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Approaches for encephalic drug delivery using nanomaterials: The current status
Journal Pre-proof APPROACHES FOR ENCEPHALIC DRUG DELIVERY USING NANOMATERIALS: THE CURRENT STATUS Anoop Narayanan V
PII:
S0361-9230(18)30950-X
DOI:
https://doi.org/10.1016/j.brainresbull.2019.11.017
Reference:
BRB 9814
To appear in:
Brain Research Bulletin
Received Date:
3 December 2018
Revised Date:
16 November 2019
Accepted Date:
27 November 2019
Please cite this article as: V AN, APPROACHES FOR ENCEPHALIC DRUG DELIVERY USING NANOMATERIALS: THE CURRENT STATUS, Brain Research Bulletin (2019), doi: https://doi.org/10.1016/j.brainresbull.2019.11.017
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APPROACHES FOR ENCEPHALIC DRUG DELIVERY USING NANOMATERIALS: THE CURRENT STATUS
Anoop Narayanan V* [email protected]
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NGSM Institute of Pharmaceutical Sciences, NITTE University, 575018
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Corresponding author
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Highlights
Drug access to the brain remains as a challenge in most of the CNS disorders.
Nanotechnology create a breakthrough in brain targeting of drugs.
Varioius nano pharmaceutical approaches used in brain drug delivery is discussed.
Mechanisms of nanoparticles crossing BBB is explored.
Abstract:
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Nanotechnology, the investigation of little structures, ranging from the size of 1 nm to 100 nm presents a breakthrough in the field of targeted drug delivery. The microvasculature in the human brain along with the blood brain barrier (BBB) offers high resistance to the entry of therapeutics agents and other substances in to the brain. Nanoparticles have certain advantages as high permeability, reactivity, surface area and quantum properties and it also meets various medical challenges which may include poor bioavailability, difficulty in targeting, organ toxicity etc. The use of nanoparticles in pharmaceuticals has been inspired by 1
various natural nanomaterials found in the body, which includes proteins, lipids etc. A brief explanation of different types of pharmaceutical approaches used in brain drug delivery is discussed here. Nanotechnology is used treatment of many illnesses which also include diseases related to the brain such as gliomas, epilepsy, migraine, cerebrovascular disease, Parkinson’s disease etc., Different type of nanoparticles are prepared, such as polymer-based nanoparticles, metallic nanoparticles, carbon-based nanoparticles, lipid-based nanoparticles, ceramic nanoparticles semiconductor nanoparticles and are studied for their usefulness in drug delivery. The primary function of nanoparticles is to deliver drug moiety to the desired targeted site by overcoming permeability issues. The shape, size and surface area
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nanoparticles help in increasing the bioavailability, drug retention and multiple drug delivery. Mechanisms of nanoparticles crossing BBB can be divided into passive and active transport, are briefly explained.
Keywords: Nanoparticles; BBB; nanotechnology; tumour; metallic nanoparticles; brain drug
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delivery
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1. Introduction
Nanotechnology is a boon to the humanity enabling scientists to create medicines that can do wonders in the therapy. The extensive size reduction of drug and carrier materials into nano
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sizes can tremendously influence the physicochemical properties of these substances, thereby redefining the pharmacokinetics of drug molecules. In recent years the biological application
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of nanoparticles has been radically increased and now spreading its arms into the practical clinical scenarios. Nanoparticles (NPs) as defined, are the particulate materials whose size ranges between 1-100 nm. Since their little size range is in nanoscale they possess several
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unique properties like high permeability, high reactivity, huge surface area and quantum properties (Kamal et al., 2011; Surendiran et al., 2009). Nanoparticles still meet various medical challenges which may include poor stability and organ toxicity. The use of nanoparticles in medicines has been inspired by several natural nanomaterials found in the body such as proteins and lipids. For an instance, a lipid and polymer-based nanocarrier with drug encapsulated in it was attempted for the purpose of sustained and targeted drug delivery (Chen et al., 2016). 2
The size of animal cells ranges from 10,000 to 20,000 nm and hence nanoparticles can easily enter cells and organelles to interact with DNA and any other proteins. It also helps to detect the onset of diseases in a little amount of tissue or body fluids; they can also identify diseases in micro level and deliver the treatment. Due to their tiny sizes and larger surface area, nanoparticles often interact with biomolecules such as receptors and enzymes on both sides of cells. Nanoparticles made up or biomaterials consisting macromolecules serves as a substrate for molecular assembly such as drugs or other therapeutic substances. Nano formulation can also be found in the form vesicles as in liposomes with a membrane or layer surrounding a core material in it. Nanoparticles are mostly found in spherical or cylindrical
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shape, but it can also be seen in the rod, plate and many another forms that can be created by various processes (Idrees, 2013). 2. Challenges in brain targeting
The micro vasculature in the human brain is unique and that occupies the 3% of the brain’s
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volume. Extremely small capillaries of 7 to 10 μm are present in the brain with an average inter-capillary distance of 40 μm whereas the size of an RBC varies from 6 to 8 μm.
