Advances in Intrathecal Nanoparticle Delivery: Targeting the Blood–Cerebrospinal Fluid Barrier for Enhanced CNS Drug Delivery
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Pharmacokinetics of Intrathecal NPs in CSF
3.2. Blood–CSF Barrier: Structural Features, Permeability, and Function
3.3. Classifications and Characteristics of NPs That Influence Permeability
3.3.1. Classification of NPs
- Lipid-based NPs: Lipid-based NPs encompass liposomes, micelles, solid lipid nanoparticles (SLNPs), and emulsions, valued for their biocompatibility, ability to encapsulate both hydrophilic and hydrophobic drugs, and controlled release capabilities. Among these, liposomes stand out in antibiotic delivery research due to their structural and compositional versatility, which enhances PKs and PDs [80]. Liposomes protect antibiotics, enabling targeted delivery to infection sites while minimizing toxicity to healthy tissues. They interact with bacterial cell walls to increase antibiotic concentration within bacteria, enhancing therapeutic efficacy [80,81].
- Polymeric NPs: Polymeric NPs encompass dendrimers, polymersomes, and polymer micelles. These NPs offer structural flexibility, a high drug-loading capacity, and controlled release profiles. They are particularly useful for delivering drugs that require prolonged and targeted delivery.
- Cell-derived biomimetic NPs: Cell-derived biomimetic NPs include exosomes and stem cell-derived NPs. These NPs mimic natural cellular structures, enhancing their biocompatibility and ability to evade immune detection, making them ideal for delivering therapeutic agents to the CNS.
- Inorganic NPs: Inorganic NPs, such as gold NPs, iron oxide NPs, and mesoporous silica NPs, offer unique properties like magnetic responsiveness and enhanced imaging capabilities. These NPs are used for therapeutic delivery and diagnostic purposes.
3.3.2. Key Properties of NPs Affecting Transport and Distribution
- Size: The size of NPs significantly influences their ability to cross biological barriers. Smaller NPs (<100 nm), especially those around 37–39 nm, are more likely to traverse the BCSFB via transcellular routes such as RMT or adsorptive-mediated transcytosis [82,83]. The effective pore size of the BCSFB is approximately 0.0028 μm, allowing paracellular diffusion of very small NPs and suggesting that 99.8% of the BCSFB’s surface area is involved in transcellular diffusion [84]. NP size is critical for distribution and efficacy. NPs > 20 nm can cross the CNS barriers, while those <5 nm are excreted by the kidneys, and those >200 nm are removed by organs like the liver and spleen [85]. Ideal brain-delivery NPs are <100 nm [83]. For example, 50 nm gold NPs have the highest cellular uptake in HeLa cells [86].
- Surface charge: Surface charge affects NP stability, cellular uptake, and biodistribution [87,88]. Positively charged NPs often exhibit enhanced cellular uptake through electrostatic interactions with negatively charged cell membranes, facilitating their transport across barriers [89]. Zeta potential is a measure of the surface charge of NPs in suspension, influencing their stability and interaction with biological membranes. A high zeta potential (either +/−) typically indicates good stability, reducing the likelihood of aggregation and promoting consistent delivery.
- Surface characteristics: Surface characteristics, like hydrophobicity, hydrophilicity, and targeting ligands, crucially determine NP interactions with biological systems. Surface modifications improve targeting efficiency, reduce off-target effects, and enhance therapeutic outcomes by stabilizing NPs and preventing rapid immune clearance. Rigid copolymer ligands and auxiliary lipids can increase NP robustness [90]. Hydrophobic surfaces improve cell uptake and immune activation [91]. Specific ligands, such as antibodies and peptides, enhance targeting and drug availability [92]. For instance, T7 peptides target the brain by binding to transferrin receptors on glioma cells [93].
- Morphology of NPs: the shape of NPs affects distribution and uptake efficiency. Nonspherical NPs, like nanorods, show better cell entry compared to spherical ones [94]. PEG-modified nanorods are less absorbed by macrophages than nanospheres [95], indicating that shape influences drug delivery and uptake [85,94,95].
