Critical Review of Alcohol, Alcoholism and the Withdrawal Symptoms-III. An Introduction to Nanoparticles and their Applications in Alcoholism Treatment
Alcoholism is a complex heterogeneous disease with many contributing factors that may vary from person to person, and are known to have a major impact on treatment outcome. Thus, a single treatment strategy may not work for everyone, stressing an urgent need to develop personalized treatments based on the person's genetic and environmental factors. Recent advancements in nanotechnology have allowed construction of unique Nanoparticles (NPs) having potentials for personalized treatments by: (i) Delivering Therapeutic Drugs (TDs) to specific sites, (ii) Releasing TDs on-demand by internal or external cues, and (iii) Serving as vectors for transfection of cDNA-plasmids into the host's gene to increase the gene expression and/or siRNA to inhibit the gene expression.
There are substantial, but not compelling evidence for application of Engineered NPs (ENPs) on screening and treatment of alcoholism. The key factor that confers the ENPs their unique therapeutic potency is that, irrespective of differences in their composition, ENPs exhibit some common unique physicochemical properties (such as high surface area to volume ratio, high surface reactivity that is inversely related to the size, and unique electronic, optical and magnetic properties) not found in bulk particles. The therapeutic potency/toxicity ratio of an ENP may determine its therapeutic index, possibly because the physicochemical characteristics that confer the ENPs their unique properties are also responsible for their toxicity. Therefore, the aims of this review are to discuss (1) The ENPs' structure, physicochemical properties, beneficial properties and toxicity, and (2) Their relevance in development if individualized treatment against alcoholism.
Nanoparticles, Clusters, Nanotechnology, Nanotoxicology, Bulk particles, Surface molecules, Surface area and volume ratio, Metals, Semiconductors, Magnetism, Dendrimers, Isotropic, Anisotropic, Precautionary principle
Alcoholism is a chronic, multifaceted disorder in which the gene-environment interactions play a key role in the disease's etiology [1,2]. The consequences of alcohol abuse that results in development of alcoholism have been attributed to the alcohol's toxic effects on the brain . Figure 1 shows several neurobiological circuits that are central to different stages of addiction [4-11] (Figure 1).
Different neurotransmitter systems targeted by alcohol are GABA [12,13], glutamate , serotonin , nor epinephrine , neuropeptide Y , vasopressin , adenosine  and Dopamine (DA) [2,20-22]. Because of (i) The mechanistic complexities of alcoholism  and (ii) Diverse interaction of genetically differently people to their environment, the current common therapy consisting of a combination of psychological, behavioral and pharmacological approaches exhibits high individual variability in treatment outcomes including high incidence of relapse. Therefore development of an individualized, patient-specific treatment strategy is highly desirable.
Earlier attempts to design patient-specific treatment have failed because of lack of technology to establish alcoholism subtypes, inability to use the markers for identifying endophenotypes and a lack of diverse pharmacologic agents with proven efficacy at improving particular drinking outcomes [24-26]. Recent developments in genetic screening and transfection techniquesh as resolved some of the gaps listed above.
(i) Genetic analysis may determine whether an alcohol-naive person possess the genetic vulnerabilities associated with the risk of developing alcoholism.
(ii) The diagnose techniques may decipher cell-signaling abnormalities that have already occurred in alcohol abusers.
(iv) Although these techniques may allow development of individualized therapy for alcoholism, technology to integrate all of the therapeutic components listed above is lacking. Recent development of novel Engineered Nanoparticles (ENPs) having unique electronic, physicochemical and biological properties bring hope to the development of patient-centric individual treatment of alcoholism and other addiction disorders.
ENP are < 100 nm at least in one dimension and behaves as a whole unit possessing unique electronic, physicochemical and biological properties distinct from those in bulk particles. As the ENPs become smaller, the proportion of atoms on the surface increases, thus they exhibit size- and shape-dependent properties such as electron confinement (transition from classic mechanics to quantum mechanics), metal to semi-conductor transition, an increase in mechanical adhesion and capillary forces, a drop in melting point, an increase in tunneling current, a blue shift in optical properties, and ferromagnetic to super paramagnetic shift . The size-dependent unique properties of NPs are exploited by the industry to design and market new electronic, medicinal (diagnostics, prophylaxis, therapeutics and site-directed drug-transport), environmental, cosmetic, and food products that are growing every day . Different ENPs are being designed and tested for screening and treatment of alcoholism and other substance addiction [31,32]. Unfortunately, the very properties responsible for ENPs' commercial application also exponentially increase their toxicity and adverse effects. As ENPs becomes smaller, its surface reactivity and toxicity increase [33,34]. The therapeutic potency/toxicity ratio may determine the therapeutic index of ENPs. Therefore, it is important to understand possible relationship between the ENPs structure and properties to develop safe and effective medicinal products including novel treatment strategies for treatment of alcoholism and development of personalized treatments. The aim of this review article is to discuss the ENPs' structural classification, physicochemical properties, surface functionalization - a critical step for NP functionality, nanoparticles applications, toxicity and risk assessment and applications in alcoholism treatment.
