Table 1.
Chitosan decorated nanosystems applied to brain and CNS disorders.
| Brain Desease/CNS Disorder | Nanosytem | Size (nm) | PDI | Z-Potential (mV) | Model Drug | Drug Loading (%) | Chitosan Coating Conditions/Method | Additional Functionalization/Targeting Agents | Reference | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Type | Nature of Nanocore | Non-Decorated | Decorated | Non-Decorated | Decorated | Non-Decorated | Decorated | ||||||
| Brain cancer (Glioblastoma, and tumor diagnosis) |
Polymeric NPs | PLGA | 117.35 ± 2.37 | 140.88 ± 5.15 | −− | −− | −14.94 ± 4.05 | 10.33 ± 0.26 | Curcumin | LE: 39.48 to 82.67 | Adsorption by immersion in CS solution at 0.02, 0.04, 0.06 %w/v. Crosslinkers: NHS and EDC | Anti-ALDH to target BCSCs and Salic Acid as BBB permeator | [13] |
| PLGA | 121.0 | 178.0 | 0.120 | 0.200 | −34.0 | 46.0 | Carboplatin | EE: 35.5 and DL: 1.8 | Adsorption by immersion in solution of conjugated CS in a range concentration 0.0008-0.2 %w/v | Folic acid | [75] | ||
| PLGA | 168 | 177 | −− | −− | −6.2 ± 2.5 | 19.6 ± 4.8 | Carmustine/O6-Benzylguanine | LE: 8.97 | Adsorption by immersion in CS solution at 0.3 %w/v | None | [14] | ||
| PCL | 170 ± 0.1 | 196 to 218 | 0.07 ± 0.02 | 0.25 to 0.20 | −20 ± 0.6 | 39 to 54 | Docetaxel | EE: ≃76.0 ± 3.0 | Coating with CS amounts at 0, 0.01 and 0.025 %w/v | None | [79] | ||
| PCL | −− | 168 to 185 | −− | 0.12 to 0.16 | −− | 28.95 to 33.8 | Lipid-core with Simvastatin | EE: ≃100 | Interfacial deposition of pre-formed CS, aqueous phase contained 0.1 %w/v low-MW CS and high-MW CS | None | [47] | ||
| Polymeric Micelles | Pluronic P123/F68® | −− | 51.5 ± 12.3 | −− | 0.692 ± 0.09 | −− | 22.38 ± 4.15 | Myricetin | EE: 91.72 ± 12.68 and DL: 15.63 ± 1.82 | By adding an aqueous solution of CS (40 mg/20 mL) and incubation at 75 °C and dialysis against de-ionized water for 24 h | None | [80] | |
| D-α-tocopheryl glycol succinate 1000 (TPGS) | 13.89 ± 1.2 | 14.25 ± 2.9 | 0.22 ± 0.05 | 0.37 ± 0.03 | −4.91 ± 0.58 | −2.32 ± 0.05 | Docetaxel | EE: 98.8 ± 1.9 | TPGS-COOH activated was conjugated to the CS by EDC and NHS in phosphate buffer saline (pH 5.5) | Transferrin | [81] | ||
| Lipid NPs | SLN (Behenic Acid) | 299.2 to 386.4 | 374.5 to 624.3 | 0.053 to 0.167 | 0.196 to 0.227 | −3.04 to −3.41 | 15.46 to 23.79 | Paclitaxel (PTX) | EE: 24 to 83 and DL: 28 to 100 gPTX/mg | Glycol chitosan was added at the beginning of the preparation of SLN where micellar solution was formed | None | [82] | |
| SLN (Vitamin E and Gelucire 44/14®) | −− | 117 to 203 | −− | 0.131 to 0.216 | −− | −− | Temozolomide | EE: 71.33 to 88.45 and DL: 7.11 to 9.23 | NPs were converted to hydrogel using CS at 1.0 %w/v solution, adding slowly with constant stirring for half an hour | None | [86] | ||
