Fig 3 - uploaded by Nicolae Ghinea
Content may be subject to copyright.
Schematic overview of major cell-surface glycan-containing components. The syndecans and glypicans form the two most common groups of heparan sulfate proteoglycans on the endothelial surface. The backbone structure of HS consists of N -acetylglucosamine-glucuronic acid disaccharides ( n =10 – 50), which are modi fi ed by the addition of sulfate groups at various positions. The syndecan family (four members) consists of transmembrane HSPGs which all have highly variable extracellular domains, but have homologous transmembrane and cytoplasmic domains. The syndecans exhibit cell-type speci fi c distribution with vascular endothelial cells (ECs) expressing syndecan-1, -2, and -4 and predominant targeting to abluminal surfaces. They are the only HSPGs that penetrate the cytoplasm, thus allowing for interaction with the cytoskeleton (syndecan-1) or focal adhesion molecules (syndecan-4). Syndecan-1 has both HS and chondroitin sulfate (CS) glycosaminoglycans (GAGs). The glypicans (six members) possess structural similarity, and typically differ in the number of GAG attachment sites in the extracellular region. They are linked to the cell surface through a COOH-terminal GPI anchor ( yellow bar in the fi gure). In contrast to the syndecans, glypicans contain HS only. The glypicans are selectively expressed on different cell types with only glypican-1 present on vascular ECs. These HSPGs are mainly targeted to luminal surfaces. Perlecan (not represented) is the least common HSPG and consists of only one variant with a total of fi ve GAG linkages. Sialylated glycoproteins contain only oligosaccharide chains with alpha- and beta-galactosyl residues, and alpha-mannosyl/glucosyl residues linked to N -acetylglucosamine. The oligosaccharide chains are terminated by sialic acid residues in the alpha 2 – 3 and/or 2 – 6 linkages. For a review on HSPG, see (13)
Source publication
Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The...
Context in source publication
Context 1
... in fact digested by an heparinase that cleaves heparan sulfates. These mainly consist of mixed proteoglycans. Heparan sulfates are the main glycosamino- glycans (GAGs) of the endothelial cell glycocalyx. The dominating heparan sulfate proteoglycans (HSPGs) at the endothelial cell surface are the syndecans and glypicans (for further details, see Fig. 3). It has to be stressed that HSPGs are suspected of playing a critical role in cellular internaliza- tion of basic peptides, growth-promoting polyamines and polycation-nucleic acid complexes, with possible applications associated with protein delivery and gene transfer into cells (13). The basement membrane contiguous to the ...
Similar publications
Cell penetrating peptides (CPPs) are short peptides that can pass through cell membranes. CPPs can facilitate the cellular entry of proteins, macromolecules, nanoparticles and drugs. RVG peptide (RVG hereinafter) is a 29-amino-acid CPP derived from a rabies virus glycoprotein that can cross the blood-brain barrier (BBB) and enter brain cells. Howev...
Stroke is a devastating disease with few therapeutic options. Despite our growing understanding of the critical mechanistic events in post-stroke brain injury, the clinical translation of these findings has been less effective. A monumental hurdle to the field has been the inability of many systemically applied therapies to efficiently cross the bl...
Developing delivery vehicles capable of penetrating cell barriers is critical for drug delivery to the brain due to the presence of the blood-brain barrier (BBB). Cell-penetrating peptides (CPPs) are one potential solution since they can enter cells; however, it is unclear whether CPPs can pass through cell barriers. In this study, the ability of t...
The hydrophilic nature of peptides and proteins renders them impermeable to cell membranes. Thus, in order to successfully deliver peptide and protein-based therapeutics across the plasma membrane or epithelial and endothelial barriers, a permeation enhancing strategy must be employed. Cell-penetrating peptides (CPPs) constitute a promising tool an...
The blood-brain barrier (BBB), a dynamic and complex barrier formed by endothelial cells, can impede the entry of unwanted substances - pathogens and therapeutic molecules alike - into the central nervous system (CNS) from the blood circulation. Taking into account the fact that CNS-related diseases are the largest and fastest growing unmet medical...
