**5.2 Nanotechnology-based delivery system: An innovative strategy**

Nanotechnology is a new branch of science involving the formulation, synthesis, and characterization of small particles, with diameters ranging from 1 to 1000 nm [186], which become key players in innovative drug delivery and cell targeting. Recent studies suggest that nanoparticle-based delivery systems represent innovative and promising approaches to improve drug solubility, prevent aciddegradation, minimize toxic side effects, and increase blood availability [187, 188]. Considering the low bioavailability of polyphenols, different strategies have been developed in order to enhance their chemical stability, solubility, and cellmembrane permeability. These goals have been achieved by adding chemical agents to preserve the structure [189], enzyme inhibitors to contrast biotransformation [190], and lipids or proteins to increase the solubility [191]. Recently, nanoparticlemediated delivery system is emerged as the most promising approach. Using biodegradable and biocompatible polymers, polyphenols can be encapsulated in different nanostructures and then possibly administrated *via* intravenous, transdermal, nasal, and oral route. As describe above, this aspect is fundamental in neurological diseases, in which polyphenols must cross the BBB, with the opportune grade of lipophilicity [162, 192, 193] and reach the brain tissue in sufficient quantities for therapeutic use. These new delivery systems are represented by nanospheres, nanocapsules, nanoemulsions, solid lipid nanoparticles, cyclodextrins, liposomes, and micelles (**Figure 7**).

Nanospheres (10–200 nm) [194] are homogeneous solid matrix particles characterized by a hydrophobic portion in the inner part and hydrophilic chains anchored on the surface. In nanospheres, the drug is dissolved, entrapped, encapsulated, or attached to the matrix of the polymer, so protected from chemical and enzymatic degradation. Various kinds of polymers are used to prepare nanospheres: polylactic acid (PLA), poly-glycolic acid (PGA), poly-lactic-co-glycolic acid (PLGA), polyethylene glycol (PEG), poly ε-caprolactone (PCL), and chitosan (CS) [195, 196].

#### **Figure 7.**

*Schematic representation of nanosized delivery systems for polyphenols. Nanoparticles can enhance polyphenol bioavailability, enhancing their adsorption across intestinal epithelium, increasing their concentration in the bloodstream, and improving their ability to cross the blood-brain barrier.*

**51**

*Polyphenols as Potential Therapeutic Drugs in Neurodegeneration*

CS, can be added to slow down nasal clearance [191].

dynamic of polymorphic transitions [198].

Nanocapsules (10–1000 nm) have a similar chemical composition but comprise

Nanoemulsions are oil-in-water or water-in-oil emulsions stabilized by one or more surfactants (i.e., phosphatidylcholine, sodium deoxycholate, sorbitan monolaurate, poloxamers, sodium dodecyl sulfate, and poly(ethylene glycol)) delivered in droplets of small dimensions (100–300 nm) [191]. The strategy allows having a higher surface area and a long-term chemical and physical stability [201, 202]. Nanoemulsions represent an innovative formulation to deliver polyphenols directly into the brain through the intranasal route. In fact, mucoadesive polymers, such as

Solid lipid nanoparticles (50–1000 nm) [194] are composed of high melting point lipid, organized in a solid core, coated by aqueous surfactants (i.e., sphingomyelins, bile salts, and sterols) [198]. Even though these nanoparticles present high biocompatibility, bioavailability and physical stability, the common undesirable disadvantages are particle growth, arbitrary gelation tendency, and unpredicted

Cyclodextrins (1–2 nm) [194] are a group of structurally related natural products formed from the bacterial digestion of cellulose. Cyclodextrins are cyclic oligosaccharides consisting of (α-1,4)-linked α-D-glucopyranose units with a lipophilic central cavity and a hydrophilic outer surface [203]. The hydroxyl functions are orientated to the exterior, while the central cavity is wrinkled by the skeletal carbons and ethereal oxygens of the glucose residues. Natural cyclodextrins are classified by the number of glucopyranose units in α-(six units), β-(seven units), and γ-(eight units) [204]. Recently, cyclodextrins containing from 9 to 13 glucopyranose units have been reported. These carriers are useful for increasing the solubility and the stability of poorly watersoluble drugs. Moreover, cyclodextrins can be derivatized with hydroxypropyl, methyl, and sulfobutyl-ether additives [203]. So, drugs can be allocated into the cavity *via* van

Liposomes (30–2000 nm) [194] are phospholipid vesicles containing one or more concentric lipid bilayers enclosing an aqueous space. Liposomes can assemble spontaneously by hydration of lipid-derivate powder (i.e., cholesterol, glycolipids, sphingolipids, long chain fatty acids, and membrane proteins) in aqueous buffer [195]. Due to their ability to capture hydrophilic and lipophilic substances, in the aqueous space or into the lipid bilayer membrane, respectively, they can protect