| Inorganic NPs | Iron Oxide | 7.5 ± 1.3 | 76 ± 4 | −− | 0.16 | −− | 4 ± 7.4 | O6-Benzylguanine | DL: 150 ± 14 BG molecules/NP | Via a coprecipitation method. CS-grafted-PEG (150 mg) was mixed with iron chlorides (9 mg Fe2+, 15 mg Fe3+) in 2.18 mL of degassed DI water until complete nucleation of NPs | Tumor targeting peptide, Chlorotoxin | [57] | |
| 34.2 ± 5.4 | 57.1 ± 1.4 | −− | −− | 17.75 ± 0.64 | 18.63 ± 1.27 | DNA encoding Human tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) | Effcient DNA binding | By reaction with aminated poly(ethylene glycol) residues of CS–PEG and CS–PEG–PEI copolymers | Chlorotoxin | [55] | |||
| 7 | 33 | −− | −− | −− | 4.2 | −− | −− | NPs were synthesized in the presence of CS-graftedPEG via coprecipitation of ferrous and ferric chlorides with ammonium hydroxide. | Chlorotoxin and Cy5.5 (near-IR fluorophore) | [98] | |||
| 7.5 | 111.9 ± 52.4 | −− | −− | −− | 19.6 ± 5.7 | siRNA to knockdown green fluorescence protein (GFP) expression | DL: 3.8 siRNA molecules/NP | nanoparticles were coprecipitated in the presence of chitosan-grafted PEG polymer | Chlorotoxin | [56] | |||
| 8 | 67.2 to 71.2 | 0.203 | 0.204 | −0.028 | 0.182 | Anti-CD20 single chain variable fragment-streptavidin fusion protein | DL: 0.7 FP molecules per NP | Via a coprecipitation method. CS-grafted-PEG (150 mg) was mixed with iron chlorides (9 mg Fe2+, 15 mg Fe3+) in 2.18 mL of degassed DI water until complete nucleation of NPs | Oregon Green 488 | [96] | |||
| Alzheimer’s Disease | Polymeric NPs | PLGA | 136.2 ± 1.09 | 142.3 ± 2.57 | 0.093 ± 0.005 | 0.091 ± 0.09 | −27.29 ± 0.97 | 46.6 ± 1.87 | Lutein | EE: 83.97 ± 1.03 and DL: 3.95 ± 0.03 | By electrostatic interaction of CS at 0.01, 0.02, 0.03 and 0.04 %w/v | None | [15] |
| PLGA | 78.1 ± 3.7 | 125.4 ± 9.1 | 0.182 ± 0.027 | 0.197 ± 0.025 | −21.2 ± 0.8 | 36.3 ± 4.0 | Huperzine A | EE: 77.0 ± 3.9 | By reaction with Mal-TMC (3 mg/7.5 mL) | Lactoferrin | [16] | ||
| PLGA | −− | ≈191.0 ± 5.0 | −− | −− | −− | ≈23.0 ± 3.0 | Rosmarinic Acid | EE: 50.0 ± 2.0 (max) | Crosslink of PAAM-CS at 0.05 %w/v with EDC and NHS | Material 197 and ApoE | [76] | ||
| PLGA | 217.33 ± 6.82 | 267.67 ± 2.52 | −− | −− | −7.64 ± 0.74 | 32.02 ± 2.65 | 6-Coumarin Probe | EE: 84.24 ± 4.22 | Redispersion of NP in CS solution at 0.3, 0.5, and 0.7 %w/v by sonication and mix | Anti-Aβ antibody | [77] | ||
| Lipid NPs | SLN (Witepsol E 85®) | 335.76 ± 34.81 | 358.44 ± 25.89 | 0.013 ± 0.00 | 0.028 ± 0.02 | −17.31 ± 0.68 | 10.54 ± 0.75 | BACE1 siRNA | −− | A CS solution at 1 %w/v is added at 1:1 w/w NP suspension, magnetically stirred overnight | Rabies virus glycoprotein known as RVG-9R | [83] | |
