Lipid-Based Nanocarriers for Neurological Disorders: A Review of the State-of-the-Art and Therapeutic Success to Date
Abstract
:1. Introduction
2. Anatomy and Physiology of the CNS
2.1. Barriers to CNS Drug Delivery
2.1.1. The Blood-Brain Barrier (BBB)
2.1.2. The Blood-Cerebrospinal Fluid Barrier (BCSFB)
2.1.3. The Blood-Brain–Tumor Barrier (BBTB)
2.1.4. Efflux Transporters
2.2. Nose-to-Brain Drug Delivery
2.2.1. Intracellular Transport
2.2.2. Extracellular Transport
2.2.3. Transcellular Transport
2.2.4. Enzymatic Activity
2.2.5. Elimination
2.2.6. Factors Affecting API Transport
Nasal pH
Isotonicity
Deposition and Access Volume
3. Bilayered Lipid Nanocarriers
3.1. Liposomes
3.2. Pharmacosomes
3.3. Ethosomes and Transferosomes
3.4. Niosomes
3.5. Unilayered Lipid Drug Delivery Systems
3.5.1. Solid Lipid Nanoparticles
3.5.2. Nanostructured Lipid Carriers
3.5.3. Lipid-Drug Conjugates (LDC)
3.5.4. Nanocapsules
3.5.5. Micelles
3.5.6. Self-Nanoemulsifying Drug Delivery Systems
3.6. Submicron Emulsions
Microemulsions and Nanoemulsions
4. The Application of Lipid Based Nanocarriers in the Treatment of Neurological Disorders
4.1. Neurodegenerative Disorders
4.1.1. Alzheimer’s Disease
4.1.2. Parkinson’s Disease
4.1.3. Dementia
4.2. Epilepsy
4.3. Ischaemic Stroke
4.4. CNS Neoplastic Disease
5. Conclusions and Future Perspectives
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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---|---|---|---|---|---|---|---|---|
Alzheimer’s | Donepezil | SLN | Glyceryl monostearate | Solvent Emulsification–Diffusion Technique | IN | Wistar Rats | Improved bio distribution and pharmacokinetics | [207] |
Donepezil + Curcumin | NLC | Precirol (Solid lipid) and Capmul MCM (liquid lipid) | Hot High-Pressure Homogenization | IN | Wistar Rats | Higher drug concentration in the brain | [208] | |
Galantamine | SLN | Glyceryl behnate (Compritol®) | Micro-Emulsification | IN | Wistar Rats | Significant memory restoration capability and two-fold increase in bioavailability | [209] | |
Rivastigmine | Liposomes | Egg phosphatidylcholine and Cholesterol | Ammonium Sulphate Gradient Loading Method. | IN SC PO and IP | Male Sprague Dawley rats | Enhanced BBB penetration and improved brain delivery | [211,212,213] | |
Rivastigmine | Liposomes | Phosphocholine, dihexadecyl phosphate and cholesterol | Lipid Layer Hydration and The Heating Methods | SC | Wistar Rats | Preventing amyloid plaque formation | [211,212,213] | |
Rivastigmine | Liposomes | Dipalmitoylphosfotidyl choline (DPPC) and cholesterol | Film Formation Method | IP and PO | Balb-C type mice | Inhibition of AChE | [211,212,213] | |
Parkinson’s | Ropinirole HCL | SLN | Dynasan 114 and stearylamine | Emulsification-Solvent Diffusion | IN | Mice | Reduction in signs of Parkinsonism-like symptoms and comparable with marketed oral formulation | [230] |
Piribedil | SLN | palmitic acid (PA) and polyvinyl alcohol (PVA) | Hot Homogenization Followed by Ultrasonication | IN | Wistar rats | Four-fold increase in AUC, increased nose-to-brain uptake | [226] | |
Bromocriptine | NLC | Tristearin, stearic triglyceride (tristearin), Miglyol 812, caprylic/capric triglycerides (tricaprin) Mivaplex 600, stearic monoglyceride (monostearin) | Homogenization Or Ultrasonication | IV | Sprague–Dawley rats | Rapid onset of action, long lasting activity (5 h) | [227] | |
Apomorphine hydrochloride | SLNs | tripalmitin, Hydrogenated soybean phosphatidylcholine | Emulsification | PO | Wistar rats | A 12- to 13- fold higher bioavailability | [229] | |
Basic fibroblast growth factor | Phospholipid-based gelatin nanoparticles | N/A | Water-In-Water Emulsion and Freeze-Drying Technique | IN | hemiparkinsonian Sprague–Dawley rats | Stimulated dopaminergic function | [234] | |
Glial cell-derived neurotrophic factor | TAT- LNC | (Precirol ATO and Mygliol® | Melt Emulsification Technique | IN | male C57BL/6J mice | Reduction in microgliosis and motor recovery | [235] | |
Selegiline | NE | grape seed oil and Sefsol 218 | High Energy Emulsification Method | IN | Wistar rats | Decreased dopamine loss, Brain: blood ratio of 2.207 indicating the ability to deliver the drug into brain | [242] | |
