Nanoparticle as a powerful tool to penetrate the Blood-brain barrier in the treatment of Neurodegenerative disease: Focus on recent advances

 

Kalaiselvi S, Manimaran V, Damodharan N

Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur - 603203.

 

ABSTRACT:

 

 

INTRODUCTION:

For as long as a couple of decades, there has been impressive research enthusiasm for the drug movement, utilizing particulate transmission method like transporters for small along with huge atoms. A nano-particle has been utilized like a substantial way to deal with modifying, also for the betterment of pharmacokinetic plus pharmacodynamics properties about different kinds of medication particles.^[1] The nanoparticles are characterized like a solid, colloidal, submicron-sized particle in diameter ranging from 1 to 1000 nm, in which the drug transporter might be biodegradable.^[2] Many properties of nanoparticles are size-dependent.

 

The liquefying purpose of nanoparticles is reduced while the size has come to the nanometer scale.^[3] The controlled medication delivery structure is outlined to give a proper response near to the appropriate site of activity for extended timeframes also enhancing the treatment.^[4] It is not simple particles, is made out of three-component structured layers: a) Surface layer that contains an assortment of little molecules, surfactants, metal particles, and polymers. b) Shell layer contains artificially various materials from the core in entire perspectives. c) Core, it is a focal part of nanoparticles. ^[5] The neurodegenerative disease occurs with a progressive loss of a weak group of neurons that may differ among the inactive neuronal damage for the metabolic or lethal ailments. The classification of neurodegenerative disorders depends on the (a) principal clinical symptoms like dementia, parkinsonism, motor neuron dysfunction, and (b) anatomic segments of neurodegenerative diseases like extrapyramidal disorders, frontotemporal plus spinocerebellar degeneration.^[6] The amyloidosis, tauopathy, alpha synucleinopathy, and TDP-43 proteinopathy are some common neurodegenerative disorders that may affect the nervous system of about 3 crores people in the world.^[7] The Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis occur because of the misfolding and dysfunction of proteins. Also, neurodegeneration disorder occurs with impairment in the mitochondrial region, oxidative stress, and environmental conditions. Moreover, aggregation of proteins also environmental deposition varies from one disease to another disease.^[8] Comparative pathways like an aggregation of the protein, including the fibril development, also amyloid disposition are useful for linking all these kinds of disorders. The above viewpoint on pathogenicity implies an extensive kind concerning the neurodegenerative disorders that might be assorted like brain amyloidosis. This vision may produce an innovative perspicacity toward latent curative strategies that might be relevant over the broad spectrum of neurodegenerative disorders. ^[9] A significant objective in structuring nanoparticles composition is to control the dimension of the molecules, the surface also features about pharmacologically dynamic action to accomplish the site-explicit activity of the medication at the restoratively ideal rate and dosage regimen.^[10,11] A motivation behind why nanoparticles are appealing for such reasons are existing depending on their significant and unique highlights.^[12]

 

Ideal Properties of Nanoparticles:

The subsequent properties are necessary to be deliberated as a feasible strategy for delivery of drug as nanoparticles.^[13] Non-harmful,  non-provocative, biocompatible, biodegradable, immunogenic and thrombogenic properties are not present, the reticuloendothelial structure was avoided, economic and versatile production process, and easy to compile and categorize are the few properties of nanoparticles.^[14,15]

 

ADVANTAGES:

1.     Both hydrophilic and hydrophobic medication particles can be intertwined in nanoparticles. Clearance time of nanoparticles is longer, and the bioavailability of drugs can be expanded possibly by nanoparticles.

2.     Shelf stability of nanoparticles is longer, and it can be fit for being secured for a time as long as one year. So many routes such as oral, parenteral, nasal, and so forth can be utilized by the nanoparticles.

3.     Both active plus passive targeting has been accomplished through efficient managing of a dimension, regarding specific particle also surfaces properties about nanoparticles.

4.     While the drug is transported near the place of localization, the drug will be released in a controlled and sustained manner.

5.     Enhanced drug curative efficiency and decreased adverse reaction can be done by modifying the medication distribution in the organ and successive elimination of drugs.^[16,17]

 

DISADVANTAGES:

Regardless of these focal points, nanoparticles do have impediments.

1.     Handling of nanoparticles is not easy, in both wet and dry forms due to the aggregation of particles, because of its little dimension including a wide surface region.

2.     It includes higher assembling costs, which may probably lead to an expansion at the expense of formulation; also, it has low epitome proficiency.

3.     They may trigger an allergic reaction and unfavourable susceptible response.

4.     Broad utilization of poly (vinyl liquor) as stabilizer may have lethality issues.

5.     Likewise, little particles size and enormous surface area promptly bring about constrained medication loading and burst discharge.^[18,19]

 

NANOMATERIALS AND NANOPARTICLES: CLASSIFICATION AND TYPES:

 I.     Nanomaterials categorized depend upon the materials:

It is categorized into the organic, inorganic and carbon-based.

 

Organic-Based Nanomaterials:

Organic-based nanomaterials are dendrimers, micelles, liposomes, polymeric nanoparticles, and ferritin.^[20]

 

a)    Dendrimers: It has high branches, a globule shape, and particles dispersed in a uniform size. The fluorescent stains, catalysts, also more particles are attachable on many molecular hooks present in the surface of dendrimers.^[21] Either a complex system or encapsulation of drug particles is the two methods for preparing dendrimers.^[22] The dendrimers may act as a non-steroidal anti-inflammatory formulation, antimicrobial, antiviral, anticancer,function as a vector to penicillin, and a screening device for high-throughput medicine development.^[23] The receptor found on the endothelial cells in the blood-brain barrier surface is synergist with transferrin, help to cross the blood-brain barrier.^[24]

 

b)    Micelles: The manufacturing of nanostructures such as micelles either by the pure and little quantity of a surfactant or huge amphipathic mass fragments (i.e., polymer and lipids).^[25] The micelle contains a hydrocarbon chain of long fatty acids; it comprises little atoms having both hydrophilic (polar-head) and a hydrophobic (nonpolar-tail) groups.^[26] The poly-ethylene oxide is a hydrophilic segment also poly-propylene oxide, polylactic acid, and polyethers (polyesters) are hydrophobic segments have been using for the delivery of drugs. The poly (acrylonitrile butadiene acrylate) copolymer with PEO-PPO-PEO composition (Pluronic and Poloxamer) has been utilizing copolymers in the micelles.^[27]

