Review Article |
Corresponding author: Viliana Gugleva ( viliana.gugleva@gmail.com ) Academic editor: Plamen Peikov
© 2023 Viliana Gugleva, Velichka Andonova.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Gugleva V, Andonova V (2023) Drug delivery to the brain – lipid nanoparticles-based approach. Pharmacia 70(1): 113-120. https://doi.org/10.3897/pharmacia.70.e98838
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The complex structure of the human brain defines it as one of the most inaccessible organs in terms of drug delivery. The blood-brain barrier (BBB) represents a microvascular network involved in transporting substances between the blood and the central nervous system (CNS) – enabling the entry of nutrients and simultaneously restricting the influx of pathogens and toxins. However, its role as a protective shield for CNS also restricts drug access to the brain. Since many drugs cannot cross the BBB due to unsuitable physicochemical characteristics (i.e., high molecular weight, aqueous solubility, etc.), different technological strategies have been developed to ensure sufficient drug bioavailability. Among these, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are promising approaches thanks to their lipid nature, facilitating their brain uptake, small sizes, and the possibilities for subsequent functionalization to achieve targeted delivery. The review focuses on applying SLNs and NLCs as nanocarriers for brain delivery, outlining the physiological factors of BBB and the physicochemical characteristics of nanocarriers influencing this process. Recent advances in this area have also been summarized.
blood-brain barrier, ligands, nanostructured lipid carriers, receptors-mediated transcytosis, solid lipid nanoparticles
The human brain is considered one of the most challenging therapeutic areas for drug delivery due to its protective physiological barriers (blood-brain and blood-cerebrospinal fluid barrier) (Abbot et al. 2010). Hereof, still, nowadays, most treatments for neurodegenerative diseases (Parkinson’s/Alzheimer’s disease, etc.) generally result in symptom relief (
Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are among the most exploited platforms for brain delivery due to their superior safety profile in terms of potential cytotoxicity, biodegradability, or biocompatibility compared, for instance, to the polymeric or inorganic counterparts (
The blood-brain barrier plays a significant role in maintaining homeostasis in the CNS by controlling the transport of substances between the bloodstream and the brain (
Several potential routes have been proposed regarding the transport mechanisms across the BBB, as illustrated in Fig.
Depending on the energy necessity, the transport mechanisms may be broadly classified into passive (transcellular and paracellular diffusion) and active (adsorptive transcytosis, receptor-mediated transcytosis, carrier-mediated transport) (
Active mechanisms transport drugs across the BBB by using different targeting moieties, such as transporters, receptors, etc., or by an unselective approach, as in adsorptive-mediated transcytosis (
Receptor-mediated transcytosis is one of the most prospective strategies for drug/nanocarrier delivery across the BBB. It facilitates the selective uptake of various macromolecules (proteins, peptides) by interacting with the receptors expressed on the endothelial cell’s membrane (
Brain endogenous transporter systems are involved in CNS delivery via carrier-mediated transport or active efflux transporters. Carrier-mediated transport is implemented by solute carriers (SLC), which assist the bi-directional movement of essential nutrients such as glucose, amino acids, nucleotides, vitamins, etc., mediated by a concentration or electrochemical gradient (
In addition to the already discussed transport mechanisms, drug delivery to the brain may also be achieved via cell-mediated transport. The immune cells (neutrophils, macrophages, lymphocytes) associated with inflammatory and other pathological conditions are reported to penetrate successfully across the BBB without compromising its integrity (
The colloidal delivery approach as a brain access strategy has gained enormous attention over the years due to the advantages various nanocarriers provide, such as improved solubility/stability and bioavailability of incorporated active agents, protection from environmental factors (i.e., enzyme degradation), possibility to adjust biodistribution, including target specificity (