Structure of Nanoparticles
ENPs are the simplest form of diverse structures (Figure 2) with sizes in 1 nm to 100 nm range.
According to their shape, ENPs are classified as 0, 1, 2 and 3 dimensional particles [35,36]. The '0' Dimensional (0D) ENPs are nanospheres and nanoclusters less than 100 nm in all dimensions (electrons are fully confined). The '1' Dimensional (1D) ENPs such as nanotubes, nano-rods and nano-fibers are less than 100 nm in at least two dimensions (electrons are both confined and delocalized). The '2' Dimension (2D) ENPs such as graphene, molybdenum disulfide and single-layer crystal composed of germanium are less than 100 nm in at least one dimensions (electrons are confined and delocalized both), while '3' Dimensional (3D) materials such as dispersions of nanoparticles, bundles of nanowires, and nanotubes as well as multi-nanolayers that are not confined to the nanoscale in any dimension (electrons are delocalized). Structurally, ENPs can be classified as following:
• Metal nanoparticles (gold, copper, silicon, iron, etc.) are widely used in catalysis, electronics, sensors, photonics, environmental remediation and medicine. Porous silicon nanoparticles contain microscopic reservoirs that can hold and protect sensitive drugs in a pH-sensitive manner. Acidic pH disrupts the drug-nanoparticle binding, thus releasing the drug load.
• Polymeric nanoparticles are prepared from synthetic polymers such as poly(2-hydroxy ethyl methacrylate), poly(N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), polyacrylamide or natural polymers such as gums (Ex. Acacia, Guar, etc.), chitosan, gelatin and sodium alginate .
• Biochemical nanoparticles such as DNA, proteins and poly-amino acids such as poly-L-lysine and ploy-L-serine are synthesized from biological precursors. DNA nanoparticles are three strands of DNA with a lipid and functional molecule attached to its ends. In water solution, the combination of hydrophilic DNA and lipophilic lipids causes the units to self-assemble into hollow spheres consisting of multiple layers of DNA, lipid and cargo.
• Carbon Nanotubes (CNTs) are formed from rolling-up graphite sheets. Depending on the direction of hexagons, carbon nanotubes can exhibit metallic or semi-conductor properties. CNTs are twice as strong as steel, but weigh many times less. In 1996, a new form of carbon - the Buckminster fullerene was discovered that looks like a nanometer-sized soccer ball made from 60 carbon atoms [33,37].
• Nanoclays are layers of mineral silicates nanoparticles. Organically-modified or hybrid organic-inorganic nanomaterials have potential uses in polymer nanocomposites, as rheological modifiers, gas absorbents and drug delivery carriers.
Physicochemical Properties of Nanoparticles
As the ENPs get smaller, there is a gradual size-dependent transition in their physical (increase in hardness, strength and ductless), optical (color change and surface Plasmon) and surface related (greater surface area to volume ratio) properties [33,38]. Below certain size (usually < 10 nm), the electronic properties of nanoparticles switch from classical mechanics to quantum mechanics . The goal of this sub-sections is to discuss (i) Size-dependent properties common to all chemically diverse ENPs and (ii) Chemical-composition related distinct properties.
Common properties of all ENPs
All ENPs, irrespective of their chemistry, exhibit comparable surface reactivity, thermodynamics, and electronic and mechanical properties described below.
The surface reactivity
ENPs exhibit exceptionally high Surface Area to Volume (S/V) ratio compared to their bulk counterparts. As the ENPs' size decreases, the percentage of atoms at the surface increases relative to the core atoms, resulting in a decrease in the ENP's melting point and an increase in the (valance-conduction) band energy gap, thus many metals may become semiconductor at nanometer level [40,41]. To understand the ENP's surface effects, it is important to understand the characteristics of the core and surface atoms (Figure 3). The core atoms form stable covalent bonds with the nearest neighboring atoms. The surface atoms contain non-bonded electrons, exhibiting greater uncompensated spin. Therefore, the surface atoms exhibit relatively lower Nearest Neighbor (NN) number (Figure 3) and relatively greater free energy, anisotropy, bond defects and surface strain. These properties confer the surface atoms many unique physicochemical characteristics not present in the core atoms.