 

c)     Liposomes: The liposomes having vesicles in the form of spherical shape comprises one or more bilayers of lipid (hydrophobic) that may be natural or artificial phospholipids, in which an enclosing of an aqueous (hydrophilic) layer on the lipid membrane. Lecithin (phosphatidylcholine) is an amphiphilic phospholipid. ^[28] The characterization of liposomes based upon the dimension and the number of bilayers. Liposomes contain unilamellar (ULV) and multilamellar (MLV) vesicles with various sizes.^[29] The liposomes have some benefits, such as biodegradable, non-harmful, and non-immunogenic. Liposomes act as an effective vector for several medications such as an antibacterial, antiviral, insulin, and antineoplastic.^[30]

 

d)    Polymeric nanoparticles: It comprises both vesicular and matrix systems made up of natural or artificial polymers. Albumin and chitosan are natural polymers. Examples are poly-butyl cyanoacrylate, polylactic acid, and polylactic-coglycolic acid.^[31] Nanocapsule utilizes non-harmful polymer, and it has a polymeric layer inside that encapsulation of the aqueous layer. The polymers are biodegradable, biocompatible, and low adverse effects than solid-lipid nanoparticles and higher durability than liposomes.^[32] There is an enhancement on the diffusion of drugs through the blood-brain barrier because of the susceptible nature of polyethylene glycol. The using of polymeric nanoparticles for neurodegenerative disorders by continuous administration can accumulate polymer that may cause unwanted toxicity.^[33]

 

Inorganic-Based Nanomaterials: It comprises gold, silver, silica, ceramic, and quantum dots.^[34]

 

a)    Gold nanoparticles: The gold nanospheres are found very first from gold nanoparticles after that nanorods, and nanoshells identified. Because of poor poisonous effects, it may cross the BBB also penetrate the CNS by a simple process.^[35] Gold nanoparticles carry curative medicine to the brain and spinal cord and treat malignant growth by the radiation method. It has many uses in both medicines and drug delivery processes such as immunoassays (detects specific proteins through their properties as antigens or antibodies), targeted drug delivery, optical imaging (recognize the appearance of DNA in a specimen), identifying aminoglycoside antimicrobials like streptomycin, gentamicin, and neomycin.^[36]

b)    Silver nanoparticles: These nanoparticles have silver in the range of one nanometer to 100 nanometers of dimension. The neem, capsicums (bell peppers), and pawpaw are employing for efficient biogenesis based on the official research information.^[37] The Ag nanoparticles with globular shape are generally utilizing one; moreover diamond, octagon shape and transparent films are also familiar.^[38] The uses of Ag nanoparticles are relevant to human medication, estimating possible efficiency, poisonous quality, and cost-effective. It is also useful for microbicidal activity against eukaryotic micro-organisms and infections, also act as skin protection cream.^[39]

 

a)    Zinc oxide nanoparticles: The zinc oxide categorized under metal oxide nanomaterials, including the size of fewer than 100 nm in diameter.^[40] The dimension, pH, compatibility, and exposure periods of molecules show a significant part in the properties of zinc oxide nanoparticles.^[41] The analyzing of massive microbicidal action toward various pathogenic food microbes are pencillium expansum, escherichia coli, staphylococcus aureus, and pseudomonas aeruginosa. The using zinc oxide particles in calamine moisturizer, emollients, and suntan cream can cure epidermis and dermis infections.^[42]

 

b)    Silica nanoparticles: The composition of nanoparticles is by condensing the indefinite shape of silicon plus oxygen. It has unique compatibility, non-toxic, thermic resistance, and easy manufacture process.^[43] The combination of silver plus silicon/copper nanoparticles has better microbicidal action, and efficient towards various pathogens such as Escherichia coli, Bacillus subtilis. These nanoparticles are applicable in the luminous display instrument, cosmic rays, lepidolite electronic battery, silica nanowires, diagnosing, scanning, photo-electronic, detecting and ablation treatments.^[44]

 

c)     Ceramic nanoparticles: The synthesis of ceramic nanoparticles by applying high heat also subsequent freezing of the compound comprises chemical, metals and metalloids elements (Ca, Ti, Si). The oxygen, carbon, ester of phosphoric acid, and carbonates are fundamental for making these nanoparticles.^[45] Using aluminium oxide (Al2O3) plus titanium dioxide (TiO2) for production of these nanomaterials. Nanoceramic is effective against many diseases like microbial infections, elevated intraocular pressure, and tumour. Hence, it has been taken an incredible consideration from scientists because of their utilization in catalytic action, deterioration of stains, and scanning purposes.^[46]

 

d)    Quantum dots: Quantum dot is a semiconducting nanomaterial that has a dimension of 2-10 nanometers then increase from 5-20 nanometers later encapsulating with a polymer. The immediate excretion of particles having less than 5 nanometers through the kidney.^[47] It contains a group of atoms either from Ⅱ and Ⅵ (CdSe, CdTe), or Ⅱ and Ⅴ (INP, InAs) on each core although this remains very harmful.^[48] To enhance the photo-stability and outputs of radiation by introducing the shell that has cadmium and zinc sulfide to restrict the quenching of an electron over that core.^[49] Quantum dots have been using for medicinal purposes like rapid examining about deoxyribonucleic acid, labelling of specific cells, light-emitting diodes, optical-electrical transducers, and targeted drug delivery.^[50]

 

Carbon-Based Nanomaterials: Elements are fullerenes, nanotubes, nanofibers, graphene and carbon black.^[51]

 

a)    Fullerenes: The definition of fullerenes is a nanoparticle which has carbon atoms in the form of spherical shape with the symmetric and compact structure. Fullerenes possessing globular shape, circular/tubular form can also name as carbon/buckytubes.^[52] The carbon having lesser than 300 atoms for the formation of buckyballs are describing as endo-fullerenes and buckminsterfullerene. The buckminsterfullerene exists a stiff cage-like fused-ring arrangement and also possessing sixty carbon molecules (C60).^[53] Because of impressive engineering features, it has been using in nano-electronics, photoelectric area, and cosmic rays generation also in biomedical purposes like analysis or scanning/detecting of ailments.^[54]