Micelles (5–100 nm) are colloidal dispersions, consisting of amphiphilic copolymers (i.e., PEG, PLGA, and PCL) that assemble naturally in water at a specific concentration and temperature [207]. When polymer concentration is greater than the critical micelle concentration, micelles start to be assembled: hydrophobic fragments of amphiphilic reagents form the core, whereas hydrophilic portion form the shells [208]. Micelles are characterized by high stability, biocompatibility, and

The use of biodegradable and biocompatible polymers allows rationalizing the design of innovative nanostructures able to encapsulate polyphenols that can cross the BBB, improving the limitations associated with conventional administrations. In this scenario, curcumin is the most studied drug candidate, due to the prominent results obtained in the animal model of neurodegenerative diseases [209–211].

**5.3 Nanotechnology as an innovative delivery system of polyphenols**

der Waals forces, hydrophobic interactions, or hydrogen bonds [205].

drugs from early inactivation, degradation, and loss [206].

ability to keep in solution poorly soluble drugs.

an oily or aqueous core, which is surrounded by a thin polymer membrane [197, 198]. The cavity can contain the drug in liquid or solid form. Furthermore, the medication can be carried on nanovector surface or absorbed in the polymeric

*DOI: http://dx.doi.org/10.5772/intechopen.89575*

membrane [198–200].

#### *Polyphenols as Potential Therapeutic Drugs in Neurodegeneration DOI: http://dx.doi.org/10.5772/intechopen.89575*

*Neuroprotection - New Approaches and Prospects*

and micelles (**Figure 7**).

**5.2 Nanotechnology-based delivery system: An innovative strategy**

Nanotechnology is a new branch of science involving the formulation, synthesis, and characterization of small particles, with diameters ranging from 1 to 1000 nm [186], which become key players in innovative drug delivery and cell targeting. Recent studies suggest that nanoparticle-based delivery systems represent innovative and promising approaches to improve drug solubility, prevent aciddegradation, minimize toxic side effects, and increase blood availability [187, 188]. Considering the low bioavailability of polyphenols, different strategies have been developed in order to enhance their chemical stability, solubility, and cellmembrane permeability. These goals have been achieved by adding chemical agents to preserve the structure [189], enzyme inhibitors to contrast biotransformation [190], and lipids or proteins to increase the solubility [191]. Recently, nanoparticlemediated delivery system is emerged as the most promising approach. Using biodegradable and biocompatible polymers, polyphenols can be encapsulated in different nanostructures and then possibly administrated *via* intravenous, transdermal, nasal, and oral route. As describe above, this aspect is fundamental in neurological diseases, in which polyphenols must cross the BBB, with the opportune grade of lipophilicity [162, 192, 193] and reach the brain tissue in sufficient quantities for therapeutic use. These new delivery systems are represented by nanospheres, nanocapsules, nanoemulsions, solid lipid nanoparticles, cyclodextrins, liposomes,

Nanospheres (10–200 nm) [194] are homogeneous solid matrix particles characterized by a hydrophobic portion in the inner part and hydrophilic chains anchored on the surface. In nanospheres, the drug is dissolved, entrapped, encapsulated, or attached to the matrix of the polymer, so protected from chemical and enzymatic degradation. Various kinds of polymers are used to prepare nanospheres: polylactic acid (PLA), poly-glycolic acid (PGA), poly-lactic-co-glycolic acid (PLGA), polyethylene glycol (PEG), poly ε-caprolactone (PCL), and chitosan (CS) [195, 196].

*Schematic representation of nanosized delivery systems for polyphenols. Nanoparticles can enhance polyphenol bioavailability, enhancing their adsorption across intestinal epithelium, increasing their concentration in the* 

*bloodstream, and improving their ability to cross the blood-brain barrier.*

**50**

**Figure 7.**

Nanocapsules (10–1000 nm) have a similar chemical composition but comprise an oily or aqueous core, which is surrounded by a thin polymer membrane [197, 198]. The cavity can contain the drug in liquid or solid form. Furthermore, the medication can be carried on nanovector surface or absorbed in the polymeric membrane [198–200].

Nanoemulsions are oil-in-water or water-in-oil emulsions stabilized by one or more surfactants (i.e., phosphatidylcholine, sodium deoxycholate, sorbitan monolaurate, poloxamers, sodium dodecyl sulfate, and poly(ethylene glycol)) delivered in droplets of small dimensions (100–300 nm) [191]. The strategy allows having a higher surface area and a long-term chemical and physical stability [201, 202]. Nanoemulsions represent an innovative formulation to deliver polyphenols directly into the brain through the intranasal route. In fact, mucoadesive polymers, such as CS, can be added to slow down nasal clearance [191].