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(Duvernoy et al., 1983) This micro vascular network controls the transport of materials into the brain in a great extent. (Wong et al., 2013)
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The blood capillaries in the central nervous system (CNS) are lined with a superior type of endothelial cells known as blood-brain barrier (BBB), which structurally differ from any
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other capillaries present in other parts of the body. These capillaries are sealed with tight junctions; because of this property the BBB avoids access of many foreign materials into the brain. (Fig. 1)
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The complex integration between neighbouring endothelial cells are formed due to tight junctions and adherent junctions (fig 2). The endothelial cells of BBB join to form junction
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complex in the most apical section of the plasma membrane of adjacent cells. These are created by the interaction of several transmembrane proteins that extends and forms the cytoplasm, by a protein associated with cytoplasmic actin; forming a link between the endothelial cells. (Loch-Neckel and Koepp, 2010) The barrier properties of endothelial cells are supported by the lining of mural cells, immune cells and glial cells. The outer side of the capillaries are majorly occupied by the astrocyte endfeet. (Dobbing, 1961)
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Lipid soluble solutes diffuse freely through the capillaries as in the blood capillaries intercellular cleft, pinocytosis and fenestrate are virtually non-existent, and therefore components must pass transcellular. (Singh, 2013) The Blood Brain Barrier (BBB), the Blood-cerebrospinal fluid barrier (B-CSFB) and the blood-tumor barrier are the tough puzzles which make the delivery of drugs to the brain much more challenging than rest of the organs. As we pointed out in the above sentences, along with other barriers, BBB has a unique structure which may delay supply drugs to the brain, also to the spinal cord. There is a presence of very high trans-endothelial electrical resistance of >1500 Ωcm2 along the tight junction of BBB when compared to any other capillaries of the tissue, where it is just 3-30
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Ωcm2. (Ribecco-Lutkiewicz et al., 2018) Mainly because of the reasons mentioned above there is a reduction in the passive diffusion of aqueous based drugs to the brain in comparison with other organs of the body.
The impedes of drug transport is an enzymatic reaction which serves to protect the brain
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along with the physicochemical properties of drugs, these serve as an additional problem in the drug permeation across BBB. The two main types of traporters expressed in CNS are
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efflux transporters and nutrient transporters. Efflux transporters such as BCRP (Breast Cancer Resistance Protein), MRP-1 (multidrug resistance protein) and P-glycoprotein (MDRL) creates barrier to lipophilic substrates by transporting them across BBB against concentration
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gradient.(Dobbing, 1961; Lingineni et al., 2017) Polar nutrient transporters which transports glucose, amino acids, mono carboxylic acids are dependable for the delivery of polar
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compounds to the brain but their structural specificity remains as a hurdle.(SanchezCovarrubias et al., 2014) Some of the influx transport mechanisms that can be effectively utilized for drug delivery are large neutral amino acid transporter (LAT1) as in case of L-
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dopa, organic anion and cation transporters (OAT & OCT) and the choline transporters (CHT).(Mittapalli et al., 2010)
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The blood-cerebrospinal liquid obstruction (B-CSFB) is fantastic, offering one more hindrance that mindfully controls the entrance of molecules carried by the blood to the interstitial liquid of the cerebrum parenchyma and CSF attributable to the choroid plexus and the arachnoid film. At last, the blood-tumor barrier (BTB) coming about because of adjustments in cerebral microvasculature as the tumor makes it considerably more troublesome for medications to penetrate than normal brain endothelium, prompting outstandingly low additional tumoral interstitial medication and consistent development of intracranial malignancies. (M Zaki, 2012) 4
3. Different approaches used brain drug delivery Researchers used different strategies to increase the permeability of drug into the BBB. The first approach was an invasive route that finds a way through the obstacle of BBB by directly administering drug into the brain. Direct invasive route of the drug into the brain involves intracerebral and intrathecal administration it also requires a craniotomy. These dimensions have certain advantages, a wide range of small and large molecules can be delivered. Intranasal administration is also realised due to the bridge between brain and nose, known as olfactory bulb. Various compounds can be transported into the CNS through this intranasal
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path which also includes toxic agents, pathogens, viruses etc. An alternate approach involves disruption of BBB, where a hypertonic solution introduced
into the circulation via carotid artery, and the junctions open up due to the shrinking of cells. This mechanism utilises 30 minutes for a drug to administer. During this time, the tight
cellular junction between brain capillary endothelial cells have a paracellular diffusion (fig 2)
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of water-soluble drugs and solutes increased, on the other context, it also allows toxins
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present in the blood to pass through BBB.