 

b)    Nanotubes: A nanotube is a part of fullerene that has a large concave shape, further the walls made through one molecule thick sheets of carbon referred to as graphene.^[55] Further, dividing these nanotubes as a single graphene sheet having less than 0.7 nm in diameter and more sheets of graphene (multi-walled) has 100 nm. Because of its valuable features, it has been beneficial to engineering science, microelectronics, recombinant DNA technology, chemotherapy, and biosensors.^[56]

 

c)     Carbon nanofibers: Chemical vapour deposition, electro-spinning, and phase partition equipment are using for the synthesis of nanofibers.^[57] The researchers have brought carbon nanofiber a great consideration because of the unique features like excellent dimensional durability, incredible thermic and current resistivity. Using these nanofibers in an infinite area like catalysis process, nanomaterials, detectors, biotechnology, and delivery of medication.^[58] It has a few disadvantages, such as a swelling in the lung, pneumonic inflammation, fibroma, and redness in the granulation tissues. ^[59]

 

d)    Graphene: Graphene is a stronger one compare to diamond and steel also it has a zero-gap semiconductor for the conductivity nature. ^[60] Because of the peculiar features like good thermal potential, elasticity, unique biochemical properties, and the enormous surface region makes an essential consideration within the area of bioscience and research work. A few methods for preparing graphene are mechanical cleavage, exfoliation of graphite, chemical vapour deposition, and the organic synthesis process. ^[61] Graphene oxide, reduced graphene oxide, and the mono and poly-layer graphene are the available variety nowadays. It is useful for therapeutic purposes such as regenerating of neural function and CNS dysfunctions like paralysis also Parkinson disorder. ^[62]

 

e)     Carbon black: Carbon black has particles in the colloid type contains not less than 96% of indefinite carbon and a little amount of oxygen, hydrogen, nitrogen and sulphur. Combustion methods and thermic breakdown of gas or liquefied hydrocarbons to generate the carbon black.^[63] It has a very low ignition temperature and non-combustible. The admixture of the atmosphere with graphene may cause eruptive and dangerous effects. The presence of black dye beneficial in forming watercolours, cosmetics, varnishes, and paints.^[64]

 

II.     Nanomaterials Categorized depends upon the Dimensions:

a)    Zero-dimension:The entrapment of electrons has no dimension. The light-emitting diodes, cosmic cells, single-electron conductors, and lasers apply to study the quantum dots, which is widely significant in zero-dimensional nanomaterials.^[65]

 

b)    One-dimension:The electrons move with the x-axis < 100 nanometers. It is applicable in micro-electronics and biochemistry for decades. The making of thin layers (dimension 1-100 nanometers) or monolayer in cosmic cells also as catalysis.^[66]

 

c)     Two-dimension: The movement of the electron within the x, y-axis. The two-dimension nanomaterial is a single layer and crystalline material. It is useful in the photovoltaics, semiconductors, electrodes, and also in the purpose of purifying water.^[67]

 

d)    Three-dimension: The movement of the electron within the x, y, z-axis. The three-dimension nanostructures comprise a significant material because of its large-scale use in catalysis, magnetic, and anode substances.^[68]

III.          Nanomaterials Categorized depends upon the Origin:

a)    Natural nanomaterials: Through organic species or anthropogenic exercises, it produces natural nanomaterials. Nanomaterials are available in a) Atmosphere: full of the troposphere. b) Hydrosphere: seas, ponds, streams, groundwater, and aqueous drains. c) Lithosphere: rocks, soils, and lava. d) Biosphere: a smaller scale living beings and higher living forms (people).^[69]

 

b)    Synthetic (engineered) nanomaterials: The nanomaterials produce through automatic granulating, motor fumes, and smog, further synthesize of nanomaterials by physical, synthetic, physiological or composite methods. Nanomaterials are very useful in estimating the performance and conclusion of synthetic nanomaterials in different ecological media.^[70]

 

Manufacturing of Nanoparticles:

The following are the methods to produce nanoparticles:

 

Solvent Evaporation: In the first step, the emulsification of aqueous non-miscible organic solution has a polymer plus hydrophilic drug in a continuous phase. The next step involves evaporation of the polymer-solvent, producing a precipitate of polymer to develop an oil-in-water emulsion. Methylene chloride, trichloromethane, and ethyl ethanoate is the organic solvent for dissolving the drug plus polymer then emulsified in an aqueous phase has emulsifying agent. Dodecyl sulphates, polysorbates, and polyvinyl acetate are surface active agents in preparing nanoparticles.^[71] Either by raising the temperature or decreasing pressure also through constant mechanical mixing, the organic solvent vaporizes that leads to precipitation of polymer and manufacturing of a stable oil-in-water emulsion. Finally, collecting the nanoparticles through freeze-drying, or centrifugation also cleaning with purified liquid to eliminate the added emulsifying agents. Polylactide, cellulose acetate phthalate, and poly (beta-hydroxy butyrate) are the polymers applicable in this method.^[72]

 

Nano-Precipitation/Solvent Displacement: The general steps involved in these processes comprise dissolving the drug and solution of preformed polymer (PLGA or PLGA-PEG) in a semi-polar water-soluble solvent like ethanol/methanol or acetone then emulsifying this mixture into an aqueous phase containing stabilizer or lipophilic surfactant subject to continuous magnetic blending.^[73] The absolute solubility of both phases leads to polymer precipitation following the rapid displacement of organic phase results in the manufacture of nanoparticles. While enhancing the stirring rate plus polymer concentration leads to control and a reduction in the particle size. The poly (lactic-co-glycolic acid) nanoparticles exhibit an enhanced bioavailability of proteins plus peptides.^[74]

 