Citations
... Transcytosis of antibodies and their fragments can occur through several mechanisms, including receptor-mediated transcytosis (RMT), adsorptive-mediated transcytosis, and cell-mediated transcytosis [164,165]. One of the most exploited receptors for RMT is the transferrin receptor (TfR), which naturally facilitates iron transport into the brain. ...
Antibodies that can selectively remove rogue proteins in the brain are an obvious choice to treat neurodegenerative disorders (NDs), but after decades of efforts, only two antibodies to treat Alzheimer’s disease are approved, dozens are in the testing phase, and one was withdrawn, and the other halted, likely due to efficacy issues. However, these outcomes should have been evident since these antibodies cannot enter the brain sufficiently due to the blood–brain barrier (BBB) protectant. However, all products can be rejuvenated by binding them with transferrin, preferably as smaller fragments. This model can be tested quickly and at a low cost and should be applied to bapineuzumab, solanezumab, crenezumab, gantenerumab, aducanumab, lecanemab, donanemab, cinpanemab, and gantenerumab, and their fragments. This paper demonstrates that conjugating with transferrin does not alter the binding to brain proteins such as amyloid-β (Aβ) and α-synuclein. We also present a selection of conjugate designs that will allow cleavage upon entering the brain to prevent their exocytosis while keeping the fragments connected to enable optimal binding to proteins. The identified products can be readily tested and returned to patients with the lowest regulatory cost and delays. These engineered antibodies can be manufactured by recombinant engineering, preferably by mRNA technology, as a more affordable solution to meet the dire need to treat neurodegenerative disorders effectively.
... [4][5][6][7] Currently various approaches and methodologies are attempted for transporting drugs across the BBB, such as opening the TJ using chemical stimulants like sodium dodecyl sulphate, transport system-mediated delivery (adsorptive-mediated transcytosis (AMT), cationic proteins, and cell-penetrating peptides (CPP) capable of entering cells) and nanocarrier-based delivery using liposomes and polymeric nanoparticles. [8][9][10][11][12][13][14][15][16][17][18][19][20] Among various systems, considerable research has been reported over the years on the use of polymeric/liposomal/inorganic nanoparticulate drug delivery systems for crossing the BBB to deliver a number of therapeutic agents. [21][22][23][24][25][26][27][28] While the nanoparticle (NP) approach is interesting from the point view of examining the possibility of delivering drugs across the BBB, there are many problems associated with nanocarriers, especially when targeting the brain. ...
Targeting therapeutic agents to the brain to treat central nervous system (CNS) diseases is a major challenge due to the blood–brain barrier (BBB). In this study, an attempt was made to deliver a model drug such as doxorubicin (DOX), to the brain in a mouse model through DOX-Polysorbate 80 (DOX-PS80) conjugates. DOX was successfully conjugated with the non-ionic surfactant Polysorbate 80 (PS80) by carbamate linkage and the conjugate was characterized by different spectroscopic techniques, such as FTIR, UV-Visible and NMR. The DOX conjugation efficacy was found to be 43.69 ± 4.72%. The in vitro cumulative release of DOX from the conjugates was found to be 4.9 ± 0.8% in PBS of pH 7.3 and 3.9 ± 0.6% in simulated cerebrospinal fluid (CSF) of pH 7.3 at the end of 10 days. An in vitro BBB permeability assay was carried out using bEnd.3 cells and DOX-PS80 conjugate showed a 3-fold increase in BBB permeability compared with controls. In vitro cytotoxicity assay using U251 human glioblastoma cells showed an IC50 value of 38.10 μg mL⁻¹ for DOX-PS80. Cell uptake studies revealed that DOX-PS80 was effectively taken up (90%) by the bEnd.3 and U251 cells and localized in cytoplasm at the end of 24 h. Pharmacokinetic parameters for DOX-PS80 were evaluated using in silico studies. Tumor spheroid assay and in vivo experiments in Swiss albino mouse demonstrated the possibility of DOX-PS80 conjugate crossing the BBB and delivering the drug molecules to the target site for treating CNS disorders.
... PLGA NPs can penetrate through the BBB by passive diffusion, which is limited by the size and lipophilicity of PLGA NPs. On the other hand, PLGA NPs can enter the brain via active transcytosis and endocytosis, which is usually achieved by modifying the structure of PLGA NPs to endow the target delivery [22,23]. In our previous study, we observed that the PLGA NPs encapsulated with EVG cross the BBB mainly through clathrin-mediated endocytosis in vitro [20,24]. ...
Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood–brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders.
... Several considerations must be considered when selecting a linker to bind an antibody to transferrin to facilitate entry into the brain. First and foremost, it is crucial to understand the mechanisms by which molecules, including antibodies, can cross the BBB [73]. TfRs are one of the targets for transporting molecules across the BBB. ...
... Optimization may be necessary to achieve the desired pharmacokinetics and brain distribution. Finally, assessing the safety profile of the linker and ensuring the specificity of brain targeting are important considerations to minimize off-target effects and potential toxicity [73]. ...
The recent setbacks in the withdrawal and approval delays of antibody treatments of neurodegenerative disorders (NDs), attributed to their poor entry across the blood–brain barrier (BBB), emphasize the need to bring novel approaches to enhance the entry across the BBB. One such approach is conjugating the antibodies that bind brain proteins responsible for NDs with the transferrin molecule. This glycoprotein transports iron into cells, connecting with the transferrin receptors (TfRs), piggybacking an antibody–transferrin complex that can subsequently release the antibody in the brain or stay connected while letting the antibody bind. This process increases the concentration of antibodies in the brain, enhancing therapeutic efficacy with targeted delivery and minimum systemic side effects. Currently, this approach is experimented with using drug-transferring conjugates assembled in vitro. Still, a more efficient and safer alternative is to express the conjugate using mRNA technology, as detailed in this paper. This approach will expedite safer discoveries that can be made available at a much lower cost than the recombinant process with in vitro conjugation. Most importantly, the recommendations made in this paper may save the antibodies against the NDs that seem to be failing despite their regulatory approvals.
... The Brunauer-Emmet-Teller (BET) equation [7] was later developed to extend the Langmuir equation to cover multilayer sorption. Therefore, accurately determining the adsorption heat is critical to better understand the adsorption process and advance its potential applications in various fields, including separation and purification (e.g., [11,12]), catalysis (e.g., [13]), drug delivery (e.g., [14,15]), adsorption chillers (e.g., [16][17][18][19]), and surface area measurement for porous materials (e.g., [20][21][22][23][24]). For instance, Langmuir [25] utilized the concept of adsorption heat of oxygen gas on platinum to investigate the mechanism of the catalytic action of platinum. ...
Adsorption heat is a cornerstone concept underpinning almost all the existing theoretical isotherms for porous media. Yet, it remains elusive what this concept stands for and what are the physical sources for it. Here, a rigorous thermodynamic formulation is derived for the adsorption process with the aid of the law of mass action, leading to an expression of adsorption heat as the external chemical potential difference between two adjacent adsorbate layers. The interaction between adsorbent and adsorbates like van der Waals is theoretically identified as the intermolecular source for the change of adsorption heat. Thereby, adsorption heat is formulated as a spatially varied function of the distance to adsorbent surfaces. This adsorption heat function facilitates the establishment of a two-parameter sorption isotherm equation. The equation can be theoretically converted to two widely used adsorption isotherm equations, namely Brunauer–Emmet–Teller (BET) and Guggenheim-Anderson-de Boer (GAB) equations, and shows excellent performance in capturing experimental isotherm data of a wide array of materials. The comparative analysis demonstrates that the derived two-parameter isotherm equation outperforms the two-parameter BET equation and the three-parameter GAB equation in most cases. Such performance verifies the generality of the derived isotherm equation, thus further confirming the validity of the derived formulation of adsorption heat.
... [359] Additionally, Caban et al. utilized positively charged chitosan-modified PLGA NPs for the co-delivery of PTXL and flurbiprofen, achieving precise targeting of the glioma tissue. [360] AMT has a lower affinity than RMT, lacks specificity, can occur in blood vessels at other sites, [361] and has some toxic effects at large doses. [362] However, the vesicles formed during AMT have a larger volume, indicating that they can accommodate a drug with a larger molecular weight. ...