Solid lipid nanoparticles (50–1000 nm) [194] are composed of high melting point lipid, organized in a solid core, coated by aqueous surfactants (i.e., sphingomyelins, bile salts, and sterols) [198]. Even though these nanoparticles present high biocompatibility, bioavailability and physical stability, the common undesirable disadvantages are particle growth, arbitrary gelation tendency, and unpredicted dynamic of polymorphic transitions [198].

Cyclodextrins (1–2 nm) [194] are a group of structurally related natural products formed from the bacterial digestion of cellulose. Cyclodextrins are cyclic oligosaccharides consisting of (α-1,4)-linked α-D-glucopyranose units with a lipophilic central cavity and a hydrophilic outer surface [203]. The hydroxyl functions are orientated to the exterior, while the central cavity is wrinkled by the skeletal carbons and ethereal oxygens of the glucose residues. Natural cyclodextrins are classified by the number of glucopyranose units in α-(six units), β-(seven units), and γ-(eight units) [204]. Recently, cyclodextrins containing from 9 to 13 glucopyranose units have been reported. These carriers are useful for increasing the solubility and the stability of poorly watersoluble drugs. Moreover, cyclodextrins can be derivatized with hydroxypropyl, methyl, and sulfobutyl-ether additives [203]. So, drugs can be allocated into the cavity *via* van der Waals forces, hydrophobic interactions, or hydrogen bonds [205].

Liposomes (30–2000 nm) [194] are phospholipid vesicles containing one or more concentric lipid bilayers enclosing an aqueous space. Liposomes can assemble spontaneously by hydration of lipid-derivate powder (i.e., cholesterol, glycolipids, sphingolipids, long chain fatty acids, and membrane proteins) in aqueous buffer [195]. Due to their ability to capture hydrophilic and lipophilic substances, in the aqueous space or into the lipid bilayer membrane, respectively, they can protect drugs from early inactivation, degradation, and loss [206].

Micelles (5–100 nm) are colloidal dispersions, consisting of amphiphilic copolymers (i.e., PEG, PLGA, and PCL) that assemble naturally in water at a specific concentration and temperature [207]. When polymer concentration is greater than the critical micelle concentration, micelles start to be assembled: hydrophobic fragments of amphiphilic reagents form the core, whereas hydrophilic portion form the shells [208]. Micelles are characterized by high stability, biocompatibility, and ability to keep in solution poorly soluble drugs.

#### **5.3 Nanotechnology as an innovative delivery system of polyphenols**

The use of biodegradable and biocompatible polymers allows rationalizing the design of innovative nanostructures able to encapsulate polyphenols that can cross the BBB, improving the limitations associated with conventional administrations. In this scenario, curcumin is the most studied drug candidate, due to the prominent results obtained in the animal model of neurodegenerative diseases [209–211].

In fact, the efficacy of curcumin is so far limited by the poor aqueous solubility, low adsorption in the gastrointestinal tract, and rapid metabolism. Nanosphere of PGLA containing curcumin can be the right strategy for crossing BBB. Recent studies indicated how curcumin-PGLA nanoparticles can interfere with Aβ aggregation and improve the brain self-repair mechanism, increasing the neural stem cell proliferation and neuronal differentiation [212]. In the same way, liposomes loaded with curcumin can efficiently inhibit the *in vitro* formation of Aβ fibrils and deposition in the brain [213]. Curcumin-solid lipid nanoparticles seem to be effective for MD and central oxidative stress [214]. In addition, curcumin and piperine co-loaded glycerol mono-oleate nanoparticles can interfere with Syn aggregation, reducing oxidative damage and apoptosis [215]. Curcumin was also taken in consideration for intranasal delivery to the central nervous system by nanoemulsions. In the presence of CS, nanoemulsions of curcumin (added in the oil phase) can effectively cross the mucosa without showing cytotoxicity [209].

Another good candidate is resveratrol. It is known for its ability to induce the degradation of APP and to remove Aβ [216]. But, due to its rapid and extensive metabolism, resveratrol is subjected to a *person-to-person* bioavailability. PEG-PCL and PGLA nanoparticles loaded with resveratrol let a controlled release profile of the drug, essential for prolonging its plasmatic level and the antioxidant activity [217, 218]. A promising approach is the oil-in-water nanoemulsion [219]. Adding Vitamin E and other surfactants, this formulation can reach the brain *via* the nasal route, with encouraging efficacy [220]. Furthermore, the co-encapsulation of curcumin and resveratrol (1:1 weight ratio) in mucoadhesive nanoemulsions protects the active substances from degradation and preserves their antioxidant properties. Notably, *in vivo* quantification in animal brain indicated an increase of the amount of the two polyphenols after 6 hours [221]. Unfortunately, these systems have not yet reached clinical trials, but the results accumulated so far encourage new original therapeutic approaches.