Size dependent thermodynamic properties
The Gibbs free energy of bulk particles (Gb) is defined as Gb (p, T) = H - TS where H is change in enthalpy, T is temperature and S is the entropy . Surface atoms have minuscule role in determining the bulk particle's Gb. In ENPs, the surface free energy begins to dominate the core free energy, thus size becomes the key determinant of their thermodynamic properties. For ENPs, Gsurface is inversely related to the Diameter (D). Table 1 shows examples of surface free energy of different nanoparticles and corresponding bulk particles. In all cases, the free energy in bulk particles was lower than that in nanoparticles. Nanoparticles capped with functional groups or embedded in another particle exhibited lower free energy. This suggests that the free surface energy of nanoparticles also depends upon their functionalization and environment (Table 1).
In bulk particles, Electrons (e-), bound with a positively charged Electron-Hole (e-h+ complex), are distributed in discrete energy bands called occupied orbital's [43-45]. The number of electrons in Valance Orbital or Highest Occupied Molecular Orbital (HOMO) determines the electrical properties of an atom . When an electron in HOMO is excited by absorbing energy (light or heat), it separates from the 'hole' and jump into the conduction band, resulting in creation of a positively charged 'hole' in HOMO [47,48]. The newly formed 'hole' attracts neighboring electron, resulting in propagation of a positively charged hole-current in HOMO, moving opposite to the direction of the electron current in the conduction bands . In metals, since the HOMO and LUMO overlap, electrons from both HOMO and LUMO can bind the 'hole' (Figure 4).
Unlike the bulk particles, nanoparticles less than 100 nm gets quantized and acquire wave-particle duality [49,50]. Electrons are found within certain energy-states called the Density of States (DOS). Electrons cannot jump from HOMO to the Lowest Unoccupied Molecular Orbital (LUMO) if the DOS is occupied (the Pauli Exclusion Principle). The DOS of a system describes the number of states at each energy level that are available for occupation by electrons. In metals, the LUMO, HOMO and the Fermi level (Ef) overlap, thus electrons nearest to the Fermi level cross to the conduction band. In semi-conductors, there is an energy gap between HOMO and LUMO with the Fermi level situated in between (at 0 K, Ef = E gap/2). The electrons in HOMO must be energized to the Ef for its translocation from HOMO to LUMO. In insulators, a large band gap prevents electron transfer (Figure 4). For bulk particles, the band structure is intrinsic property of an atom that is independent of the particles' size or shape. For nanoparticles, the band structure is influenced by the particles' size and shape. The band structure in the ENPs is strongly influenced by their size and shape. Smaller nanoparticles (less than 10 nm or smaller than the electron wavelength) confine the motion of randomly moving electrons to a specific energy level (discreteness), a process known as quantum confinement. As the ENPs become smaller, a decrease in confining dimensions makes the energy levels discrete, resulting in an increase or widening up of the band-gap energy. Since the band-gap energy and wavelength are inversely related to each other, the wavelength decreases, resulting in emission of blue radiation by the nanoparticles as opposed to red radiation emitted by the bulk particles.
Nanoparticles, along with exhibiting size-dependent increase in electronic band-gap, also exhibit a size-dependent increase in Optical Band-Gap (Og), a level of energy that activates the electron-hole complex, but is not able to free the electron for conduction . The electron then returns to its original state by emitting photons in the process. The energy of the emission photon is equal to the Og energy . A decrease in semiconductor particle size from bulk level (> 500 nm) to nano-level (< 10 nm) resulted in a drop in absorption from 200 nm to 450 nm . Thus, as the particle size decreases, a shift in the absorption towards lower wavelengths occurs possibly because of a size-dependent increase in the Og. Absorption occurs at higher energies, resulting in a shift towards shorter wavelengths.
When the size of a nanoparticles approaches or become smaller than 10 nm, they acquire physical properties (such as friction, hardness, elastic modulus, fracture toughness, scratch resistance, fatigue strength, etc.) different from their bulk counterparts [54-59]. Mechanical properties may modulate the molecular forces that drive the molecular interaction, thermodynamic properties and interface of the nanoparticles with the liquid or other particles . Biological systems such as proteins and DNA create interfaces with the surrounding fluids that may govern their interactions with ENPs. Interaction of cell membranes with ENPs is governed by the mechanical properties, such as friction, adhesion or elasticity, of both the cells and the materials since cells dynamically react to the mechanical cues . Therefore, an understanding of the mechanical properties of ENPs is essential to bring nanomedicine from bench to clinical applications.