Selegiline and quercetin | LNC | Labrafil M 2130 CS and Capryol 90 | Modified Emulsiosonication Method | IP | Wistar rats | Increased behavioral response and effect of quercetin on increasing the bioavailability by modulating the P-gp inhibitor | [243] | |
Vitexin | SLN | N/A | Hot Melt Emulsification And Ultrasonication Method | N/A | Mice | Neuroprotective effect observed via improved total reactive antioxidant in striatum | [247] | |
Dementia | Resveratrol | SLN | stearic acid, lecithin and taurocholate | Refer To Method | PO | Sprague Dawley (SD) rats | Reduced mitochondrial oxidative stress | [252] |
Aphanamixis Polystachya leaf extract (ethanol) | Liposomes | Phospholipid extracted from Egg yolk | Solvent Injection Method | PO | Swiss albino mice | Significant improvement in memory function, locomotor activity, and ambulatory performance | [249] | |
Curcumin | SLN | D-L-Homocysteine, Glyceryl monostearate, and Stearic acid | Modified Solvent Evaporation Method | caudal vein | Sprague Dawley rats | Reduced oxidative stress | [253] | |
Rivastigmine | NLC | Combination of solid and liquid lipids | High Pressure Homogenization Technique | TD | Wistar rats | Increased Cmax and AUC, resulting in increased bioavailability | [256] | |
Epilepsy | Carbamazepine | ME | oleic acid | Oil- In- Water Emulsion | IN | Sprague Dawley rats. | Significantly higher CBZ ME via intranasal route and protection from seizures | [267] |
Topiramate | NE | Capmul MCM C8 | Oil- In- Water Emulsion | IN and PO | Wistar rats | Improved bioavailability | [271] | |
Clonazepam | SLN and NLC | Glycerol oleate and oleic acid | High Pressure Homogenization Technique | IN | Swiss Albino mice | NLCs showed prolonged the onset times for convulsion | [275] | |
Embelin | NLC | solid lipid (cetyl palmitate) and liquid lipid (octyldodecanol) | Emulsification And Ultrasonication Method | IN | Wistar rats | Higher concentration of drug into brain for NLCs as compared to plain embelin and marketed formulation | [276] | |
Lamotrigine | NLC | Glyceryl monostearate as solid lipid and oleic acid as liquid lipid a | Solvent Evaporation Method | PO and IN | Wistar rats | Accumulation and longer retention of the drug in the brain Significant improvement in latency and duration of tonic hindlimb extension, up to 24 h post seizure induction. | [277] | |
Valproic acid | NLC | Cetyl palmitate soy lecithin S100, 0.1 mL of octyldodecanol, and 400 mg of VPA, | Emulsion–Solvent Diffusion and Evaporation Method | IN and IP | Wistar rats | NLCs administered via IN showed higher brain:plasma concentration in comparison with NLCs via IP NLCs administered via IN and IP showed similar protective effects to seizure induction | [278] | |
Ischaemic Stroke | Baicalein | NLC | Tripalmitin, Gelucire® and Hydrogenated soybean phosphatidylcholine 80% | Sonication | IV | Wistar rats | Significantly higher accumulation of the drug from NLCs in all parts of the brain | [280] |
Baicalein | SLN | N/A | N/A | IV | Sprague Dawley rats | A 5.69-fold higher AUC, 6.84-fold higher Cmax than that of the Baicalein solution. Improved bioavailability of baicalin in cerebral spinal fluid | [281] | |
Fas ligand Antibody | PEG-lipid nanoparticles | Monostearin, medium chain triglyceride, Polyethylene glycol monostearate and ODARITC | Solvent Diffusion Method | IV | C57BL/6J wild-type mice | Significant improvements in brain injury and in neurological deficit after ischaemia at significantly lower dose in comparison with regular dl-NB | [282] | |
Vinpocetine | Cyclodextrin- NLC | Compritol® 888 ATO and Miglyol® 812N | Water In Oil Emulsification | PO | New Zealand white male rabbits | The relative bioavailability of VP in cyclodextrin-loaded NLC was 592% compared with VP suspension and 92% higher than VP–NLC. | [285] | |
Edaravone | Micelle | methoxypoly (ethylene glycol)-b-poly (D,L-lactic acid) (PEG-PLA) | Solvent Evaporation Strategy | IV | ICR mice | The agonistic micelle (EDV-AM) delivered more EDV into brain Ischemia, more rapidly salvaged ischemic tissue EDV-AM showed highest efficiency of in accelerating axonal remodeling and improved functional behaviors | [290] | |
mRNA—brain derived neurotrophic factor (BDNF) | Nano -Micelle | N/A | Synthesis Of Block-Copolymers | intraventricular injection | Wistar rats | Prevention of ischemic neuronal death | [292] | |