3.4. Penetration of IT-NPs in CSF across BCSFB
3.5. Strategies to Enhance NP Penetration and Efficacy across the BCSFB
Active Targeting Strategies
- Monoclonal Antibodies: Extensive research has concentrated on antibodies targeting the transferrin receptor to facilitate brain delivery via nanocarriers. This receptor is highly expressed in brain tissues and the microvessel ECs of the BBB [146]. The OX26 antibody, originally developed to target the transferrin receptor, has been shown to enhance the delivery of daunomycin and plasmids through liposomes [147,148,149], as well as peptides via polymersomes in rat models [150]. Similarly, the transferrin antibody 8D3 has demonstrated improved delivery of DNA plasmids in mouse models [151]. Nevertheless, there is a crucial need to develop antibodies targeting the human CNS, as OX26 and 8D3 are specific to rodent transferrin receptors, which limits their translational applicability [145]. The insulin receptor, expressed at the BBB and on glioma cell membranes, along with the epidermal growth factor receptor (EGFR) found in brain tumor cells, are key targets for brain delivery via immuno-liposomes [152,153,154]. The 83-14 antibody targeting the insulin receptor has markedly increased the delivery of liposomes containing antisense oligonucleotides to gliomas [152]. Likewise, immuno-liposomes with the anti-EGFR antibody IMC-C225 have improved the delivery of chemotherapeutic agents to brain tumor cells [153]. However, the 83-14 antibody, initially a mouse anti-human antibody, has shown efficacy only in larger Old-World primates such as Rhesus monkeys, highlighting the necessity of species specificity in targeted delivery systems [154].
- Cell-Penetrating Peptides (CPPs): NPs coated with CPPs offer a potential strategy to enhance CNS barrier selectivity and facilitate drug transport to the CNS. The trans-activator of transcription (TAT) peptide, derived from HIV-1, is particularly notable for this purpose [155]. TAT induces receptor-mediated endocytosis and can be utilized to tag NPs, resulting in increased brain levels of various therapeutic agents such as ciprofloxacin, coumarin, and macromolecules [156,157,158]. Additionally, synthetic peptides have been employed successfully for brain delivery by modifying their sequences to mitigate inherent biological activities that may cause adverse effects [159,160,161,162]. Recent advancements include the use of novel peptide-based carriers known as Angiopeps for brain drug delivery [163]. These peptides, derived from the Kunitz domain, have demonstrated higher transcytosis rates and parenchymal accumulation compared to other targeting moieties like avidin and lactoferrin. While the exact mechanism of Angiopeps’ cell penetration remains to be elucidated, it is likely mediated by the LDL receptor-related protein-1 (LRP1).
- Targeting with Endogenous Molecules: Apolipoproteins, such as apolipoprotein A (ApoA) and apolipoprotein E (ApoE), have been effectively utilized to target LDL receptors at the BBB. Non-ionic surfactants, particularly polysorbates, promote ApoE adsorption on nanocarrier surfaces, enhancing their targeting capabilities [164,165]. Alternatively, nanocarriers can be directly conjugated to apolipoproteins. For instance, Michaelis et al. demonstrated that direct conjugation of human serum albumin NPs to ApoE via covalent linkages resulted in superior therapeutic effects and prolonged efficacy compared to indirect approaches using albumin with ApoE adsorbed on the surface [166]. Various other substrates, including thiamine, transferrin, folate, glycosides, and lactoferrin, have been evaluated for targeting receptors at the BBB [167,168,169,170,171,172,173]. Although generally less specific than monoclonal antibodies, these substrates offer the advantage of being endogenous molecules present in the human body, potentially reducing the risk of severe immunogenic responses or adverse effects.