Particle-specific physicochemical properties
Dendrimers are hyper-branched synthetic polymers that can be engineered into well-defined structures for various biological and pharmacological functions (Figure 5). Dendrimers contain a Core group (C), branching Generations (G1 to G4) and end-groups that can be functionalized with functional groups such as an Antibody (Ab) or another dendrimer containing a fluorescing group. During synthesis, as dendrimers grow in size, different generations begin to show distinct features that are amplified with increasing generations [61,62]. Some of the unique properties of dendrimers are described below.
Intrinsic viscosity (η)
Intrinsic viscosity characterizes the frictional contribution of polymers in dilute solutions . Dendrimers exhibit a size-dependent biphasic change in η values: the values increase as the dendrimer size increased from G0 to G4, then, further increase in the dendrimer size decreased the η values [64,65]. Unlike the η values, the hydrodynamic radius of the dendrimers increased linearly as their size increased .
The dendrite-box concept
The branched structure of dendrimers contains empty and defined-sized spaces surrounded by either hydrophilic or hydrophobic environment. These spaces can accept and store guest particles. The hydrophobic particles accumulate in the sites surrounded by a hydrophobic surface, while hydrophilic particles accumulate in sites surrounded by the hydrophilic environment. Once entrapped, the particles are protected from the external environment. The entrapment-space is known as the dendrimer box .
One of the outstanding properties of dendrimers is their ability to mimic biological particles, especially globular proteins such as insulin (3G dendrimer), cytochrome (4G dendrimer), and hemoglobin (5G dendrimer) [67-70]. Dendrimers also mimic histone clusters, thus they make stable complexes with the DNA and enhance gene expression [71,72]. Like proteins, dendrimers may respond to many external stimuli and adapt a tight-packed (resembling native proteins) or extended (resembling denatured proteins) conformation [73-75].
Host-guest complex formation
Properties of carbon nanotubes - metals or semiconductors
CNTs are formed by folding of a hexagonal graphene sheet consisting of unit cells . Figure 6A-i shows three different patterns of graphene sheet folding, resulting in formation of three electronically different nanotubes. When n = m (like 5,5 or 6,6), the nanotubes belong to the armchair family (Figure 6A-ia), whereas when n = 0 or m = 0, they are called zigzag tubes (Figure 6A-ib). All other combinations of n and m are called chiral nanotubes (Figure 6A-ic).
The chiral angle ranges from 0° (zigzag) to 30° (armchair). The armchair CNTs exhibit metallic properties, while the zigzag and chiral CNTs can be semiconductor (containing a band gap between HOMO and LUMO) if n - m is a multiple of 3, otherwise they are metallic [79-84]. Band gaps of 0.4 to > 1 eV have been reported for SWNTs (Figure 6B).
Iron oxide nanoparticles, in addition to size-dependent surface characteristics, also exhibit size-dependent electron confinement and a transition from ferromagnetic (a high susceptibility to magnetization, the strength of which depends on that of the applied magnetizing field, and that may persist after removal of the applied) to super-paramagnetic (magnetization can randomly flip direction under the influence of temperature) field [85-88]. As shown in Figure 7, ferromagnetic bulk particles are multi-domain particles in which each domain's local magnetization is saturated but not parallel to other domains' local magnetization.
In the presence of a magnetic field, all domains exhibit parallel spin, resulting in development of magnetic field. As the particle size decreases to below 100 nm, transition from a Multi-Domain (MD) state to pseudo Single-Domain (mixture of multi-domain and single-domain properties, SSD), Single-Domain Para Magnetic (disordered atoms or electrons, SD-PM), Single-Domain Super Para Magnetic (spin reversal and loss of magnetic moment, SD-SPM), Single-Domain Sub-Super Para Magnetic (very high magnetic anisotropy showing freezing behavior, SD-SSPM) states may occur (Figure 7). The paramagnetic nanoparticles can be used in bio-imaging, while the super para magnetic nanoparticles can be used for separation processes in biochemistry.
Surface Functionalization - A Critical Step for NP Functionality
Bare (as synthesized) nanoparticles are nonfunctional because they agglomerate rapidly due to van der Waals force , Zeta (ς) potential and/or the pH (close to the nanoparticles' IEP for 'zero charge') of the dispersion liquid. A ς values greater than + 25 mV or less than - 25 mV typically indicates a stable colloid because of charge repulsion between two ENPs. Surface functionalization with diverse ligands stabilizes ENPs and confer them specific functionality (Figure 8).
Studies have shown that mono- or poly-thiol ligands such as thiolated polyethylene glycol (x-PEG-SH where x is different reactive groups for attaching a functional group such as medicine, antibody, fluorescent groups, etc.) form stronger bond with gold and silver colloid's surface, thus stabilizing the suspension [57,90-94]. Non-colloid nanoparticles can be chemically attached to Poly-L-Lysine (PLL), Poly-L-Glycone (PLG) or PEG for stabilization (Figure 7). The PEGylated ENPs, for performing specific functions, require specific end groups (-NH2, -COOH, -OH, -N3 and/or –SH) that interact, via either covalent or non-covalently binding, with drugs, imaging dyes, antibodies of specific proteins (Figure 9).