Spontaneous Emulisification/Solvent Diffusion: This technique involves two types of solution one are the organic solution comprises a polymer, oil and drug in a partially water-soluble solvent and another is an aqueous solution which has water plus surface active agents/ stabilizer. The heterogeneous mixture has a water-soluble and a little quantity of a water-insoluble organic solvent which undergoes the emulsification process to produces an interfacial toward the extrinsic region that leads to the manufacturing of nanospheres. The removal of solvent by the filtration or evaporation.^[75] Large encapsulation capacities, lack of homogenization, great batch-to-batch productivity, and no difficulty in the scale up process are the few benefits about this method.^[76]

 

Salting-Out: The organic solution has a polymer and a drug in a polar (water-miscible) solvent like acetone or ethanol. Adding the above mixture into the aqueous solution which has a high concentration of a salting-out substance, plus colloidal/emulsion stabilizer like polyvidone or cellulose hydroxyl ethyl ether undergoes mechanical shear stress to form an oil-in-water emulsion. The diffusion of the solvent into the aqueous phase, leading to the formation of nanospheres. The tangential flow filtration and centrifugation process are useful in eliminating the residual solvent and salting-out agent.^[77] The salting-out agent may be electrolyte (magnesium chloride, magnesium acetate, and calcium chloride), or non-electrolytes (sucrose) substances.^[78]

 

Dialysis: It is an easy and efficient way to produce little and compact dispersible nanoparticles. Add an appropriate extent of an organic solution containing a polymer in the dialysis bag. It makes the dialysis process toward the non-solvent miscibility substance. The advantage of using dimethyl formamide to obtain different polymeric substances such as PBLG-PEG and PLA-PEG copolymer.^[79] It uses semi-porous layers which enable the inactive movement to lessen the blending of non-solvent with polymer solution.^[80]

 

Polymerization: Incorporating the polymerization of a drug and monomer in an aqueous medium having surface-active agents undergoes robust agitation to form nanoparticles. Either through ultra-centrifugation or re-suspending it in an iso-osmotic medium having no emulsifier is useful to purify/eliminate the stabilizer.^[81] It produces an n-butyl cyanoacrylate or ethyl 2-cyano prop-2-enoate compound.^[82] There are two varieties to make nanoparticles are (a) Dispersion Polymerization: It comprises an initiator, monomer, stabilizer, and non-solvent. It is useful to produce a polyacrylamide and poly-methyl methacrylate polymer. (b) Emulsion Polymerization:It comprises an initiator to conduct a polymerization process.^[83]

 

Coacervation/Ionic-Gelation:The coacervation process uses hydrophilic polymers (gelatin, chitosan, sodium alginate) to produce nanoparticles. It comprises two liquid forms; one has chitosan plus PEO-PPO copolymer, and another has polyanion STPP. Adding a positive charge chitosan drop by drop to the anionic compound such as tri-polyphosphate under continuous agitation further undergoes centrifugation and drying process.^[84] Ionic- gelation forms a gel from fluid substance because of ionic synergy at a normal temperature. The few benefits of this method are bio-compatibility and low toxicity. To eliminate the solvents under a decrease in pressure by using a rotary vacuum evaporator. The centrifugation process is done to purify the nanoparticles, and then it is collected.^[85]

 

Supercritical Fluid Technology:It incorporates the utilization of eco-friendly dissolvent (CO₂, nitrogen) and holds a lesser amount of organic element to produce nanoparticles. Using supercritical fluid such as carbon-dioxide because of the harmless nature, non-combustibility, and cheap cost. Initially, dissolving of the drug and a polymer in an organic solution to produce a suspension. Then pulverization of the solution by a capillary nozzle to supercritical CO₂.^[86] The SCF technology has two principal techniques. A) Supercritical anti-solvent: In this procedure, the dissolution of a drug/solute in the methanol solventadd a few drops of supercritical solution to make atomization of the solutes due to the indissolubility nature of solute in the SCF. Further, solute precipitates which leads to the synthesis of a nanoparticle.^[87]  B) Rapid expansion of supercritical solutions: In the RESS method, the drug soluble in SCF. The precipitation of nanoparticles occurs when the super saturation degree is high with low pressure leads to the poor expansion of SCF. It is an efficient technique to produce a small size of PFPE-diamide nanoparticles.^[88]

 

Characterization of nanoparticles:

Particle Size:The using of laser diffraction spectroscopy and electron microscopy for measuring the morphology, particle diameter, and size distribution of nanoparticles. It further determines the in-vivo performance and toxicity. This method affects the stability, release, and loading of a drug. Because of its small size particles and mobility, it has prominent intra-cellular uptake. Rapid drug release also diffusion occurs with small size particles having a degradation substance of polylactic acid made may aggregate and disperse outside of the particles. During the storing and transporting period, the small size of nanoparticles that lead to aggregation is the main drawback.^[89] The following are the methods to determine the particle size in brief:

 

Dynamic light scattering: Nowadays, photon-correlation spectroscopy should be a rapid also the most popular procedure to determine the size of nanoparticles. It is an active technique to define the size distribution and the polydispersity index. It can determine the sub-micron size ranges of particles about less than one nanometer in the colloidal suspension. The beam of monochromatic radiation passes against the suspension of spherical particles in the brownian movement creates a doppler effect and shows a variation in the incoming radiation wavelength also relating this variation with the particle size.^[90] In photon correlation spectroscopy, the results from the large size particles might be sensitive and suitable to measure the narrow size of particles to the extent of about 1-500 nanometers. Either scanning or transmission electron microscopy is useful in verifying the results obtained from the dynamic light scattering method.^[91]

 

Scanning Electron Microscopy: It provides high-resolution photographs by scanning the surface of a sample with the beam of an electron, also determines the dimension and structure of nanoparticles.^[92] During the characterization, converting of the nanoparticle’s suspension to a dehydrated particle later mounting this over the specimen holder subsequent coating by a conductive element like gold using a sputter coater. Finally, scanning of the sample through a narrow adjusting electron beams. The sample surface emits secondary electrons, which is useful in getting characteristic features of the surface. Besides, it is a tedious process, expensive, plus requires complete information on size distribution. This method produces different signals like characteristic X-rays, cathode-luminescence light, back-scattered and transmitted electrons.^[93]

 