| Nanovesicles | Niosomes (Tween-20®) | 165.2 ± 3.1 | 180.2 ± 1.5 | 0.211 ± 0.020 | 0.248 ± 0.016 | −41.6 ± 1.4 | 29.5 ± 1.6 | Pentamidine | EE: 10 | By adding CS (0.05 mg/mL in acetate buffer 0.2 M, pH 4.4) solution to the different niosome samples (1:1 ratio), stirring for 1 h at room temperature | None | [94] | |
| Parkinson’s Disease | Lipid NPs | NLC (Precirol ATO5® and Mygliol®) | 201.5 ± 5.6 | 205.9 ± 6.3 | 0.315 ± 0.03 | 0.275 ± 0.02 | 19.9 ± 3.1 | 21.9 ± 1.8 | Glial cell-derived neurotrophic factor (GDNF) | EE: 87.62 to 87.66 and DL: 1.31 μgGDNF/mgNP | TAT was covalently linked to CS, then NLC dispersion was added dropwise to the TAT-CS solution under continuous agitation for 20 min at room temperature | Cell-penetrating peptides; transactivator of transcription (TAT) | [49] |
| NLC (Flaxseed oil and Tristearin) | 38.41 ± 2.23 | 44.45 ± 1.5 | 0.309 ± 0.02 | 0.281 ± 0.05 | −11.4 ± 0.98 | 16.15 ± 0.9 | Ropinirole-dextran sulphate nanoplex | EE: 92.75 ± 2.30 and DL: 17.26 ± 1.10 | 0.5% w/v of aqueous TMC-CS solution was added to the aqueous dispersion of NLC, stirring for 2 h | None | [87] | ||
| Liposomes | Phosphatidylcholine | −− | −− | −− | −− | −− | −− | Levodopa | −− | Electrostatic adsorption using a CS solution | None | [92] | |
| Emulsions | Microemulsion (Capmul MCM L8®, Tween-80®, PEG400 or Transcutol®) | 24.9 ± 4.60 | 37.1 ± 8.80 | −− | −− | −6.82 ± 2.80 | 13.7 ± 2.90 | Cabergoline | Load of 0.167 %w/w | By adding CS solution (1 %w/w in acetate buffer pH 5) with stirring to the continuous phase such that the final content of chitosan in the formulations is 0.5 %w/w | None | [102] | |
| Epilepsy | Polymeric NPs | PLGA | 93.46 ± 3.94 | 106.31 to 142.43 | 0.106 ± 0.01 | 0.239 to 0.364 | −12.63 ± 0.08 | 21.64 to 24.34 | Catechin Hydrate | EE: 80.36 to 81.66 and DL: 5.98 to 6.87 | Immersion in acidic (0.50% of acetic acid) CS solution (2.0 or 4.0 mg/mL) with 2.0 h of interaction | None | [17] |
| PLGA | 85.12 to 89.3 | 91.9 to 96.5 | 0.314 to 0.332 | 0.111 to 0.255 | −2.53 to −3.47 | 17.47 to 20.29 | Analogues of thyrotropin releasing hormone (NP-355 and NP-647) | EE: 47.94 to 52.56 and DL: 51.5 to 188.01 μg/mg of NPs | Electrostatic adsorption in CS solution at 1 mg/mL followed by stirring for 2 h at 400 rpm at room temperature | None | [18] | ||
| Cerebral Ischaemia | Polymeric NPs | PCL | 163.4 to 234.6 | 201.3 to 283.6 | 0.146 to 0.364 | 0.253 to 0.409 | −21.22 to −6.22 | 17.8 to 25.9 | Glycyrrhizic Acid | EE: 77.94 to 74.43 and DL: 4.17 to 4.84 | By incubation (2 h) with drug of an equal volume of CS solution (2 mg/mL in 65% acetic acid) | None | [20] |