In the third strategy, permeability is zoomed in by chemical modification to advance transcellular migration of the drug. Transcellular migration includes passive diffusion, a
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unique transport system and endocytosis. This strategy comprises minimal neurotoxicity when compared to disruption of BBB. (Roy Sandipan, 2012)
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Utilising nanoparticles as a carrier for encephalic drug delivery is an improved update of previous treatments. Moreover, nanoparticles can be guided more effectively to the olfactory nerve endings. The formulation of the drugs along with nanoparticles as a carrier creates a
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foundation of a promising approach of dosage. Formulations have proven to be reliable for application due to its liquid nature and have longer retention time due to its mucoadhesive
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and thermosensitive properties. Since the size of the nanoparticles is minute, they can directly approach the brain, and can be administered in smaller doses which helps to minimize any peripheral side effects (Abbas et al., 2018). A sort of biomimetic nanoparticles named as red platelet layer covered nanoparticles helps in holding the troublesome natural elements of cell films while displaying physicochemical properties that are reasonable for efficient drug delivery. RBC nanoparticles can achieve broadened blood distribution and exhibit minimised immunogenicity while assessing it with standard manufactured nanoscale medication delivery systems. (Chai et al., 2017) 5
Symmetric dendrimeric and non-symmetric hyperbranched polymers known as dendritic polymers are nanometre-sized, highly stretched macromolecules which comprise of a focal centre, fanning units and quite useful terminal groups that fluctuate in size from 1 to 1000 nm. The main highlight is that the bioactive compound is encapsulated in the nanocavity. Furthermore, polymers successfully established many approaches in preparing a varied choice of compounds used in the preparation of formulation and many other materials used in packaging, bottles, surgical sutures etc. Polymers consist significant amount of functional groups on their external surface, this structural feature of polymer helps in inducing powerful binding due to multivalency effect to the multiple cell receptors.
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Nanotechnology has been employed for gels in nanosize networks; that is made up of the hydrophilic polymers. These hydrophilic polymers can hold water-solvent peptides and
proteins which are therapeutics; this ability is due to the presence of cross-linked porous
networks. The extent of pores of nanogels is 10-400 nm usually. Subsequently, they are large
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enough to stay away from clearance from the course by glomerular filtration in the kidneys
while little enough to restrict freedom by the reticuloendothelial framework. Nanogels have
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likewise been perceived as vehicles for medication conveyance and its sophistication to the cerebrum and can be intended for upgrade responsive degradation and medication discharge
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(Bode et al., 2017).
Recently nano particulate systems were used in delivery of several drugs directly into brain through intra nasal routes. Such attempts included the delivery of docetaxel and loperamide
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using PLGA nanoparticles and insulin using chitosan nanoparticles. By the use of nanomedicine, the opportunity has been improved in the diagnosis and treatment of brain cancer. Several kinds of nanoparticles have been engaged as a drug delivery agent in the
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brain cancer therapy. These may include but not limited to gold nanoparticles, organic based hydrogel, polymer, gadolinium, liposomes, semi conduct quantum dots and micelles. Such
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nano substances developed often consists of targeting ligands that can help in specific penetration of the drug across the BBB. (Chai et al., 2017; Meyers et al., 2013) Delivery of insulin was successfully attempted as dry powder formulation using chitosan nanoparticles.(Dyer et al., 2002) 4. Nanotechnology in CNS disorders: Numerous amount advances have been carried out in the field of drug delivery every year to improvise treatment and understanding mainly against central nervous system (CNS) 6
disorders. Even after several efforts have been made in this particular area, it still did not meet challenges completely. The principal objective of BBB it is to maintain an environment in a constant order within CNS and to provide necessary nutrients. Although BBB is made up of tight junction of endothelial cells in the microvessels of the brain and BBB, its high restriction in the trading of outsider materials among blood and tissue parenchyma, despite everything it permits entry of proteins, for example, antibodies and so on into the cerebrum. Hence here the main challenge of a drug is to pass BBB. With the end goal to defeat previously mentioned test, enhanced medication conveyance has created by utilising colloidal drug transporters, for example, nanoparticles including liposomes, polymeric nanospheres
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and nanogels. Liposomes due to their potential drug carrier to target any specific organ including brain have gained high attention. Liposomes are tiny counterfeit vesicles of circular shape which comprise of a fluid centre composed by at least one bilayers made out of natural or synthetic, biocompatible and biodegradable lipids like organic layers. Nanoparticles can be combined with protein and peptides which help in the transfer of a drug across a biological
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membrane, in addition to that nanoparticles protect drugs against enzymatic degradation.