Transmission Electron Microscopy: In this microscopic method, the transmitting of electron beam upon an ultra-thin sample, a further interaction of electrons and atoms (inelastic/elastic scattering, diffraction) to form a white and black image; then magnifying and focusing the image on an imaging instrument (fluorescent screen, photographic film) either detecting the image using a sensor like a charged coupled device camera. It also gives information about the surface characteristic, size, morphology, and size distribution of the nanoparticles.^[94] To analyze the particle size, by using manual or automatic methods. The penetration will be more with the higher energy electrons and allowing less transparent samples. It is a complex a tedious process in preparing the sample, due to the necessity to have an ultra-thin film for the transmittance of electrons. Also, TEM is beneficial in tumor study, virology, nanotechnology, and analysis of semiconductor.^[95]

 

Surface Charge/ Surface Hydrophobicity: Zeta potential is the potential difference between the dispersal medium and the stationary film of liquid attached to the dispersed particle. A surface charge reflects the electric potential and further dispersing medium and particle composition influence the surface charge.^[96] The nature and intensity of the surface charge are more significant to determine the biological environment interaction similar to the electrostatic interaction of bioactive composites. The zeta potential values are useful in predicting the size range of the surface hydrophobicity. ^[97] To enhance the possibility of achievement in drug targeting, it is essential to reduce the opsonization, prevention of the phagocytes, and to lengthen the dispersion of nanoparticles in-vivo condition by coating nanoparticles with the biodegradable hydrophilic copolymers/surface-active agents like polyethylene glycol, polyoxyethylene, pluronic, and tween 80. Hydrophobic interaction chromatography, biphasic partitioning, and contact angle measurements are the different methods to determine the surface hydrophobicity.^[98]

 

Surface Analysis: X-ray photoelectron spectroscopy allows us to analyze the chemical substance on the nanoparticle’s surface. The nitrogen adsorption technique is useful to measure the surface area of the powder. There is existence of an inverse correlation between the size of the particles and surface area.^[99] The Brunauer-Emmett-Teller method was generally utilized for analyzing the total surface area. This specific surface are gives an average diameter of particles within the nanometer range if the particles remain as a round shape also in small size distribution. The large area of the powder can access by the gas because of not firmly bond particles which produce a high degree of particles size with no agglomeration. Therefore, the measurement of the surface area yields a value near to that gotten via electron microscopy.^[100]

 

Drug Loading: To characterize the release of a drug depends upon the loading of a drug within the nanoparticles is significant. Enhancing the drug loading may speed up the release of a drug but sometimes enhancement may further delay the releasing of a drug; illustrating this through the potential crystallization of a drug within a specific nanosphere. Either supernatant liquid or filtrate is suitable to determine the drug content.^[101] There are two methods to perform drug loading. The first one is an incorporation method that needs the incorporation of drugs while synthesizing the nanoparticles. The second one is an adsorption/absorption method that absorbs a drug after the nanoparticle synthesis.^[102]

 

Drug Release: The rate of drug release relies upon the solubility of the drug, desorbing of the adsorbed drug, diffusion of the drug into a matrix, nanoparticle matrix abrasion or deterioration, a combination of erosion and diffusion techniques.^[103] Solubility, dispersion, and degradation of the nanoparticle influence a drug release. Drug loading via the incorporation process produces a fast, little burst impact and influence the sustain drug release. The solubility of a drug and diffusion within the polymeric layer which seems like a barrier for drug release serves as a determining part.^[104] There are numerous methods available to determine the in-vitro drug release of nanoparticles: side-by-side diffusion cells including artificial/natural layers, reverse dialysis sac diffusion, controlled agitation, and centrifugation or ultra-filtration.^[105]

 

Focus on Recent Advancement: The nanoparticulate method can overwhelm difficulties like low stability, reduction in bioavailability, and permeability across biological barriers. The above difficulties happen in therapeutic agents such as oral insulin, coagulation agents, and hormones. The nanoparticle was useful in treating the tumor, neoplastic, viral disease also beneficial in gene therapy and preparation of vaccines. ^[106] Polysorbate 80 coated nanoparticles and poly (n-butyl cyanoacrylate) nanoparticles can pass the BBB, further successive opening of a tight-packed layer with hyperosmotic mannitol that gives sustain/control release of drugs to heal the disease such as brain cancer. A poly lactic-co-glycolic acid nanoparticle with epigallocatechin gallate made by a double emulsion procedure may help to treat temporal convulsion.^[108] Gold nanoparticles can eradicate the alzheimer disease with amyloid plaques. Nanocapsules, nanospheres, liposomes, carbon nanotubes, nanogels, nanofibers, nanomicelles, and nanosuspensions are the different efficient nanostructure for treating neurodegenerative diseases. Nanocapsules plus nanospheres deliver therapeutic drugs into a brain by crossing the BBB. Nanosuspension is an outstanding nanocarrier for efficient characteristic features like immense drug loading potential. Carbon nanotube may improve the chronic electric stimulation of the central nervous system to cure the disorders. A new design possible in nanotechnology was nanorobots which have a lot of advancements proceeding nowadays.^[109] Condensing of DNA plasmids with nanoparticles also was useful in healing neurodegenerative disorders. Therefore, knowing the significant about the nanotechnology to prevent those disorders also, yet there is more scope available for analyzing plus finding more newly manufactured nanoparticles for treating the neurodegenerative disorders in the future.^[110]

 

CONCLUSION:

Nanoparticulate system has the dimension of the colloidal particles in the nanometric range which possess high potentiality and converting of the poorly soluble plus biologically unstable drugs into an optimistically active drug. The review tells about the summary of how drugs target the brain because of the existence of biological barriers. This barrier inhibits the entering of undesired matters inside the brain due to the tightly bound layer of endothelial cells. Nanoparticles provide an enormous utilization in treating the many CNS dysfunctions like alzheimer’s, parkinson’s, huntington, and convulsion diseases. Also, the article concentrates upon several applications of nanoparticles like the discovering and delivery of a drug into the brain bypassing those barriers and diagnostics imaging of the disorders. The merging of diagnostic plus therapeutic abilities to treat disorder based on theranostic strategies. Depending upon the effectiveness, an eco-friendly nature; Nanotechnology might play a vital role in the future.