3.6. Clinical Application of IT-NPs in CNS Diseases
4. Discussion
4.1. Selection and Challenges in NPs for DDS
4.2. Toxicity of Nanoparticles
4.3. NP Uptake Pathways across the BCSFB
4.3.1. Receptor-Mediated Transcytosis
- Transferrin Receptor Pathway: The transferrin receptor TfR1 has been a primary target for enhancing the delivery of compounds to the brain due to its selective expression in the cerebral microvessel endothelium relative to other endothelia. TfR1 is also present in the BCSFB and has been identified in both rat and human CP epithelia [235,236,237]. The mechanism of TfR1-mediated iron delivery into cells is well understood. Iron-loaded transferrin binds to TfR1 at the clathrin-coated pits on the cell membrane, and the complex is internalized by endocytosis. Iron is released from transferrin in acidifying endosomal vesicles and is exported to the cytosol for metabolic functions or storage. TfR1 is recycled to the cell membrane, releasing iron-free transferrin with low affinity at neutral pH. This route of iron delivery to the brain requires the export of cytosolic iron at the brain-facing membranes of BBB and BCSFB cells, possibly involving ferroportin or another mechanism [238]. Recent studies suggest that TfR1-mediated transcytosis may occur in the choroidal ependymocytes, although the exact mechanism remains unclear. Evidence supporting this comes from experiments utilizing a novel engineered receptor/ligand system expressed specifically in this barrier [239]. The mechanisms underlying transcytosis, particularly the triggers for endocytosis and vesicular pathways, remain poorly understood. Moreover, the impact of TfR1-mediated transcytosis at the BCSFB on antibody-based therapeutic drug delivery targeting the BBB is still being investigated. Furthermore, the canonical endocytosis pathway involving TfR1 recycling could be utilized in strategies for CNS delivery, as demonstrated with gold NPs [240]. Transferrin-conjugated NPs with a pH-sensitive linker showed enhanced brain penetration in mice post-systemic administration compared to non-cleavable linker-bound NPs. Acidic endosomal pH likely dissociates gold particles from stable transferrin-TfR1 complexes, aiding brain access. Further research is needed on particle sorting and release mechanisms at the endothelial abluminal membrane. This effective delivery method in the choroidal epithelium warrants exploration at the BCSFB.
- The Insulin Receptor Pathway: Insulin transportation through the BBB relies on RMT [241]. Inspired by the OX-26 anti-TfR1 antibody model, a monoclonal antibody was developed against the human insulin receptor. This antibody demonstrated endocytosis in human cerebral capillaries and swift transcytosis in non-human primate brain parenchyma [242]. Consequently, an antibody-based delivery platform emerged, facilitating the engineering of recombinant bifunctional fusion proteins to transport therapeutic proteins, like growth factors or enzymes, across the BBB [243]. Fusion constructs coupling a humanized anti-insulin receptor monoclonal antibody with lysosomal enzymes are currently in phase I clinical trials for lysosomal storage disorders affecting the brain (according to the NCT02262338 Health USNIO, ClinicalTrials.gov registry and results database 2016). Previous investigations into the distribution of insulin receptors in the brain revealed a high insulin-binding capacity not only at the BBB but also in the CP [244,245]. The CP was identified to possess the highest density of insulin-binding sites among all brain structures [245,246]. Further confirmation of insulin receptor gene expression in the CP was obtained through in situ hybridization [247]. Although direct evidence of insulin RMT across the BCSFB is lacking, continuous blood infusion of insulin in dogs and humans raised the CSF level of the hormone concurrently with the plasma level [248,249]. Modeling of insulin uptake kinetics in CSF from plasma suggested the existence of an intermediate compartment between blood and CSF, possibly corresponding to parenchymal interstitial fluid or CP tissue [248,250]. The rapid elimination of insulin from the CSF following IVT perfusion, relative to the elimination of a CSF bulk flow marker, indicated that insulin receptors in the BCSFB could mediate the CSF-to-blood transcytosis of the hormone, contributing to insulin signal termination [251]. In summary, the exploration of insulin RMT offers promising avenues for the development of antibody-based delivery platforms, potentially revolutionizing therapeutic interventions for brain disorders.
