications to improve gefitinib delivery across the in vitro BBB model of bEnd.3 cells. Gefitinib was encapsulated in small unilamellar liposomes modified with glutathione (GSH) and Tween 80 (SUV-G+T; one ligand plus one surfactant) or RF (SUV-RF; one α-helical cell-penetrating peptide). GSH, Tween 80, and RF were tested by the sulforhodamine B (SRB) assay to find their non-cytotoxic concentrations on bEnd.3 cells. The enhancement on gefitinib across the BBB was evaluated by cytotoxicity assay on human lung adenocarcinoma PC9 cells under the bEnd.3 cells grown on the transwell inserts. Our findings showed that gefitinib incorporated in SUV-G+T or SUV-RF across the bEnd.3 cells significantly reduced the viability of PC9 cells more than that of free gefitinib. Furthermore, SUV-RF showed no cytotoxicity on bEnd.3 cells and did not affect the transendothelial electrical resistance (TEER) and transendothelial permeability of sodium fluorescein across the BBB model. Moreover, flow cytometry and confocal laser scanning microscopy were employed to evaluate the endocytosis pathways of SUV-RF. The results indicated that the uptake into bEnd.3 cells was mainly through adsorptive-mediated mechanism via electrostatic interaction and partially through clathrin-mediated endocytosis. In conclusion, cell penetrating peptide-conjugated SUV-RF shed light on improving drug transport across the BBB via modulating the transcytosis pathway(s). Full article