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(Bode et al., 2017)
5. Various treatments that can be carried out using nanomedicines
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5.1. Treatment of brain cancers by using nanomedicine:
The complexity of brain cancer treatment faced is due to the presence of numerous obstacles
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which includes BBB. The WHO has classified gliomas in 3 significant classes ie; astrocytoma, oligodendroglioma and oligoastrocytoma (mixed gliomas). Astrocytomas are the most common of the three categories. Usually, astrocytomas are treated by chemotherapy,
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radiotherapy and surgical method, with a primary objective of lengthening survival time and improving health rather than curing the disease (Craciunescu et al., 2003). Tumor treatment
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can disrupt the properties of vascular endothelium, and it may also disrupt the BBB. In the early stages of a tumor, there are no changes in the structure of BBB, as the tumor progress occurs BBB remains intact which makes surgical resection inflexible or, in other words, the fast backslide of cerebrum tumors. Subsequently, conventional chemotherapeutics cannot be conveyed to the brain successfully (Hua et al., 2018). 5.2. Nanocarriers used in the treatment of epilepsy:
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Epilepsy is a most severe type neurological disorder which affects approximately 50 million people globally. It is characterised by recurrent seizures, which involves the involuntary movement of the entire body or a part of the body for a brief period. A seizure is resultant of excessive electrical discharges in cells of the brain. Even though there are some successful anti-epileptic drugs (AEDs) found in the market, but there may be chance epilepsy becoming out of control in many patients, which leads to failure of AEDs. More over oral and intravenous routes were not very effective due to the hindrance offered by blood brain barrier.(Bennewitz and Saltzman, 2009) Biodegradable nanoparticles formulated with a drug molecule encapsulated by using polymeric nanoparticles whose size range lies between 50-
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200nm, resulting in increased bioavailability. For example, chitosan nanoparticles containing antiepileptic drug through intranasal route for used brain targeting. The formulation of
chitosan nanoparticles has overcome the limitation of low bioavailability due to short halflife, degradation due to proteolysis and small drug reaching the brain (Kaur et al., 2018).
Most of the drugs which are formulated in the form of nanoparticles and having lipophilic
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nature along with small particle enhance drug uptake by increasing the retention time at the application site by its mucoadhesive property. Also, it's thermosensitivity properties which
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help in the reduction of peripheral side effects (Abbas et al., 2018).
An electro-responsive hydrogel nanoparticles were developed to facilitate the delivery of
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anticonvulsants such as phenytoin sodium. The nanopaticels modified with angiopep-2 showed a greater distribution in the CNS and were able to release phenytoin during
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seizures.(Wang et al., 2016) 5.3. Parkinson’s disease:
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Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system (CNS) that mainly affects the motor system. For the most part, side effects come gradually
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after some time. In the initial stages of the disease, it includes gradual development of shaking, unbending nature and trouble with strolling. In the advanced stages, dementia becomes common, depression and anxiety are also common. Other symptoms may include emotional problems and sleep. The aetiology behind Parkinson's is obscure. However, it is acceptable to include genetic components (Rana et al., 2015). There are many standard dosages form available in the market, but it has the disadvantage of low bioavailability. Hence parenteral route is often preferred to attain affectively. Chitosan nanoparticles can be formulated to increase uptake of the drug into the brain. Due to its method of formulation 8
entrapment efficiency increases and further coating with nanoparticles helps in the effective conveyance of the medication to the cerebrum. For example, Ropinirole hydrochloride (RHCl) is non-ergoline dopamine (D2) receptor agonist used in combination therapy with levodopa to treat Parkinson’s disease. Numerous other methodologies have been produced to transfer medication to the cerebrum with the assistance of poly (lactic-co-glycolic corrosive) [PLGA] nanoparticles, nanostructured lipid transporter situated in situ gel and so on. The parenteral course is a lone alternative with the end goal to bypass hepatic first-pass metabolism (Ray et al., 2018). According to several researchers nose to brain transport of nanoparticles is an effective