- The LDL Receptor Pathway (A Gateway for Cholesterol Delivery to the Brain): This passage highlights the low-density lipoprotein (LDL) receptor’s role in brain cholesterol homeostasis. The LDL receptor, a high-affinity cell surface protein, binds LDL particles (carrying cholesterol) via apolipoprotein B. It then facilitates their internalization through coated pits. These LDL particles are delivered to lysosomes for degradation, releasing cholesterol for cellular use. Importantly, the LDL receptor is more abundant at the BBB compared to other ECs. This strategic positioning allows it to mediate the transcytosis of LDL particles, delivering cholesterol to brain cells [252]. Research has identified specific peptide ligands that bind the human LDL receptor’s extracellular domain using phage display biopanning [233]. These optimized peptides exhibit high affinity for the receptor without competing with endogenous LDL. In vivo, studies using biphoton microscopy demonstrated that these peptides can extravasate from blood vessels in the spinal cord and accumulate in the surrounding brain tissue. Conversely, a scrambled control peptide remained confined within the blood vessel lumen. Further investigation is necessary to understand the transcytosis mechanism better and evaluate its potential for delivering therapeutic cargo to the brain. Limited information exists regarding LDL receptor expression at the BCSFB. While transcripts have been detected in the mouse CP (Allen Institute for Brain Science), recent immunohistochemical analysis of human CP tissues revealed consistent expression of the receptor in choroidal epithelial cells across all seven patients tested [253]. Future studies exploring LDL-RMT for CNS drug delivery should consider investigating both the BBB and BCSFB in parallel.
- The LDL Receptor-Related Protein Family: LDL receptor-related proteins (LRPs) are a family of cell surface receptors involved in endocytosis and transcytosis of macromolecules across barrier-forming cells [254]. They have been explored as potential targets for drug delivery to the CNS [255,256]
- (A)
- LRP1 and the BBB: LRP1 was initially considered a promising target for brain drug delivery due to its ability to bind Kunitz protease inhibitor domain-containing peptides like angiopep2 [256]. However, LRP1 expression in human BBB endothelium is debated. While some studies detected LRP1 in mouse brain microvessels, others failed to find it in human brain tissues [257,258,259].
- (B)
- (C)
- LRP2 and LRP8 as Potential CNS Drug Delivery Targets: LRP2 and LRP8 are other LRP family members with potential for CNS drug delivery. LRP2 is highly expressed in the CP throughout life and mediates transcytosis of leptin and insulin-like growth factor I from blood to CSF [224,263]. LRP8 is also highly expressed in the CP and shows apical localization, suggesting a role in CSF transport [264,265]. LRP8 knockout mice have lower brain selenium levels, suggesting its involvement in brain selenium uptake [266]. While LRP1’s role at the BBB remains unclear, LRP1, LRP2, and LRP8 in the CP highlight their potential for targeted CNS drug delivery. Further research is needed to understand LRP-mediated transcytosis mechanisms and develop specific peptide ligands or other triggers for an LRP-based DDS. The LRP receptors in the BBB and BCSFB are summarized in Table 5 below:
- The Folate Pathway: Folates, essential vitamins for vital metabolic processes, require facilitated transport across cell membranes due to their poor permeability at physiological pH. Three distinct systems have been identified for this purpose, each characterized by varying affinities for the physiologically active form of folate, 5-methyltetrahydrofolate (5MTHF), and differing pH preferences. Notably, two of these systems are classified as facilitative transporters, belonging to the extensive solute carrier superfamily [49]. The reduced folate carrier (RFC, SLC19A1) is a broadly expressed transporter with low affinity, operating effectively at normal pH levels and mainly found in the choroidal epithelium’s apical