For achieving intracellular drug-release, acid- or enzyme-cleavable linkers that remain stable at physiological pH, but disintegrate at (i) pH less than 6.0 or (ii) in the presence of substrates, can be used [95-97]. For cancer treatment, the cathepsin B substrates such as Gly-Phe-Leu-Gly (GFLG) are used as the linker. Since cathepsin B is highly over expressed in cancer cells, the cathepsin B substrate-linkers are disintegrated, resulting in on-site release of drugs and/or dyes [98,99]. Metal nanoparticles can also be functionalized with tunable switches  in which multiple components are not chemically bonded, but cannot dissociate because of their topological linkage. Many studies have reported DNA catenane systems with potential use in DNA topological labeling [101-104]. Functionalized nanoparticles have diverse applications described below.
NPs play a central role in recent technological advances in the areas of disease diagnosis, drug design and drug delivery [105,106]. Multi-model magnetic nanoparticles contrast agents such as Super Paramagnetic Iron Oxide Nanoparticles (SPION) are anticipated to lead the way to advancements in understanding biological processes at the molecular level . NPs improve efficiency of drug delivery by enhancing their bioavailability and reducing side-effects of a drug, and play an important role in development of bioassays, biosensors and biomedical devices, and bio fuel cells. Nano-chips may be a new paradigm for total chemical analysis systems [108,109]. Nanorobotics and nano-manipulation technologies will allow moving and manipulating nanoscale materials and nanoscale robotics . Table 2 lists current applications of NPs in biology and medicine.
Application of nanoparticles in alcoholism treatment
Recently, nanoparticles-based therapeutic agents have acquired prominence in diagnosis and treatment of diseases including drug addiction and alcoholism, although they are not yet approved for clinical use. A review of literature provided substantial evidence for possible application of nanoparticles in diagnosis and treatment of addiction. Results from selected studies are presented below.
Alcohol Oxidase (AOx) functionalized Gold Nanoparticles (AuNPs) for development of alcohol biosensor
Chinnadayyala, et al.  have designed a simple AuNP-based biosensor for sensitive detection of alcohol. They synthesized AuNP using AOx protein in alkaline (pH 8.5) condition with simultaneous stabilization of the nanoparticles on the AOx protein surface. The AuNPs-AOx conjugate was encapsulated with Polyaniline (PANI) that was stabilized on a Glassy Carbon Electrode (GCE) by chitosan-nafion mixture (Figure 10). The biosensor was then utilized for detection of alcohol ampere metrically using H2O2 as redox indicator at +0.6 V. The fabricated bio-electrode was successfully used for the selective determination of alcohol in beverage samples (Figure 10).
Gómez-Anquela, et al.  used AuNPs capped with thiotic acid to coordinate with the Zn (II) present in the catalytic center of Alcohol Dehydrogenase (ADH). The complex, in combination with Azure A (the NADH oxidation molecular catalyst) was electro grafted onto carbon screen-printed electrodes (Figure 11) that were efficient ethanol biosensor. The final bio-sensing device was highly efficient in ethanol oxidation with low over potential of -0.25 V with a detection limit of 0.14 ± 0.01 µM and a stable response for more than one month. Luo, et al.  constructed a disposable blood alcohol biosensor prepared by immobilizing Alcohol Dehydrogenase (ADH) and Nicotinamide Adenine Dinucleotide (NADq) coated by Nafion combined with AuNPs onto the surface of Meldola's blue modified screen-printed electrodes. The sensor was capable of detecting blood alcohol concentration in laboratory medicine and forensic medicine samples.
Anti-oxidative enzyme nano-complex enhance alcohol degradation
Luo, et al.  constructed a robust enzyme nano-complex (Figure 12) by assembling or conjugating selected enzymes (anti-oxidative enzymes) with synergic or complementary functions in a nano-complex, followed by its encapsulation within a cross-linked polymer nanocapsule.