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method for brain drug delivery. Chitosan, PLGA, solid lipid nanoparticles etc are often employed for this purose.(Kulkarni et al., 2015) recent studies have shown that gold
nanoclusters are effective in Parkinson’s therapy. They found to prevent α-Synuclein (α-Syn) fibrillation demonstrating good neuroprotective effects in Parkinson’s disease cell models in
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vitro.(Gao et al., 2019)
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5.4. Migraine treatment:
An intense, cerebral headache is the most widely recognised neurological, vascular ailment
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which causes a throbbing and throbbing agony around the head. Generally, neurological, vascular impairment includes odd affectability of supply routes in the cerebrum causing in triggers, which for the most part prompts quick changes in the vein breadth. Therefore,
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different courses in the mind and scalp expand bringing about appalling torment in the head. The patients who are suffering from such neurological disease has an extreme vomiting,
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gastric stasis and nausea. Oral treatment mostly unsuccessful during migraine attacks because of its unpredictable absorption and delayed gastric emptying from the gastrointestinal tract. Hence the alternate technique involves nasal drug delivery transporting, helps in direct transport of the medication to the brain given by olfactory or potentially trigeminal nerve framework present between the olfactory epithelium and the cerebrum. This method comprises a few disadvantages of rapid clearance of the medication by the nasal mucosal layer cilia, the concentration of the drug, dosage form, and others. Nanoformulation modification of intranasal route helps in delaying rapid clearance, and adequate amount 9
reaches the targeted site in the brain (Abdou et al., 2017). Rizatriptan benzoate nano emulsions were prepared for anti-migrane therapy. The emulsions were incorporated into a mucoadhesive gel form for better retention and prolonged release of the medicament.(Bhanushali et al., 2009; Harjot et al., 2016) In another study rizatriptan benzoate solid lipid nanoparticles were formulated and its pharmacokinetics was studied in wistar rats. Smooth surfaced particles ranging from a particle size of 145 to 298 nm which release the drug in 8 hrs were used for the study. The drug analysed in cerebrospinal fluid and in blood following an oral as well as intravenous administration. The formulation showed increased Cmax and AUC which was superior to marketed oral product and I.V. administered
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drug solution. (Singh et al., 2015) 5.5. Cerebrovascular disease:
Cerebrovascular disease is a medical condition that affects the blood vessels of the brain and cerebral circulation. Arteries with the function of supplying oxygen and nutrients to the brain
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are often damaged or deformed. The cerebrovascular disease results in the change in the structure of blood vessels and causes atherosclerosis. Atherosclerosis is a process where
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blood vessels in the brain become narrow, resulting in a reduction of cerebral perfusion. The most common way to represent cerebrovascular disease is an ischemic stroke or mini-stroke
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and sometimes, a haemorrhagic stroke. Hypertension (high blood pressure) gives an essential contribution to stokes; other risk factors contribute strokes are smoking and diabetes. (Yamamoto, 1994) Due to the difficulties in the transport of drug to the brain due to BBB,
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various attempts have discovered to overcome the problem such as carrier-mediated transport (CMD), receptor-mediated transport (RMT) and nano-sized system that includes nanosuspension, nanoparticles and micelles with different administration route. Intranasal
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route is often used administered drug for brain targeting since it has high bioavailability and avoids first-pass hepatic metabolism. (Ding et al., 2015) Ultrasmall superparamagnetic iron
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oxide particles found conjugating with vascular cell adhesion molecule‐ 1 making it possible to detect cerebral ischemia by MRI imaging.(Ajetunmobi et al., 2014; Fréchou et al., 2013) PLGA nanoparticles containing antioxidant enzymes such as superoxide dismutase produced promising results in preclinical testing in ischemic stroke models. Metal nanoparticles such as cerium oxide, platinum and selenium were able to reduce infarct volume above 50% when tested in rodent models.(Poellmann et al., 2018) 6. Brain targeting nanomaterials: 10