membrane. Conversely, the proton-coupled folate transporter (PCFT, SLC46A1) functions optimally at acidic pH, with lower affinity, primarily in the intestinal epithelium but also in the CP. PCFT immunolabeling reveals staining in both basolateral membranes and cytoplasm [267,268]. Folate receptors (FR) facilitate folate endocytosis at neutral pH without clathrin, with FR-alpha (FRα) mainly in specialized epithelia, notably the choroidal epithelium, showing intense immunoreactivity, especially in the human CP [267,268]. FRα exhibits a low binding constant in the nanomolar range, akin to plasma concentrations. CSF folate levels are 3- to 4-fold higher than blood. FOLR1 gene mutations, causing cerebral folate deficiency, lower CSF folate but not blood levels. FRα, present only in the CP, is crucial for folate delivery. The proposed pathway posits the following under normal conditions: (1) FRα-mediated endocytosis facilitates basolateral membrane folate uptake, (2) within acidifying endosomes, folates are released from FRα and exported by PCFT, and (3) RCF transports folates across the apical membrane into CSF [269]. Recent research employing both in vitro and in vivo methods unveiled a new folate delivery mechanism across the choroidal epithelium [267]. In Z310 rat choroidal cells expressing human FRα (hFRα), fluorescent folates and FRα were co-transported from the basolateral to the apical membrane and released into exosomal vesicles. This exosome-mediated delivery was supported by hFRα presence within intraluminal vesicles of multivesicular bodies. IVT injection of hFRα-positive exosomes from transfected Z310 cells into mice resulted in their penetration into the brain parenchyma, particularly astrocytes, away from the ventricular wall, while hFRα-negative exosomes remained at the periventricular border. FRα-containing exosomes were also found in human CSF, correlating with CSF levels of 5MTHF. The CP significantly contributed to CSF exosomes, with 38% being FRα-positive in control individuals. This novel mechanism, coupling RMT with targeted distribution via exosomes, holds promise for cerebral drug delivery. Additionally, cancer cells, notably pediatric ependymal tumors, frequently overexpress FRα [270]. Folate-conjugated anticancer agents entering the CSF via the CP can directly target tumors, enhancing penetration into the target cells.
- Plasma Protein Transport: Decades ago, plasma protein transfer from blood to CSF in newborn rats, demonstrated using labeled albumin and immunoglobulins, was attributed to the immaturity of the BCSFB [50]. However, the current understanding largely disregards this explanation, with accumulating evidence supporting a specific and developmentally regulated mechanism of protein transfer across the choroidal epithelium. Immunoreactivity of various plasma proteins was observed in choroidal epithelial cells during fetal life in multiple mammalian species, including humans [271,272,273]. Actual protein transfer from blood to CSF was confirmed using exogenous human albumin in sheep fetuses or rat neonates [274,275]. This protein uptake and transfer pathway by the CP appears to be specific, as not all plasma proteins can be detected within choroidal epithelial cells [274]. Moreover, the lack of correlation between CSF/plasma concentration ratios and the molecular radius of transported proteins suggests the involvement of a receptor-mediated transfer mechanism [273,276]. Extensive research has aimed to identify choroidal receptors for plasma proteins and characterize the cellular mechanism supporting transport to the CSF. Given the structural dissimilarity of transported proteins, multiple pathways are anticipated [277]. For instance, bovine fetuin administered to Monodelphis fetuses was taken up by choroidal epithelial cells following intraperitoneal injection but not after IVT administration, suggesting a unidirectional transfer mechanism from blood to CSF, unless influenced by physiological concentration gradients [271]. The BCSFB transporters and receptors relevant to drug delivery are summarized in Table 6.