 

REFERENCES:

1.      Mohanraj VJ et al., Nanoparticles- A Review. Tropical Journal of Pharmaceutical Research. June 2006; 5 (1): 561-573

2.      KonwarRanjit et al., Nanoparticle: An overview of preparation, characterization, and application. Int. Res. J. Pharm. 2013; 4(4): 47-57

3.      Akbari.B et al., Particle size characterization of nanoparticles- A particle approach. Iran. J. Mater. Sci. Eng.2011;8(2).

4.      Vauthier C et al., Poly (alkyl cyanoacrylates) as biodegradable materials for biomedical applications. P. Adv Drug Deliv Rev. 2003 Apr 25; 55(4): 519-48.

5.      A. Mohamad et al., Nanoparticles: A review on their synthesis, characterization and physicochemical properties for the energy technology industry. J. Adv. Res. Fluid Mech. Therm. Sci. 2018; 46(1):1-10

6.      Michel Goedert.Alpha-synuclein and neurodegenerative diseases.Nature reviews neuroscience. July 2001; Volume 2: 492-501

7.      Sheikh S et al., Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions. Journal of Neurodegenerative Diseases, 2013; 1–8.

8.      Dobson, C. M. Protein folding and misfolding. Nature international journal of science. 2003; 426(6968): 884–890.

9.      Syed TazibRahaman. A Review on Treatment for Neurodegenerative disease with the help of nanosciences. World J Pharm Sci 2018; 6(9): 153-162.

10.    P. Velavan et al., Nanoparticle as drug delivery systems. J  Pharm  Sciand Res Vol. 2015; 7(12): 1118-1122

11.    Sapra P, Tyagi P, Allen TM. Ligand-targeted liposomes for cancer treatment. Curr Drug Deliv 2005;2:369-81

12.    Vila et al., Design of biodegradable particles for protein delivery. J Control Release 2002; 78: 15-24.

13.    Mu L, Feng SS. A novel controlled release formulation for the anticancer drug paclitaxel (Taxol(R)): PLGA nanoparticles containing vitamin E TPGS. J Control Release 2003; 86: 33-48.

14.    Muhammad Adnan Younis, IftikharHussain Bukhari, Qaisar Abbas, Neelam Bin Talib, Sana Shaukat. Synthesis, importance and applications of metal oxide nanomaterials. Int. J. Tech. 2018; 8(2): 49-57

15.    Kishore UttamKothule et al., Development and Characterization of Chitosan Nanoparticles and Improvement of Oral Bioavailability of Poorly Water-Soluble Acyclovir. Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1241-1245.

16.    Davinder et al., Nanoparticles: An overview. Journal of Drug Delivery and Therapeutics; 2013; 3(2):169-175

17.    Jawahar N and Meyyanathan SN. Polymeric nanoparticles for drug delivery and targeting: A comprehensive review. Int J Health Allied Sci 2012; 1: 217-23.

18.    Abhilash M., Potential applications of Nanoparticles, International Journal of Pharma and Bio Sciences 2010; 1(1): 1-12

19.    Varde NK and Pack DW. Microspheres for controlled release drug delivery. Expert OpinBiolTher 2004; 3(1): 35-51.

20.    Kreuter J. Evaluation of nanoparticles as drug-delivery systems. PharmaActaHelv 1983;58:242-50

21.    W. H. De Jong and P. J. Borm. Drug delivery and nanoparticles: application and hazards. Int J Nanomedicine.2008; 3(2):133-149.

22.    Anirudha Malik et al., Dendrimers: a tool for drug delivery. Adv. Biol. Res. 2012; 6(4): 165-169.

23.    Li Y., Cheng Y., Xu T. Design, synthesis and potent pharmaceutical applications of glycodendrimers: a mini-review. Curr Drug Discov Technol. 2007; 4:246-54.

24.    Cheng Y et al., Pharmaceutical applications of dendrimers: promising nanocarriers for drug delivery. Front Biosci. 2008; 13:1447-71.

25.    Meckeet al., Direct observation of lipid bilayer disruption by poly (amidoamine) dendrimers. ChemPhys Lipids. 2004;132:3-14.

26.    Rangel-Yagui CO, Pessoa A, Tavares LC. Micellar solubilization of drugs. Journal of Pharmacy and Pharmaceutical Sciences. 2005; 8:147–163. 

27.    Gaucher G et al., Block copolymer micelles: preparation, characterization and application in drug delivery. J. Control. Release. 2005; 109:169–188.

28.    Aliabadi HM and Lavasanifar A. Polymeric micelles for drug delivery. Expert Opin. Drug Deliv. 2006; 3:139–162.

29.    AbolfazlAkbarzadeh et al., Liposome: classification, preparation, and Applications. Nanoscale Res.Lett. 2013; 8(102):1-9.

30.    Vemuri, S., Rhodes, C.T. Preparation and characterization of liposomes as therapeutic delivery systems: a review. Pharm. Acta Helv. 1995; 70 (2): 95–111.

31.    Zhang, L., Granick, S., 2006. How to stabilize phospholipid liposomes (using nanoparticles). Nano Lett. 2006; 6 (4): 694–698.

32.    Nagavarma, B.V.N et al., Different techniques for preparation of polymeric nanoparticles - a review.  Asian J.Pharm. Clin. Res. 2010; 5(3): 16-23.

33.    Gref R, et al. Biodegradable long-circulating polymeric nanospheres. Sci 1994; 263:1600-1603.

34.    Reis et al., Nanoencapsulation-Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine2006; 2(1):8-21.

35.    KarunakaranSulochanaMeena, ThyagarajanVenkataraman, SingaravelGanesan, PrakasaRaoAruna. Gold–Nanoparticles A Novel Nano-Photosensitizer for Photodynamic Therapy. Asian J. Research Chem. 4(1): January 2011; Page 58-63.

36.    RinkuJaiswal, Shripal Singh, HemantPande. Magnetic Nanoparticles Activated Carbon: Preparation, Characterization and Application: A Review article. Asian J. Research Chem. 8(12): December 2015; Page 757-768

37.    Daniel MC and Astruc D. Gold nanoparticles: assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology. Chem Rev 2004; 104:293-346.