| PCL | 181.3 to 254.0 | 224.5 to 284.0 | 0.143 to 0.297 | 0.216 to 0.419 | − 22.31 to − 28.17 | 18.64 to 26.04 | Eugenol | EE: 68.13 to 71.04 and DL: 4.29 to 5.14 | [21] | ||||
| Emulsions | Nanoemulsion (Capmul MCM®, Tween-80® and PEG-400) | 91.39 ± 1.89 | 98.31 ± 1.17 | 0.372 ± 0.014 | 0.386 ± 0.021 | −19.24 | 13.91 | Naringenin | Load of 2.0 %w/v | At the end of emulsion formation, CS Solution is added (2.3 mL at 0.50 %w/v) | None | [100] | |
| Schizophrenia and Bipolar Disorders | Polymeric NPs | PLGA | −− | 306.1 to 700.0 | −− | 0.173 to 0.462 | −− | 5.67 to 24.7 | Chlorpromazine Hydrochloride | EE: 18.61 to 36.72 and DL: 2.32 to 4.59 | Via amide bond formation mediated by carbodiimide, with 12 h immersion at room temperature | None | [19] |
| Lipid NPs | NLC (Glyceryl monostearate and Oleic Acid) | 167.30 ± 7.52 | 181.58 to 186.97 | −− | −− | −4.34 ± 1.37 | 5.51 to 18.88 | Asenapine Maleate | EE: 82.46 to 84.24 | Glycol CS solutions at 0.01, 0.05, 0.1, 0.2 and 0.4 %w/v were added to NCL suspension, stirring for 24 h | None | [88] | |
| Emulsions | Nanoemulsion: Capmul MCM®, Tween-80® and polyethylene glycol 400) | 20.1 ± 1.65 | 23.6 ± 2.11 | 0.264 ± 0.08 | 0.292 ± 0.06 | −28.41 ± 2.14 | −25.5 ± 1.32 | Olanzapine | Load of 8.5 mg/mL (Drug Content of 97.96 0.24%) | By addition of CS (0.50 %w/w) to aqueous phase in emulsion preparation. The dispersion was stirred for 1 h | None | [101] | |
| Migraine and pain | Lipid NPs | SLN (Glycerol Tripalmitate) | −− | 192.0 to 301.4 | −− | −− | −− | 30.2 to 51.4 | Sumatriptan Succinate | EE: 76.3 to 91.1 | CS solution (1% glacial acetic acid) as aqueous phase (with 150 a 250 mg of CS) is incorporated in the solvent injection method | None | [84] |
| NLC (Compritol® and Labrafil®) | −− | 255 | −− | 0.27 | −− | 34.1 | Almotriptan Maleate | EE: 80 | Adsorption by immersion in CS solution | None | [89] | ||
| Nanovesicles | Bolaamphiphilic vesicles (bolalipids GLH-19 and GLH-20) | 67.8 to 117.2 | −− | 0.155 to 0.277 | −− | 39.5 to 53.0 | −− | Kyotorphin and Leu-Enkephalin (analgesic peptides) | EE: 5.8 to 11.2 | CS-Vernolic acid conjugate was added at a molar concentration 5-fold lower than GLH-19 or GLH-20, at a molar ratio of 2:1, during film formation | None | [95] | |
| Polymeric NPs | PLA | 121.2 ± 5.2 | 140.5 ± 5.4 | −− | −− | −29.28 ± 2.39 | 33.71 ± 3.24 | Neurotoxin from venom of Naja naja atra | EE: 75.17 to 83.51 | Addition of CS solution (0.2 %w/v) in second aqueous phase in the resulting w/o/w emulsion, sonicated for 53 s | None | [78] | |