Exemplified by the synthesis of a triple-enzyme nanocomplex. Inhibitors for each enzyme were respectively conjugated to a single-stranded DNA with a designed sequence. Complementary assembly of the DNA molecules forms a DNA-inhibitor scaffold of a triple-enzyme nanocomplex. Subsequent in situ polymerization resulted in a thin layer of polymer network around each nanocomplex, and the formation of nanocapsules containing a triple-enzyme core and a permeable shell (step II). Then, removal of the DNA-inhibitor scaffolds creates a highly robust enzyme nanocomplex (step III). The nanocomplexes can be further functionalized to acquire both desired surface properties and targeting capability. This study showed that the nano-complex was more effective than the mixture of enzymes for Blood Alcohol Concentration (BAC) and Alanine Amino Transferase (ALT) reduction (Figure 13). The unique n(AOx-Cat) architecture enabled effective removal of toxic H2O2 and prevented the AOx inactivation . They showed that the H2O2 degradation regenerates molecular oxygen that accelerates alcohol oxidation kinetics and leading to more significant BAC reduction. Although alcohol oxidation generates another toxic intermediate, acetaldehyde, an effective ALT reduction will removal of acetaldehyde .
Enhancing the drug's bioavailability
Vyas, et al.  and Emerich, et al.  have shown that Nano-Functionalized Therapeutic Drugs (NFTDs) exhibited greater bioavailability than corresponding free therapeutic drugs possibly by reducing their biodegradation and/or increasing their intracellular accumulation. Yin, et al.  synthesized a hydrolysable cross-linked poly (ethylene glycol-graft-methyl methacrylate) di-block nano-polymer carriers for naltrexone that improved its bioavailability and site-directed release, resulting in reduced side effects. Banks, et al.  synthesized a nano-6-β-naltrexol, the major active metabolite of naltrexone, and administered it via a transdermal patch for treatment of alcoholism. They designed a Micro Needle (MN) skin permeation enhancement system that provided a 3.6 fold enhancement in steady state plasma concentration in vivo.
Engineered nanoparticles facilitate targeted delivery of therapeutic agents
Sharma, et al.  have shown that microinjection of Glial-Derived Neurotrophic Factor (GDNF)-conjugated nanoparticles into the rat striatum and nucleus accumbens is able to block self-administration of cocaine in rats. Green-Sadan, et al.  showed that transplantation of a GDNF-expressing astrocyte cell line into the striatum and nucleus accumbens attenuated cocaine-seeking behavior in Sprague-Dawley rats. Then, they developed a nano-GDNF system as a safe and effective method for introducing GDNF into the brain. An administration of GDNF-conjugated nanoparticles microinjected into the striatum and nucleus accumbens suppressed cocaine self-administration in rats. Furthermore, a cocaine dose response demonstrated that decreased lever response in rats that received GDNF-conjugated nanoparticles persisted after substitution with different cocaine doses. Carnicella, et al.  either an activation of the GDNF pathway or direct administration of a nano-GDNF formulation in the Ventral Tegmental Area (VTA) reduces moderate alcohol intake in a rat operant self-administration paradigm (receiving a 20% ethanol solution in an intermittent-access two-bottle choice drinking paradigm). They showed that microinjection of GDNF into the VTA 10 min before the beginning of an ethanol-drinking session.
(i) Significantly reduced ethanol intake and preference, but did not affect total fluid intake and
(ii) Decreased both the first bout of excessive ethanol intake at the beginning of the session, and the later intake occurring during the dark cycle.
These data suggest that GDNF-conjugated nanoparticles may serve as a novel potential treatment for drug, including alcohol, addiction. Rao, et al.  showed that, in addition to the GDNF, upregulation of Glutamate Transporter-1 (GLT1) by ceftriaxone (a beta-lactam antibiotic) effectively attenuated drug-seeking and drug-consumption behavior in rodent models. However, ceftriaxone treatment was not effective in vivo because of poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. They synthesized a nano-formulated GLT1 activators that selectively permeated the blood brain barrier and accumulated into the brain.
Receptor modulation by hydrated fullerenes
Tykhomyrov, et al.  have reported a protective effects of an aqueous solutions of hydrated C60 fullerenes (C60HyFn) with C60 concentration of C60HyFn on the CNS, which is above all due to its antioxidant activity, which results in the phenomenon of advanced viability of astroglial cells. On the other hand, there are some observations indicating possibilities of indirect C60HyFn involvement in the metabolism of some neurotransmitters. In particular, it has been previously shown that C60HyFn manifest positive influence on adrenergic, GABAergic, histaminergic and especially on serotoninergic systems that improve adaption capacity of organism to the action of various deleterious factors (http://fullwater.com.ua) . Taking into consideration the wide range of biological activity of hydrated fullerene both at molecular and physiological levels, absence of any toxicity, and effectiveness even in super-small doses, aqueous solutions of C60HyFn can be proposed as reliever of CNS dysfunctions induced by alcohol consumption and continual alcoholization.