38.    Gong P et al., Preparation and antibacterial activity of Fe3O4@Ag nanoparticles. Nanotechnology. 2007; 18(28): 604–611.

39.    MahendraRai et al., Silver Nanoparticles as a New Generation of Antimicrobials. Biotech. Adv. 2009;27(1): 76-83.

40.    Sharma V.K et al., Silver nanoparticles: Green synthesis and their antimicrobial activities. Advances in Colloid and Interface Science. 2009; 145(1-2): 83-96.

41.    Saraf R., Cost-effective and monodispersed zinc oxide nanoparticles synthesis and their characterization. Int. J. Adv. Appl. Sci. 2013; 2: 85-88

42.    Lopes, S., et al., Zinc oxide nanoparticles toxicity to Daphnia Magna: size-dependent effects and dissolution. Environ. Toxicol. Chem. 2014; 33 (1): 190–198.

43.    Chuang, H.-C., et al., Cardiopulmonary toxicity of pulmonary exposure to occupationally relevant zinc oxide nanoparticles. Nanotoxicology. 2014; 8 (6): 593–604.

44.    Cousins B et al., Effects of a nanoparticulate silica substrate on cell attachment of Candida albicans. J. Appl. Microbiol. 2007; 102: 757-765.

45.    Egger S et al., Antimicrobial properties of a novel silver-silica nanocomposite material. Appl. Environ. Microbiol. 2009; 75: 2973-2976.

46.    Yang L et al., Nanophase ceramics for improved drug delivery: current opportunities and challenges. Am Ceram Soc Bull 2010; 89(2):24-31.

47.    Thomas S et al., Ceramic nanoparticles: fabrication methods and applications in drug delivery. Curr. Pharm. Des. 2015; 21: 6165–6188.

48.    Ghasemi Y et al., Quantum dot: magic nanoparticle for imaging, detection and targeting. Acta Biomed. 2009; 80(2):156-165.

49.    Larson DR et al., Wise FW. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science. 2003; 300:1434-1436.

50.    Michalet X et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 2005; 307(5709):538-544.

51.    Qi, L and Gao, X. Emerging application of quantum dots for drug delivery and therapy. Expert Opin. Drug Deliv. 2008; 5 (3): 63–67.

52.    Anu Mary Elias and M P Saravanakumar. A review on the classification, characterisation, synthesis of nanoparticles and their application. IOP Conf. Ser.: Mater. Sci. Eng. 263 (2017) 032019.

53.    Bosi S et al., Fullerene derivatives: an attractive tool for biological applications. Eur. J. Med. Chem. 2003; 38(11-12):913-923.

54.    Ma H, Liang X-J. Fullerenes as unique nanopharmaceuticals for disease treatment. Sci. ChinaChem. 2010; 53(11):2233-2240.

55.    Venkatesan P et al., Microencapsulation: A Vital Technique In Novel Drug Delivery System. J. Pharm. Sci. and Res. 2009; 1(4): 26-35

56.    Mitchell D.R et al., The synthesis of mega tubes: new dimensions in carbon materials. Inorg. Chem. 2001; 40 (12): 2751–2755.

57.    Parveen S et al., Nanoparticles: a boon to drug delivery, therapeutics, diagnostics and imaging. Nanomedicine Nanotechnology, Biol. Med. 2012; 8(2):147- 166.

58.    S. Choi et al., Hollow ZnOnnanofibers fabricated using electrospun polymer templates, ACS Nano. 2009;3: 2623-2631

59.    Ch.Prabhakar, K. Bala Krishna. A Review on Polymeric Nanoparticles. Research J. Pharm. and Tech. 4(4): April 2011; Page 496-498.

60.    Utpal Jana, Sovan Pal, G.P. Mohanta, P.K. Manna, R. Manavalan. Nanoparticles: A Potential Approach for Drug Delivery. Research J. Pharm. and Tech. 4(7): July 2011; Page 1016-1019.

61.    A.J. Parker et al., An electrochemical method for the production of graphite oxide, ECS Trans. 2013; 53: 23-32.

62.    V. Singh et al., Graphene-based materials: past, present and future, Prog. Mater. Sci. 2011; 56: 1178-1271.

63.    I. Ovid’ko, Mechanical properties of graphene, Rev. Adv. Mater. Sci. 2013; 34: 1-11.

64.    Sebok, E. B and Taylor, R. L. Carbon Blacks. Encyclopedia of Materials: Science and Technology. 2001; 902–906

65.    Morfeld P, McCunney RJ. "Carbon black and lung cancer: Testing a new exposure metric in a German cohort". Am J Ind Med. 2007; 50 (8): 565–567.

66.    Guozhong Cao. Zero-Dimensional Nanostructures: Nanoparticles. Nanostructures and Nanomaterials. 2004; 51–109.

67.    Tiwari J et al., Zero-dimensional, one-dimensional, two-dimensional and three-dimensional nanostructured materials for advanced electrochemical energy devices. Progress in Materials Science. 2012; 57(4): 724–803.

68.    Novoselov KS et al., Two-dimensional atomic crystals. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:10451-10453.

69.    Weeks, E. R. Three-Dimensional Direct Imaging of Structural Relaxation Near the Colloidal Glass Transition. Science. 2000; 287(5453): 627–631.

70.    Jameel Ahmed Mulla et al., Formulation, Characterization and in vitro Evaluation of Methotrexate Solid Lipid Nanoparticles. Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 685-689.

71.    JaisonJeevanandam et al., Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations. Beilstein J. Nanotechnol. 2018; 9:1050–1074.

72.    D. Thulasi Ram, SubhashisDebnath, M. NiranjanBabu, T. ChakradharNath, Thejeswi B. A Review on Solid Lipid Nanoparticles. Research J. Pharm. and Tech. 5(11): Nov. 2012; Page 1359-1368.

73.    Tice TR., Gilley RM. Preparation of injectable controlled release microcapsules by a solvent- evaporation process. J Control Release. 1985; 2:343-352.

74.    Govender T et al., PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water-soluble drug. J Control Release. 1999; 57(2):171-185.