Traditional Chinese Medicine (TCM) is widely used in clinical practice to treat diseases related to central nervous system (CNS) damage. However, the blood‐brain barrier (BBB) constitutes a significant impediment to the effective delivery of TCM, thus substantially diminishing its efficacy. Advances in nanotechnology and its applications in TCM (also known as nano‐TCM) can deliver active ingredients or components of TCM across the BBB to the targeted brain region. This review provides an overview of the physiological and pathological mechanisms of the BBB and systematically classifies the common TCM used to treat CNS diseases and types of nanocarriers that effectively deliver TCM to the brain. Additionally, drug delivery strategies for nano‐TCMs that utilize in vivo physiological properties or in vitro devices to bypass or cross the BBB are discussed. This review further focuses on the application of nano‐TCMs in the treatment of various CNS diseases. Finally, this article anticipates a design strategy for nano‐TCMs with higher delivery efficiency and probes their application potential in treating a wider range of CNS diseases.
... Neuropeptides and proteins molecules also follow this route for drug absorption. 55,56,57,58 Challenges of drug delivery to the brain and its probable solutions: Modification of these nanoparticles are one of the novel strategy which has huge potential in brain targeting drug delivery.One of the best examples of this kind of delivery is exosomesiRNA delivery systemically targeted to reach the brain.One of the major challenges in Exosome formulation is its modification to carry the drug molecule. 59,60,61 The transport of molecules across the BBB depends on few transport systems, i.e., carriermediated transport (CMT), receptor-mediated transport (RMT), or absorptive-mediated transport (AMT). ...
Brain tumor causes of millions of life every year due to poor treatment options. The blood-brain barrier prevents most of the treatment molecules to reach the tumor region. Tight junctions within adjacent brain endothelial cell lines including other components make the brain highly impermeable to all the unwanted and foreign materials. The antineoplastic drug molecules which has a molecular weight of less than 400 daltons and have less than 8 hydrogen bonds are only able to access the brain without any hindrance. Hence, most of the small and large anti-cancer drug molecules hardly can cross the barrier. To overcome these problems formulation scientists have adopted various strategies and techniques so that the intended drug molecule can reach the target region of the brain tumor. Among them nanosponges drug delivery is highly appreciated as emerging brain tumor targeted drug delivery. Nanosponges are tiny sponge in the size of nano range with a vesicle filled with various types of drugs. These kinds of the formulation can circulate throughout the blood and reach the target region where drugs are released in a controlled manner. This review article highlights the unique features of blood-brain barrier and novel strategies based on drug formulation to access the core of the brain tumor by overcoming the resistance rendered by blood brain barrier. In addition, it also demonstrates how nanosponges is emerging as one of the best options to prevail over various challenges associated with penetration of the blood-brain barrier.
... Furthermore, the BBB possesses transcytotic pathways, exhibits distinct morphological and enzymatic characteristics, and contains a significant concentration of mitochondria within cerebral endothelial cells. These features collectively facilitate the transfer of molecules across the endothelial cytoplasm [77]. During the process of AMT, a ligand engages in electrostatic interactions along the charged surface of endothelial cells. ...
Neurons and their connecting axons gradually degenerate in neurodegenerative diseases (NDs), leading to dysfunctionality of the neuronal cells and eventually their death. Drug delivery for the treatment of effected nervous system is notoriously complicated because of the presence of natural barriers, i.e., the blood-brain barrier and the blood cerebrospinal fluid barrier. Palliative care is currently the standard care for many diseases. Therefore, treatment programs that target the disease’s origin rather than its symptoms are recommended. Nanotechnology-based drug delivery platforms offer an innovative way to circumvent these obstacles and deliver medications directly to the central nervous system, thereby enabling treatment of several common neurological problems, i.e., Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. Interestingly, the combination of nanomedicine and gene therapy enables targeting of selective mutant genes responsible for the progression of NDs, which may provide a much-needed boost in the struggle against these diseases. Herein, we discussed various central nervous system delivery obstacles, followed by a detailed insight into the recently developed techniques to restore neurological function via the differentiation of neural stem cells. Moreover, a comprehensive background on the role of nanomedicine in controlling neurogenesis via differentiation of neural stem cells is explained. Additionally, numerous phytoconstituents with their neuroprotective properties and molecular targets in the identification and management of NDs are also deliberated. Furthermore, a detailed insight of the ongoing clinical trials and currently marketed products for the treatment of NDs is provided in this manuscript.