The size of the NPs is a crucial physicochemical parameter, affecting their biodistribution, transport across biological membranes, targeting properties, and clearance from the body (
The shape of NPs is also known to affect their cellular uptake (
Surface charge is another physicochemical characteristic affecting the transport of NPs across the BBB and their internalization. In general, cationic nanoparticles are hypothesized to be more easily internalized than their anionic or neutral counterparts due to the electrostatic interaction with the negatively charged proteoglycan (
Surface modification of the drug carriers is a widely exploited approach in nanotechnology to improve drug performance and therapy outcomes. A well-known strategy is coating nanoparticles` surfaces with hydrophilic polymers such as polyethylene glycol (PEG) to minimize recognition by the reticuloendothelial system and provide prolonged circulation time (
Type of nanocarrier | Composition | Surface modification | Target * moiety | Drug | Obtained results | Reference |
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SLNs | Cetyl palmitate, Tween-80 | β-hydroxybutyric acid-stearyl amine conjugate | MCT-1 receptor | Carmustine temozolomide | Improved brain uptake; enhanced antitumor activity vs. free drugs |
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SLNs | Sodium behenate, polyvinyl alcohol 9000/12000 | Transferrin, insulin, ST-MBS /ST-PEG-MBS linker | TfR; IR | Dodecyl-methotrexate | PEGylated functionalized SLNs successfully overcame BBB |
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SLNs; NLCs | Cetyl palmitate, Tween 60, Cetyl palmitate, Tween 60, Miglyol-812 | Transferrin, (conjugated to DSPE-PEG(2000)-NH2) | TfR | Curcumin | Improved curcumin permeation (1.5-fold) through BBB according to permeability study on hCMEC/D3 cells |
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SLNs; NLCs | Cetyl palmitate, Tween 80 Cetyl palmitate, Miglyol-812, Tween 80 | RVG29 peptide (conjugated to DSPE-PEG2000-MAL) | nAChR | Quercetin | High quercetin EE% (>80%); improved permeability through BBB vs. non-functionalized NPs, neuro-protective properties |
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SLNs | Dynasan 116 | ApoE | LDLR | Donepezil | Improved brain uptake vs. plain NPs | |
Tween 80 | DSPE-PEG-avidin | LRPs | 2-fold higher penetration of ApoE-SLNs in a BBB model vs. plain SLNs | |||
NLCs | Compritol 888 ATO, MCT 812, Myrj 52, soy lecithin, mPEG-MAL, mPEG-OH | Monoclonal antibody OX26 | TfR | Salvianolic acid B, Baicalin | Improved drugs uptake by RME; enhanced bioavailability |
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NLCs | Palmityl palmitate | Lactoferrin (Lf) | LDL | Nimodipine | Successful intracellular delivery in stroke cell model via LF-RME |
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Miglyol 812 | DSPE-PEG2000-COOH | |||||
SPC, Solutol HS15 | ||||||
SLNs | Glyceril monostearate, stearic acid, soya lecithin, Tween 80 | Angiopep-2 | LRP 1 | Docetaxel | Improved cellular internalization and cytotoxicity; prolonged circulation vs. free drug |
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SLNs | Triasterin, HSPC, DSPE, cholesterol | Tween 80-coating | P-gp; FRs | Folic acid-doxorubicin conjugate | The conjugated SLNs were successfully internalized in U87 MG brain cancer cells; high antitumor activity |
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NLCs | Stearylamine, Precirol ATO5, Capryol PGMC, Tween 80, Poloxamer 188 | Transferrin | Tf-receptor | Rapamycin | High EE%, small size; high cellular uptake vs. plain NLCs; no immunosuppressive effect |
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The numerous pathologies of CNS and the physiological constraints of the blood-brain barrier determine the constant progress of nanotechnology in this application area. Due to their composition compatibilities, excellent tolerability profile, and scaling-up capabilities, solid lipid nanoparticles and nanostructured lipid carriers are ideal candidates for brain drug delivery systems. Their subsequent functionalization with targeting moieties facilitates their brain uptake and leads to enhanced cellular internalization in a non-disruptive, physiological manner and improved therapeutic effect.
Our thanks to the graduate student Stanimira Zasheva for the assistance in the research process.