Allium cepa fraction (Ethyl Acetate Fraction) | liposomes | phosphatidylcholine and cholesterol | N/A | IN | Swiss Albino mice | Significant neuroprotection observed at 1/10th the oral dose | [293] | |
CNS Neoplastic Disease | Temozolomide | SLN | lecithin and Poloxamer 188 | Sonication | IV | Rabbits –Pharmacokinetics Kunming mice-Tissue distribution | Higher AUC/dose and the mean residence times in brain and reticuloendothelial cells-containing organs | [297] |
Paclitaxel | LNC | Labrafac® WL 1349, Lipoiïd S75-3 and Solutol® HS 15 | Emulsion Inversion Phase Process | N/A | Syngeneic Fischer F344 male rats | Inhibitory effects on efflux pump activity and reduced tumor expansion | [299] | |
Camptothecin | SLN | cetyl palmitate, Dynasan® 114 and Witepsol® E85 | Oil-In-Water Nanoemulsion Method | IV | Wistar rats | A 6-fold increase in the drug in the brain over the free drug | [300] | |
Camptothecin | SLN | cetyl palmitate | High Shear Homogenization and Ultra-Sonication | IV | Wistar rats | A 4.3-fold increase in brain concentration of the drug and detected until 24 h in brain | [301] | |
Doxorubicin | SLN | stearic acid, Epikuron 200 and taurocholate sodium salt | Oil-In-Water (O/W) Micro Emulsion | IV | Wistar rats | Significant amount of doxorubicin was detectable in the brain and CSF | [303,304] | |
Ferrocenyl diphenol tamoxifen derivative | LNC | Solutol® HS15, Lipoid® and Labrafac® | Multi-inversion Phase Processes | SC | Syngeneic Fischer F344 female rats | Significant reduction in both tumor mass and glioma volume | [305] | |
Amphetamine | LNC | DOPC, cholesterol and amphetaminylated lipid | Conventional Thin Film Hydration Method | IV | female C57BL/6 mice | LNCs with hexadecyl saturated hydrocarbon chain (16-BACL) showed highest accumulation into the brain, co-solubilized paclitaxel and PD-L1siRNA significantly enhanced the overall survivability of the mice | [306] | |
Temozolomide (TMZ) | LNC | Gelucire® 44/14 (solid lipid) and Vit. E (liquid lipid) | High Pressure Homogenization (HPH) Technique | IN | Wistar rats | Higher bioavailability and increased residence time of drug in brain | [308] | |
Temozolomide | LNC | Compritol® 888 ATO, Cremophor ELP and soybean phosphatidylcholine | Solvent Diffusion Method | IV | BALB/c nude mice | Significant inhibition (3 times) of tumor growth | [309,310] | |
Vincristine (VT) and temozolomide (T) | SLN & LNC | SLN—stearic acid (1 g) and injectable soya lecithin LNC—Compritol® 888 ATO, Cremophor® ELP and soybean phosphatidylcholine | Solvent Displacement Technique | IV | BALB/c nude mice | VT-NLCs inhibited tumor growth over 80%, followed by VT-SLNs (56%) and T-NLCs (70%) | [314] | |
Temozolomide (gene-loaded) | (TMZ/DNA-LNCs) | Compritol® 888 ATO, Cremophor® ELP and soybean phosphatidylcholine | Solvent Diffusion Method | IV | BALB/c nude mice | TMZ/DNA-NLCs inhibited tumor growth 3.3 times higher than that of free TMZ | [315] |
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Witika, B.A.; Poka, M.S.; Demana, P.H.; Matafwali, S.K.; Melamane, S.; Malungelo Khamanga, S.M.; Makoni, P.A. Lipid-Based Nanocarriers for Neurological Disorders: A Review of the State-of-the-Art and Therapeutic Success to Date. Pharmaceutics 2022, 14, 836. https://doi.org/10.3390/pharmaceutics14040836
Witika BA, Poka MS, Demana PH, Matafwali SK, Melamane S, Malungelo Khamanga SM, Makoni PA. Lipid-Based Nanocarriers for Neurological Disorders: A Review of the State-of-the-Art and Therapeutic Success to Date. Pharmaceutics. 2022; 14(4):836. https://doi.org/10.3390/pharmaceutics14040836
Chicago/Turabian StyleWitika, Bwalya Angel, Madan Sai Poka, Patrick Hulisani Demana, Scott Kaba Matafwali, Siyabonga Melamane, Sandile Maswazi Malungelo Khamanga, and Pedzisai Anotida Makoni. 2022. "Lipid-Based Nanocarriers for Neurological Disorders: A Review of the State-of-the-Art and Therapeutic Success to Date" Pharmaceutics 14, no. 4: 836. https://doi.org/10.3390/pharmaceutics14040836
APA StyleWitika, B. A., Poka, M. S., Demana, P. H., Matafwali, S. K., Melamane, S., Malungelo Khamanga, S. M., & Makoni, P. A. (2022). Lipid-Based Nanocarriers for Neurological Disorders: A Review of the State-of-the-Art and Therapeutic Success to Date. Pharmaceutics, 14(4), 836. https://doi.org/10.3390/pharmaceutics14040836