Different types of nanoformulations are prepared, such as polymer-based nanoparticles, metallic nanoparticles, carbon-based nanoparticles, lipid-based nanoparticles, ceramic nanoparticles, and semiconductor nanoparticles. Polymer-Based nanoparticles are those which are made up of polymer cores or matrix. These polymers are biocompatible and hydrolytically degradable, resulting their use in encapsulating and delivering several types of therapeutic molecules, including large biological macromolecules such as proteins and nucleic acids. (Rao and Geckeler, 2011) There two classes of polymers which are used in the preparation of nanoparticles, i.e. synthetic and a natural polymers. Several naturally derived polymers are used in the synthesis of polymeric nanoparticles, such as chitosan, gelatin,
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sodium alginate, albumin etc. Some of the synthetic polymers are polylactides (PLA), polyglycolide (PGA), poly (lactide-co-glycolides) (PLGA), polyanhydrides, polyorthoesters, polycyanoacrylates, polycaprolactone, poly-glutamic acid, poly malic acid, poly (N-vinyl pyrrolidone), poly (methyl methacrylate), poly (vinyl alcohol), poly (acrylic acid), poly
acrylamide, poly (ethylene glycol), poly (methacrylic acid). (Mallakpour and Behranvand,
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2016; Nagavarma et al., 2012)
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Carbon-based nanoparticles (CBNs) has a one-of-a-kind blend of chemical and physical properties practically, i.e., warm and electrical conductivity, high mechanical quality and optical properties which are known as multi-utilitarian natures. Because of these
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advantageous properties, it has been highly investigated in the industry for biomedical engineering, and it has been applied to biomedical purpose. One of the most tested and most
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broadly utilised normal carbon graphite customarily known as pencil lead, it is generally utilised in a few huge scale industries for various purpose like steelmaking, battery electrodes. Due to the high consumption of natural based, synthetic graphite based have been
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increased significantly. (Chaenyung Cha, Su Ryon Shin, Nasim Annabi, Mehmet R. Dokmeci and Khademhosseini, 2013; Zahid et al., 2018)
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Metal nanoparticles, the term used to describe metals of nanosizes (1-100nm) of dimensions are used as catalysts, absorbents, ferrofluids and sensors; they can be applied in electronic, magnetic and optical devices. Different materials are used in the preparation in metal nanoparticles as a precursor, for example, a metal anode, palladium chloride, potassium tetrachloroplatinate II, silver nitrate, chloroauric acid, rhodium chloride. Some of the polymers used in the formulation of metal nanoparticles are polyvinyl pyrrolidone and polyvinyl alcohol which act as stabilisers. A portion of the reducing agents is also used like
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hydrogen, sodium citrate, citric acid, carbon monoxide, methanol, formaldehyde, hydrogen peroxide. (Yonezawa, 2018) Semiconductor nanoparticles are widely used in medical purposes, such as quantum dots (QDs) are used as biosensors since it has attracted the attention of many scientists work because of their long-term photostability, makes real-time and continuous monitoring possible. A nanosensor model has been the development of immune chromatographic test strips; test strips are already an accessible tool in the market, for instance, pregnancy test strips. Semiconductor nanoparticles (NPs) referred to as II-VI, III-V or IV-VI semiconductor nanocrystals are produced using a scope of various compounds. Based on the groups in the
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periodic table into which these elements are formed they are numbered. For example, silicon and germanium are group IV, GaN, GaP, GaAs, InP and InAs are III-V, while those of ZnO, ZnS, CdS, CdSe and CdTe are II-VI semiconductors. (Hirai et al., 2000; Suresh, 2013)
Magnetic nanoparticles and ultrasmall superparamagnetic iron oxide are capable of serving as
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an aid in MRI imaging with their ability to concentrate in ischemic stroke
regions.(Ajetunmobi et al., 2014; Fréchou et al., 2013) metallic nanoparticles are also tested
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as drug carriers and as therapeutic options in various CNS disorders.(Poellmann et al., 2018) Lipid-based nanoparticles bear the benefit of being the slightest dangerous, flexible,
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biocompatible and biodegradable for in vivo applications. Considerable advancement has been made in the region of DNA/RNA and medication conveyance utilising lipid-based nanoassemblies. Phosphatidylcholine and phosphatidylethanolamine are vesicles of bilayer
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phospholipid; this helps in the formation of lipid-based nanoparticles. Commonly phospholipids are found in natural surroundings, for example, cholesterol and hydrophilic polymers which are also made up of bilayer vesicle. One of a critical part in the formation of
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liposomes is cholesterol because it supports lowering the fluidity, diminish the permeability of water-solvent particles through liposomal film bilayer which builds the strength in organic