Gold nanoparticles synthesized by plant-extract attenuate alcohol drinking and withdrawal symptoms in alcohol preferring rats
AuNPs are commonly synthesized using the traditional reduction of chloroauric acid (H[AuCl4]) by reducing agent NaBH4, N2H2, NH2OH or (CH3)2NH•BH3 [126,127] that required dispersants (such as polyethylene glycol) to prevent aggregation and complex surface functionalization for desired biological activity. Recent studies have proposed an alternative reduction method using plant extracts and gum for synthesis of AuNPs [128-134]. This process is also known as 'green chemistry for synthesis of nanoparticles' in which reactions occur at ambient temperatures (high temperatures may yield uniform size particles), neutral pH, low costs and environmentally friendly fashion . AuNPs synthesized using plant extracts demonstrated procedure-dependent variations in size (Figure 14), low protein adsorption (low corona formation), poor aggregation into larger particles, and higher stability at physiological condition compared to chemical reduction and citrate capped nanoparticles . AuNP size can be controlled by controlling temperature and/or the incubation composition.
A recent study from our laboratory (unpublished data) compared the effects of four AuNP preparations (KG@AuNP synthesized by kudzu extract and plant gum (7 to 10 mn, Figure 10), K@AuNP synthesized by kudzu extract alone, K + G + AuNPPEG that is a mixture composed of traditionally synthesized AuNP stabilized by PEG, kudzu extract and gum solution and AuNPPEG alone) on alcohol preference [(alcohol intake/total fluid intake) × 100] and the severity of the withdrawal symptoms in alcohol preferring rats. As shown in Figure 15, KG@AuNP administered rats exhibited smallest alcohol preference than K@AuNP, K + G + AuNPPEG or AuNPPEG administered rats allowed to self-administer alcohol as described previously . In addition, the severity of the withdrawal symptoms showed the following patterns: KG@AuNP rats < K@AuNP rats < K + G + AuNPPEG< AuNPPEG rats. These preliminary observations suggest that KG@AuNP (AuNP synthesized by kudzu extract and plant gum solution) protected against, while the traditionally synthesized AuNPPEG augmented the adverse effects of ethanol drinking in alcohol preferring rats. This suggests that the plant-extract synthesized AuNPs may have therapeutic potential against development of addiction in humans (Figure 15).
Smart, multifunctional nanoparticles
As discussed above, alcoholism is complex, progressive, multifaceted disorder that cannot be efficiently treated with current therapeutic approaches. Although simple functionalized ENPs, described above, provide a unique approach in addiction treatment, they lack capacity to release cargo (TDs, siRNAs and/or plasmids inserted with specific cDNAs) in spatial-, temporal- and dosage-controlled fashions, on demand. Recent progress in nanotechnology and material chemistry has allowed construction of 'smart' stimuli-driven devices that can (i) Simultaneously provide imaging, stimulation and drug delivery and (ii) Deliver the uploaded cargo on demand in selected regions and doseregime (Figure 16). The stimuli-driven NPs respond to various internal and external stimuli listed in Figure 15. The targeted release of the loaded materials to a specific site (such as a brain region) can be magnetically guided by using magnetic nanoparticles (Figure 17) [136,137]. Timed-release can be achieved using light or ultrasound cue . Further research is needed to design and validate 'smart' nanoparticles for alcoholism treatment (Figure 16 and Figure 17).
As discussed earlier, a decrease in nanoparticle size is associated with an increase in the percentage of atoms at the surface of a given material (Figure 18), leading to an increase in surface activity and acquisition of novel properties not found in bulk properties.
These unique traits of NPs are being appealed for biomedical purposes. Unfortunately, the very unique properties also enhance their intrinsic toxicity as compared to their bulk counter parts . Currently, diverse groups of pure and hybrid nanoparticles are being incorporated in household and medical products. Thus, analysis and characterization of a multitude of new materials present a real challenge, but essential to assure their safety to general public. Although numerous animal studies have evaluated the toxicity of ENPs, they did not consider appropriate particle characterization, cellular uptake mechanisms, relevant doses matrices and exposure duration [140-142]. The aim of this section is to characterize toxicity of ENPs relative to those of bulk particles.
In general, there are three basic Toxicology Principles (TP) designed for bulk particles:
1. The dose (mass-based) makes the poison (Paracelsus theory). In general, dose is defined as the mass of a chemical per unit of body weight such as g/kg body weight. From Paracelsus's time to the present, the mass-based dose has been used to determine a chemical's beneficial effects and toxicity. The mass based dose-response relationship is the key determinant of a chemical's toxicity and the risk it poses to humans and animals.
2. The biological actions of a chemical are specific to the chemical's structure. In 16th century, Ambriose Paré recognized that each chemical may exhibit unique toxicity related to its structure.
3. Humans are animals. Therefore, protection against the toxicity of agents would be impossible without the ability to study the effect of toxins in laboratory animals.