4.3.2. Carrier-Mediated Transcytosis
4.3.3. Absorptive-Mediated Transcytosis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
List of Abbreviations
5-HT | Serotonin |
5MTHF | 5-methyltetrahydrofolate |
ApoA | Apolipoprotein A |
ApoE | Apolipoprotein E |
AMT | Absorptive-Mediated Transcytosis |
API | Active Pharmaceutical Ingredient |
AUC | Area Under the Curve |
Au198 | Radioactive Gold-198 |
BACE1 | Beta-Secretase 1 |
BCSFB | Blood–Cerebrospinal Fluid Barrier (also known as Blood–CSF Barrier) |
CBD | Cannabidiol |
CMT | Solute Carrier-Mediated Transcytosis |
CNS | Central Nervous System |
CPP | Cell-Penetrating Peptide |
CPPs | Cell-Penetrating Peptides |
CP | Choroid Plexus |
CPECs | Choroid Plexus Epithelial Cells |
CSF | Cerebrospinal Fluid |
DDS | Drug Delivery Systems |
DiD | A hydrophobic carbocyanine dye |
DOX | Doxorubicin |
ECs | Endothelial Cells |
EG-1962 | PLGA-Encapsulated Nimodipine |
EXPAREL® | Liposomal Bupivacaine |
FR | Folate Receptor |
FRα | Folate Receptor Alpha |
GLUT | Glucose Transporter |
HIRMAb | Human Insulin Receptor Monoclonal Antibody |
ICM | Intracisternal Magna |
IMI/CIL | Imipenem/Cilastatin |
IT | Intrathecal |
IT-NPs | Intrathecal Nanoparticles |
IVT | Intraventricular |
LRP1 | LDL Receptor-Related Protein 1 |
LDL | Low-Density Lipoprotein |
LDLR | Low-Density Lipoprotein Receptor |
L-DOPA | Levodopa |
LPEI | Linear Polyethyleneimine |
MPSI | Mucopolysaccharidosis Type I |
NPs | Nanoparticles |
PCL | Polycaprolactone |
PCL-NPs | Polycaprolactone Nanoparticles |
PCNPs | Polymer-Coated Nanoparticles |
PEG | Polyethylene Glycol |
PEI | Polyethyleneimine |
PK | Pharmacokinetic |
PKs | Pharmacokinetics |
PDs | Pharmacodynamics |
PLGA | Poly(lactic-co-glycolic acid) |
PNPs | Polymeric Nanoparticles |
RMT | Receptor-Mediated Transcytosis |
RCF | Reduced Folate Carrier |
SAS | Subarachnoid Space |
SLNPs | Solid Lipid Nanoparticles |
siRNA | Small Interfering RNA |
TAT | Trans-Activator of Transcription |
TfR1 | Transferrin Receptor 1 |
VSOP-C184 | Very Small Superparamagnetic Iron Oxide Particle C184 |
ZO | Zonula Occludens |
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Aspects | BBB | BCSFB | References |
---|---|---|---|
Anatomy |
|
| [39] |
| Ependymal Cell do not have TJs | [40,41] | |
Transporter and Pathways |
|
| [39,43,44,49,50] |
Type of NPs | Size of NPs | Charge and Lipophilicity | Surface Properties | Shape | References |
---|---|---|---|---|---|
PEGylated PCL-NPs | 37~39 nm | Negative | Not functionalized | NA | [82] |
Au NPs | 50 nm | NA | NA | NA | [86] |
INS-GNPs | 20 nm | NA | NA | NA | [83,85] |
Nanorods (rod-shaped) | NA | NA | NA | Non-spherical | [94] |
Gold NPs | NA | Positively charged | NA | NA | [96] |
PEG-modified nanorods | NA | NA | NA | Nanorods | [95] |
INS-GNPs | 100 nm | NA | NA | NA | [83] |
Types of NPs | Route | AUC | Cmax | Tmax | T1/2 | References |
---|---|---|---|---|---|---|
CBD-NE | IT | 3.7-fold higher | 210 ng/g | 120 min | NA | [109] |
CBD-PCNPs | IT | NA | 94 ng/g | 30 min | NA | [109] |
Liposomal Cytarabine | IT | NA | NA | NA | 43 h | [25,26] |
IMI/CIL (API) | IT | NA | 4.5 µg/100 mg | 2h | 8 h | [124] |
IMI/CIL (API) | IV | NA | 1.5 µg/100 mg | 2h | <8 h | [124] |
Nanoparticle Type | Drug | Disease | Delivery Route | Phase | Size (nm) | Surface-Modification | Penetration Efficiency (%) | References |
---|---|---|---|---|---|---|---|---|