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fluid, for example, blood and synovial fluid of the liposomal layer. (Buse J, 2010; Chuang et al., 2018; Puri et al., 2009) 7. Possible mechanisms of nanoparticles entering into the brain. The primary function of the nanoparticles is to deliver drug moiety to the desired target site. The shape, size and the surface properties of nanoparticles will help in increasing the bioavailability, blood retention and effective drug delivery. Recent studies are proving their employability in cancer therapy. The mechanism of the nanoparticles, crossing BBB, divided 12
into passive and active transport. The passive transport routes are energy independent, for example, diffusion. The passive diffusion of drugs mainly applies in tumor cells through the improved penetrability and retention effect. The active transport mechanism involves the receptor mediated endocytosis and carrier proteins mediated transport where the energy is utilised in the form of ATPs. Various mechanisms are listed and classified in figure 3.(Zhou et al., 2018) Passive diffusion is considered to be the mechanism of entry of gold nanoparticles into the brain crossing BBB.(Zhou et al., 2018) The passive diffusion of nanoparticles through BBB can be enhanced by altered permeability of the barrier. Several osmotic agents
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such as mannitol which are delivered along with nanoparticles can increase the permeability of BBB, thereby increasing the nanoparticle accumulation in brain. Permeability modification is also possible by using focused ultrasound at low intensities.(Poellmann et al., 2018)
Carried mediated transport such as transcytosis of nanoparticles across the BBB is achieved
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by surface modifications using various biological or similar materials. Particles such as
liposomes bearing positive charge on their surface may adhere to the endothelium and may
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get transported.(Poellmann et al., 2018; Zhou et al., 2018) Surface functionalization of nanoparticles using polysorbate 80 caused the binding of Apolipoproteins (ApoE and ApoB) thus the particles are reported by LDL tranport mechanism.(Chacko et al., 2018; Wilson,
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2009; Zhou et al., 2018) addition of ligands such as rabies virus glycoprotein and adenosine to PLGA nanoparticles is found to increase the BBB penetration. Study conducted on carbon
8. Conclusion
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quantum dots proposed a GLUT1 and ACST2 proteins assisted transport across BBB.
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Nanomaterials have expanded the surface zone, and nanoscale impacts are utilised as a promising approach for the brain drug delivery, gene delivery, biomedical imaging and as the
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analytical biosensors. Nanomaterials have exceptional physiochemical and organic properties when contrasted with their more prominent partners. The properties of nanomaterials will impact their connections with biomolecules and cells by their size, solubility, shape, surface structure, charge and agglomeration.
Conflict of interest: None 13
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Kulkarni, A.D., Vanjari, Y.H., Sancheti, K.H., Belgamwar, V.S., Surana, S.J., Pardeshi, C. V., 2015. Nanotechnology-mediated nose to brain drug delivery for Parkinson’s disease: A mini review. J. Drug Target. 23, 775–788. https://doi.org/10.3109/1061186X.2015.1020809 Lingineni, K., Belekar, V., Tangadpalliwar, S.R., Garg, P., 2017. The role of multidrug resistance protein (MRP-1) as an active efflux transporter on blood–brain barrier (BBB) permeability. Mol. Divers. 21, 355–365. https://doi.org/10.1007/s11030-016-9715-6 Loch-Neckel, G., Koepp, J., 2010. The blood-brain barrier and drug delivery in the central
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PII:
S0361-9230(18)30950-X
DOI:
https://doi.org/10.1016/j.brainresbull.2019.11.017
Reference:
BRB 9814
To appear in:
Brain Research Bulletin
Received Date:
3 December 2018
Revised Date:
16 November 2019
Accepted Date:
27 November 2019
Please cite this article as: V AN, APPROACHES FOR ENCEPHALIC DRUG DELIVERY USING NANOMATERIALS: THE CURRENT STATUS, Brain Research Bulletin (2019), doi: https://doi.org/10.1016/j.brainresbull.2019.11.017
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APPROACHES FOR ENCEPHALIC DRUG DELIVERY USING NANOMATERIALS: THE CURRENT STATUS
Anoop Narayanan V* [email protected]
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NGSM Institute of Pharmaceutical Sciences, NITTE University, 575018
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Corresponding author
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Highlights
Drug access to the brain remains as a challenge in most of the CNS disorders.
Nanotechnology create a breakthrough in brain targeting of drugs.
Varioius nano pharmaceutical approaches used in brain drug delivery is discussed.
Mechanisms of nanoparticles crossing BBB is explored.