75.    Fessi H et al., Nano capsule formation by interfacial deposition following solvent displacement. Int J Pharm. 1989; 55:1–4.

76.    Kwon H-Y. Preparation of PLGA nanoparticles containing estrogen by emulsification diffusion method, Colloids Surf. Release, 2001; 182:123–30.

77.    Ueda H, and Kreuter J. Optimization of the preparation of loperamide- loaded poly (l-lactide) nanoparticles by high-pressure emulsification solvent evaporation. J Microencapsul. 1997; 14:593–605.

78.    Allémann E et al., In vitro extended-release properties of drug-loaded poly(DL-lactic acid) nanoparticles produced by a salting-out procedure Pharm Res 1993;10:1732-37.

79.    Ibrahiam H et al., Aqueous nanodispersions prepared by a salting-out process. Int J Pharm 1992; 87:239-46.

80.    Allemann E, Gurny R, Doekler E. Drug-loaded nanoparticles preparation methods and drug targeting issues. Eur J Pharm Biopharm. 1993; 39:173–91.

81.    Bhatia S. Natural Polymer Drug Delivery Systems. Nanoparticles Types, Classification, Characterization, Fabrication Methods and Drug Delivery Applications. 33-93

82.    Poovi G, Narayanan N. Preparation and characterization of repaglinide loaded chitosan polymeric nanoparticles. Research Journal of nanoscience and nanotechnology. 2010; 1(1): 12-24.

83.    Yadav et al.,Different Techniques for Preparation of Polymeric Nanoparticles- A Review. Asian J Pharm Clin Res. 2012; Vol 5(3):16-23.

84.    Hao L, Chi N and Triet N: Preparation of drug nanoparticles by an emulsion evaporation method. Journal of Physics 2009; 187:1-4.

85.    Hasan S. a review on nanoparticles: their synthesis and types. Res J Recent Sci 2015; 4:1-3.

86.    Couvreur P et al., Controlled drug delivery with Nanoparticles: current possibilities and future trends. Eur J Pharm Biopharm. 1995; 41:2–13.

87.    Deore et al. Nanoparticle: as targeted drug delivery system for depression. International journal of current pharmaceutical research.  Int J Curr Pharm Res. 2016; 8(3):7-11

88.    Reverchon E, Adami R. Nanomaterials and supercritical fluids. J Supercrit Fluids. 2006; 37:1–22.

89.    Sun Y et al., Polymeric nanoparticles from the rapid expansion of the supercritical fluid solution. Chemistry. 2005; 11:1366–73.

90.    Tinke, A. P., Govoreanu R. and Vanhoutte K., “Particle Size and Shape Characterization of Nano- and Submicron Liquid Dispersions, American Pharmaceutical Review”, 2006.

91.    Garg A et al., Formulation, characterization and application on nanoparticle: a review. Der Pharmacia Sinica 2011; 2:17-26.

92.    Ahmad TajuddinMohamad. Nanoparticles: A Review on their Synthesis, Characterization and Physicochemical Properties for Energy Technology Industry. Journal of Advanced Research in Fluid Mechanics and Thermal Sciences. 2018; 46 (1): 1-10

93.    Mullaicharam AR. Nanoparticles in drug delivery system. Int J Nutr Pharmacol Neurol Dis 2011; 1: 103-9.

94.    Philippe M et al., Preparation and characterization of nanoparticles containing an antihypertensive agent. Eur j pharm biopharm 1998; 46(2):137-43.

95.    Suganeswari M et al., Preparation, characterization and evaluation of nanoparticles containing hypolipidemic drug and antihypertensive drug. Int j pharm biological archives 2011; 2(3):949-53

96.    Kohane ds. Microparticles and nanoparticles for drug delivery. Biotechnolbioeng2007; 96(2):203-209.

97.    T.sudhamani et al., preparation and evaluation of ethyl cellulose microspheres of ibuprofen for sustained drug delivery, int.j.pharma research and development. 2010; 119-125.

98.    Zinutti c et al., Preparation and characterisation of ethyl cellulose microspheres containing 5- fluorouracil microencapsule, 1994; 11 (5):555- 563.

99.    Saini et al., Biotechnology: The novel drug delivery system. Int J Nutr Pharm Neuro Dis. 2011;1:82-3

100.  Y.N. Konan et al., Preparation and characterization of sterile and freeze-dried sub-200 nm nanoparticles, Int. J. Pharm. 2002; 233:239–252.

101.   R. Singh et al., Nanoparticle-based targeted drug delivery.  Experimental and Molecular Pathology. 2009; 86: 215–223

102.  Garud A, Singh D, Garud N. Solid lipid nanoparticles (SLN): method, characterization and applications. Int J Curr Pharm 2012; 1(1):384-93.

103.  Rajput N. Methods of preparation of nanoparticles–a review. Int J Adv Res Technol 2015;7:1806-11

104.  Sailaja K et al., Different techniques used for the preparation of nanoparticles using natural polymers and their application. Int J Pharm PharmSci 2011; 3(2):4550.

105.  Mehmood Y et al., Brain targeting drug delivery system: a review. Int J Basic Appl Med Sci 2015; 5:32-40.

106.  Kabanov, A.V. andH.E.Gendelman. Nanomedicine in the diagnosis and therapy of neurodegenerative disorders. Prog. Polym. Sci. 2007; 32: 1054–1082.

107.  ViharGadhvi, Kachariya Brijesh, Amit Gupta, KomalRoopchandani, Nirav Patel. Nanoparticles for Brain Targeting. Research J. Pharm. and Tech. 6(5): May 2013; Page 454-458.

108.  Modi G et al., Advances in the treatment of neurodegenerative disorders employing nanotechnology. Ann NY AcadSci 2010; 1184:154-72.

109.  Agnihotri SA, Mallikarjuna NN and Aminabhavi TM: Recent advances on chitosan-based micro- and nanoparticles in drug delivery. Journal of Controlled Release 2004; 100:5-28

110.  Modi G et al., Nanotechnological applications for the treatment of neurodegenerative disorders. Progress in Neurobiology. 2009; 88(4):272–285

 

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Research J. Pharm. and Tech 2020; 13(5): 2135-2143.