Lipid-based NPs (liposome) | DepoCyte® | Brain metastases | IT | Phase I | NA | NA | NA | NCT00854867 |
DepoCyte® | Meningeal metastasis of breast cancer | IT | Phase III | NA | NA | NA | NCT01645839 | |
Depocyt (Cytarabine) | Meningeal neoplasms | IT | Phase IV | NA | NA | NA | NCT00029523 | |
Depocyt (Cytarabine) | CNS metastases tumors | IT | Phase II | NA | NA | NA | NCT00992602 | |
Polymeric-NPs | Carmustine wafer | Glioblastoma | SI | Phase I/II | NA | NA | NA | NCT00984438 |
Carmustine implants | Brain metastases | SI | Phase II | NA | NA | NA | NCT00003878 | |
Inorganic NPs | - | - | - | - | - | - | - | - |
Cell-derived biomimetic NPs | Exosomes | CVD | Intraparenchymal | Phase I/II | NA | NA | NA | NCT03384433 |
Stem cells (MSCs) | Multiple sclerosis | IT/IV | Phase II | NA | NA | NA | NCT02166021 | |
Stem cells (HSCs) | Multiple sclerosis | IT/IV | Phase III | NA | NA | NA | NCT04047628 |
LRPs | BBB | BCSFB | References |
---|---|---|---|
LRP1 | Debated | Consistently expressed | [253,254,255,256,257] |
LRP2 | Not expressed | Highly expressed | [224,263] |
LRP8 | Expressed in development | Highly expressed | [264,265] |
Receptor | Endogenous Substrate | Evidence of Transcytosis Across CP | Clinical Relevance | References |
---|---|---|---|---|
Transferrin Receptor (TfR1) | Transferrin | Indirect | Treatment of iron-related disorders, neurodegenerative diseases | [235,236,237,278] |
Insulin Receptor (IR) | Insulin | Limited data | Regulating glucose homeostasis | [247] |
LDL Receptor | LDL | Limited data | Cholesterol transport | [253,278] |
LRP1 | Various (α2-macroglobulin, matrix metalloproteases, different carrier proteins…) | Indirect | Cholesterol transport | [253] |
LRP2 | Partial overlapping substrate specificity with LRP1, Morphogenic factors, leptin, insulin-like growth factor I (developmental relevance) | Yes, for endogenous substrate | Cholesterol | [224,263] |
transport | [264,265] | |||
LRP8 | Partial overlapping substrate specificity with LRP1, Selenoprotein P | Partial, indirect | Cholesterol | [224,263] |
transport | [264,265] | |||
Folate Receptor (FRα) | Folate | Yes, for endogenous substrate, through exosome | Cancer therapy, neurological disorders | [267,268] |
Unknown (possibly SPARC, Glycophorins) | Plasma proteins (albumin, fetuin, hemopexin, α-fetoprotein) | Yes, for exogenous proteins | Potential for targeted drug delivery, biomarker discovery | [279] |
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Madadi, A.K.; Sohn, M.-J. Advances in Intrathecal Nanoparticle Delivery: Targeting the Blood–Cerebrospinal Fluid Barrier for Enhanced CNS Drug Delivery. Pharmaceuticals 2024, 17, 1070. https://doi.org/10.3390/ph17081070
Madadi AK, Sohn M-J. Advances in Intrathecal Nanoparticle Delivery: Targeting the Blood–Cerebrospinal Fluid Barrier for Enhanced CNS Drug Delivery. Pharmaceuticals. 2024; 17(8):1070. https://doi.org/10.3390/ph17081070
Chicago/Turabian StyleMadadi, Ahmad Khalid, and Moon-Jun Sohn. 2024. "Advances in Intrathecal Nanoparticle Delivery: Targeting the Blood–Cerebrospinal Fluid Barrier for Enhanced CNS Drug Delivery" Pharmaceuticals 17, no. 8: 1070. https://doi.org/10.3390/ph17081070
APA StyleMadadi, A. K., & Sohn, M. -J. (2024). Advances in Intrathecal Nanoparticle Delivery: Targeting the Blood–Cerebrospinal Fluid Barrier for Enhanced CNS Drug Delivery. Pharmaceuticals, 17(8), 1070. https://doi.org/10.3390/ph17081070