| Neuroprotection | Polymeric NPs | PLGA | 99.6 ± 6.3 | 146.7 ± 5.1 | −− | −− | −18.3 ± 1.2 | 21.0 ± 2.9 | Coenzyme Q10 | DL: 8.8 | By covalently coupled of TMC via a carbodiimide-mediated link | None | [59] |
| Lipid NPs | SLN (Palmitic Acid) | 138.8 ± 7.6 | 311.9 to 412.0 | 0.15 ± 0.04 | 0.24 to 0.26 | −29.67 ± 1.20 | 27.08 to 35.70 | Curcumin | EE: 93.12 ± 0.06 and LC: 4.04 ± 0.01 | Surface modified with TMC by charge interaction (50:1-CS:SLN w/w) by dispersion in distilled water and stirring for 10 h | None | [85] | |
| NLC (Precirol ATO5® or Dynasan 114® and Miglyol®) | 107.12 and 159.35 | 114.48 and 191.89 | 0.342 and 0.361 | 0.287 and 0.386 | −30.30 and − 19.12 | 28.40 and 41.50 | Neurotrophic factor human insulin-like growthfactor-I | EE: 90.28 ± 0.4 | NCL dispersion is added dropwise to an equal volume of a CS solution (0.5 %w/v) kept under continuous agitation at room temperature for 20 min | None | [90] | ||
| Lipid microparticles | Stearic Acid | 68.5 ± 3.1 μm | 76.3 and 84.5 μm | −− | −− | −12.7 ± 2.1 | 24.0 and 44.6 | Resveratrol | EE: 76.5 and 81.0 | Microparticles were added to CS solution (1.75 and 8.75 %w/v), during the cooling phase of emulsion method | None | [91] | |
| Cerebrovascular Inflammation | Inorganic NPs | Gadolinium-Magnevist® (MRI contrast agent) | 164 ± 1.2 | 239 ± 4.1 | −− | −− | 11.9 ± 0.5 | 21.6 ± 1.7 | Cyclophosphamide | DL: 21.7 ± 1.3 | By emulsion-droplet coalescence technique developed at CS polymer concentration of 2.5 %w/v | Anti-amyloid antibody, IgG4.1 | [99] |
| Others (Cachexia, Traumatic Brain Injury) |
Liposomes | Lipoid S100® | 147.3 ± 4.3 | 194 ± 6.1 | 0.119 | 0.198 | −0.6 ± 0.3 | 6 ± 0.4 | Ghrelin | EE: 9.8 ± 3.7 | N-([2-hydroxy-3-trimethylammonium]propyl) CS chloride at 1 mg/mL is added dropwise to LP suspension under magnetic stirring at 3,000 rpm | None | [93] |
| Inorganic NPs | Iron Oxide | 7.0 ± 0.6 (22.7) | 50 to 70 | −− | −− | −− | −− | Reporter DNA (pCMV-td Tomato plasmid) | Efficient plasmid complex | CS-PEI magnetic-micelles (CPMMs) were prepared in a weight 1:1 ratio of CS-PEI (polyethyleneimine) (2 mg/mL) | MRI: Gadolinium chelates | [97] | |
ALDH = Anti-aldehyde dehydrogenase, ApoE = Apolipoprotein E, BBB = Blood-Brain Barrier, BCSCs = Brain Cancer Stem Cells, CS = Chitosan, DL = Drug Loading, EDC = 1-(3-dimethylaminopropyl)-3-3ethylcarbodiimide hydrochloride, EE = Entrapment or Encapsulation Efficiency, LC = Loading Capacity, LE = Loading Efficiency, MW = Molecular Weight, NCs = Nanocapsules, NHS = Hydroxysuccinimide, NLC = Nanostructured Lipid Carrier, NP or NPs = Nanoparticles, PAAM = Polyacrylamide, PCL = poly-𝛆-caprolactone, PLA = Poly (lactic acid), PLGA = Poly(lactic-co-glycolic acid), SLN = Solid Lipid Nanoparticle, TMC = N-Trimethylated chitosan.