Nanoparticles defy the 1st principle, that is the mass-based dose makes the poison [143-146], since dose in terms of size (diameter/kg), surface area/kg or particle number/kg is, if not more then, at least, as important as the mass-dose in correlating with toxicity . This is because surface molecules, not the core molecules, determining the ENPs' physicochemical, biological and adverse properties. As an example, for equal mass of 5 nm, 10 nm and 100 nm AuNPs, the particle enumeration, surface area, surface activity may increase with a decrease in their size (5 nm > 10 nm > 100 nm. Since the biomedical and toxicological properties of ENPs are dependent on their size and/or surface properties, their toxicity may increase with a decrease in size or an increase in particle enumeration (Figure 19).
The plots of mass-dose against toxicity, shown in Figure 20, revealed that different sized nanoparticles yielded different slopes and ED50 values. Thus, the mass-based dose response curve may not accurately describe the ENP toxicity, a departure from bulk particle toxicity that strictly follows the classic mass-based dose dependence. Many studies have shown that the dose as particle number, surface area (nm2), surface to volume ratio and/or surface reactivity may characterize the toxicity of nanoparticles [142,148-150]. Thus, diameter-response, surface area-response and/or enumeration-response relationships may be important in determination of the ENPs' toxicity that can be used for risk assessment. The surface area is a better index than particle enumeration or mass in determining the inflammatory effects of nanoparticles (Figure 20) [143,151,152].
An important, but least studied, aspect of ENP toxicity is formation of protein corona. ENPs, when in contact with biological fluids, adsorb diverse type of biomolecules (e.g., proteins) called protein corona that dictates the ENPs interactions with the biological systems and ensuing biological fate, therapeutic efficiency and toxicity (Figure 21) .
Rapid corona formation is found to affect hemolysis, thrombocyte activation, nanoparticles uptake and endothelial cell death at an early exposure time . In general, there are two types of corona: initially soft (reversible binding) followed by hard (irreversible binding and structure change) corona . During soft corona phase, the physicochemical characteristics of corona may change spatially and temporally, resulting in highly heterogeneous population of ENP that may alter the particle's properties and toxicity. The gold and silver nano-colloidal surface interact strongly with molecules containing monothiol or disulfide groups, partially due to the existence of several possible oxidation states of gold when it is bound to ligands (oxidation states from -I to +V are known). Interestingly, bulk gold is chemically inert and poorly reach to the thiol groups . Gold or silver nanoparticles in biological samples rapidly interact with the thiol-containing proteins, fat or other chemicals, forming a soft corona that, in time, transform into hard corona . Earlier studies have shown that sulphidation decreases toxicity of silver nanoparticles [158-164]. Corona formation onto the silver nanoparticle surface (Figure 22) protects against inflammation (interleukin-1beta, interleukin-6, interleukin-18, tumor necrosis factor alpha (TNFα), and macrophage inflammatory protein 2, Granulocyte-macrophage colony-stimulating factor)  (Figure 22)
Mechanisms of nanoparticle toxicity
Humans and animals get exposed to toxins via dermal exposure, ingestion and/or inhalation. Toxin concentrations in the systemic blood depend upon (i) The route of exposure and transfer of the ingested toxin through the membrane barriers, (ii) Metabolism and excretion and (iii) Nonspecific distribution of toxins into different tissues. A very small fraction of the toxin may reach the target site. The toxin-target interaction initiates a series of mechanisms (Figure 23), resulting in an increase in oxidative stress, activation of pro-inflammatory pathways and inhibition of anti-inflammatory pathways, resulting in inflammation dysregulation and cytotoxicity such as necrosis [165-167] DNA damage [168-170] and membrane toxicity  (Figure 23).
Nanoparticles, because of their outstanding characteristics and properties, have potential for development of novel nanoparticle-based devices for individualized treatment of alcoholism. Nanoparticles exhibit (i) High surface area to volume ratio, (ii) Surface atoms influencing the particles properties and (iii) Size- and shape-dependent physicochemical properties, quantum confinement (semiconductors), surface Plasmon resonance (some metals) and super-paramagnetism (magnetic particles) [172,173]. Therefore, surface area and/or diameter may influence a nanoparticle's beneficial effects and toxicity [174,175]. Because of the NPs' unique surface and physicochemical properties, they may have therapeutic potential against alcoholism. Unfortunately, the very physicochemical properties that confer the NPs their therapeutic potency also increase their toxicity and adverse effects. Therefore, the therapeutic index of a NP preparation depends on its therapeutic potency/toxicity ratio.
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Ashok K Singh, Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA, Tel: 612-625-6782.
© 2017 Singh AK. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.