Graphical abstract
... Secondly, peptide binding to the glycocalyx would generate larger numbers of 'artificial' targets, as occupancy of the glycocalyx is expected to be saturated at higher concentrations than for specific cell-membrane proteins. As such, adsorptive-mediated transcytosis (AMT), a transport mechanism based on unspecific binding to the cell-surface due to electrostatic interaction, is known to be saturated at concentrations several orders of magnitude higher than receptor-mediated transcytosis (RMT), a transport mechanism based on binding to specific cell-membrane proteins [4,14], with saturation constants calculated in the micromolar range. Such glycocalyx binding may explain the lack of complete saturation of CFAG peptide binding even at micromolar concentrations. ...
Current strategies to identify ligands for brain delivery select candidates based on preferential binding to cell-membrane components (CMC) on brain endothelial cells (EC). However, such strategies generate ligands with inherent brain specificity limitations, as the CMC (e.g., the transferrin receptor TfR1) are also significantly expressed on peripheral EC. Therefore, novel strategies are required to identify molecules allowing increased specificity of therapy brain delivery. Here, we demonstrate that, while individual CMC are shared between brain EC and peripheral EC, their endocytic internalization rate is markedly different. Such differential endocytic rate may be harnessed to identify molecular tags for brain targeting based on their selective retention on the surface of brain EC, thereby generating ‘artificial’ targets specifically on the brain vasculature. By quantifying the retention of labelled proteins on the cell membrane, we measured the general endocytic rate of primary brain EC to be less than half that of primary peripheral (liver and lung) EC. In addition, through bio-panning of phage-displayed peptide libraries, we unbiasedly probed the endocytic rate of individual CMC of liver, lung and brain endothelial cells. We identified phage-displayed peptides which bind to CMC common to all three endothelia phenotypes, but which are preferentially endocytosed into peripheral EC, resulting in selective retention on the surface of brain EC. Furthermore, we demonstrate that the synthesized free-form peptides are capable of generating artificial cell-surface targets for the intracellular delivery of model proteins into brain EC with increasing specificity over time. The developed identification paradigm, therefore, demonstrates that the lower endocytic rate of individual CMC on brain EC can be harnessed to identify peptides capable of generating ‘artificial’ targets for the selective delivery of proteins into the brain vasculature. In addition, our approach identifies brain-targeting peptides which would have been overlooked by conventional identification strategies, thereby increasing the repertoire of candidates to achieve specific therapy brain delivery.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12987-023-00493-6.
... For detailed reviews refer to. [30][31][32] (1) Inducing BBB permeability ( Figure 1A). One of the best-studied approaches is focused ultrasound (FUS). ...
... Furthermore, the cationization of an antibody can interfere with its target specificity, toxicity, and immunogenicity and thus needs to be carefully evaluated. 32 (3) Receptor-mediated transcytosis (RMT, Figure 1C). RMT leverages influx receptors for nutrient carriers present at the BBB. ...
... 37 (B) Charge-optimization: During adsorption-mediated transcytosis (AMT), positively charged molecules are endocytosed and transported through the BBB. 32 (C) Engaging transcytosis receptors: Receptor-mediated transcytosis (RMT) is often used with the IR, LRP1, or TfR. The affinity to the receptor determines release in the parenchyma or accumulation in the endothelium. ...
Treating brain diseases requires therapeutics to pass the blood-brain barrier (BBB) which is nearly impermeable for large biologics such as antibodies. Several methods now facilitate crossing or circumventing the BBB for antibody therapeutics. Some of these exploit receptor-mediated transcytosis, others use direct delivery bypassing the BBB. However, successful delivery into the brain does not preclude exit back to the systemic circulation. Various mechanisms are implicated in the active and passive export of antibodies from the central nervous system. Here we review findings on active export via transcytosis of therapeutic antibodies - in particular, the role of the neonatal Fc receptor (FcRn) - and discuss a possible contribution of passive efflux pathways such as lymphatic and perivascular drainage. We point out open questions and how to address these experimentally. In addition, we suggest how emerging findings could aid the design of the next generation of therapeutic antibodies for neurologic diseases.