Abstract:
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Nanotechnology, the investigation of little structures, ranging from the size of 1 nm to 100 nm presents a breakthrough in the field of targeted drug delivery. The microvasculature in the human brain along with the blood brain barrier (BBB) offers high resistance to the entry of therapeutics agents and other substances in to the brain. Nanoparticles have certain advantages as high permeability, reactivity, surface area and quantum properties and it also meets various medical challenges which may include poor bioavailability, difficulty in targeting, organ toxicity etc. The use of nanoparticles in pharmaceuticals has been inspired by 1
various natural nanomaterials found in the body, which includes proteins, lipids etc. A brief explanation of different types of pharmaceutical approaches used in brain drug delivery is discussed here. Nanotechnology is used treatment of many illnesses which also include diseases related to the brain such as gliomas, epilepsy, migraine, cerebrovascular disease, Parkinson’s disease etc., Different type of nanoparticles are prepared, such as polymer-based nanoparticles, metallic nanoparticles, carbon-based nanoparticles, lipid-based nanoparticles, ceramic nanoparticles semiconductor nanoparticles and are studied for their usefulness in drug delivery. The primary function of nanoparticles is to deliver drug moiety to the desired targeted site by overcoming permeability issues. The shape, size and surface area
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nanoparticles help in increasing the bioavailability, drug retention and multiple drug delivery. Mechanisms of nanoparticles crossing BBB can be divided into passive and active transport, are briefly explained.
Keywords: Nanoparticles; BBB; nanotechnology; tumour; metallic nanoparticles; brain drug
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delivery
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1. Introduction
Nanotechnology is a boon to the humanity enabling scientists to create medicines that can do wonders in the therapy. The extensive size reduction of drug and carrier materials into nano
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sizes can tremendously influence the physicochemical properties of these substances, thereby redefining the pharmacokinetics of drug molecules. In recent years the biological application
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of nanoparticles has been radically increased and now spreading its arms into the practical clinical scenarios. Nanoparticles (NPs) as defined, are the particulate materials whose size ranges between 1-100 nm. Since their little size range is in nanoscale they possess several
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unique properties like high permeability, high reactivity, huge surface area and quantum properties (Kamal et al., 2011; Surendiran et al., 2009). Nanoparticles still meet various medical challenges which may include poor stability and organ toxicity. The use of nanoparticles in medicines has been inspired by several natural nanomaterials found in the body such as proteins and lipids. For an instance, a lipid and polymer-based nanocarrier with drug encapsulated in it was attempted for the purpose of sustained and targeted drug delivery (Chen et al., 2016). 2
The size of animal cells ranges from 10,000 to 20,000 nm and hence nanoparticles can easily enter cells and organelles to interact with DNA and any other proteins. It also helps to detect the onset of diseases in a little amount of tissue or body fluids; they can also identify diseases in micro level and deliver the treatment. Due to their tiny sizes and larger surface area, nanoparticles often interact with biomolecules such as receptors and enzymes on both sides of cells. Nanoparticles made up or biomaterials consisting macromolecules serves as a substrate for molecular assembly such as drugs or other therapeutic substances. Nano formulation can also be found in the form vesicles as in liposomes with a membrane or layer surrounding a core material in it. Nanoparticles are mostly found in spherical or cylindrical
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shape, but it can also be seen in the rod, plate and many another forms that can be created by various processes (Idrees, 2013). 2. Challenges in brain targeting
The micro vasculature in the human brain is unique and that occupies the 3% of the brain’s
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volume. Extremely small capillaries of 7 to 10 μm are present in the brain with an average inter-capillary distance of 40 μm whereas the size of an RBC varies from 6 to 8 μm.
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(Duvernoy et al., 1983) This micro vascular network controls the transport of materials into the brain in a great extent. (Wong et al., 2013)
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The blood capillaries in the central nervous system (CNS) are lined with a superior type of endothelial cells known as blood-brain barrier (BBB), which structurally differ from any
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other capillaries present in other parts of the body. These capillaries are sealed with tight junctions; because of this property the BBB avoids access of many foreign materials into the brain. (Fig. 1)
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The complex integration between neighbouring endothelial cells are formed due to tight junctions and adherent junctions (fig 2). The endothelial cells of BBB join to form junction
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complex in the most apical section of the plasma membrane of adjacent cells. These are created by the interaction of several transmembrane proteins that extends and forms the cytoplasm, by a protein associated with cytoplasmic actin; forming a link between the endothelial cells. (Loch-Neckel and Koepp, 2010) The barrier properties of endothelial cells are supported by the lining of mural cells, immune cells and glial cells. The outer side of the capillaries are majorly occupied by the astrocyte endfeet. (Dobbing, 1961)
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Lipid soluble solutes diffuse freely through the capillaries as in the blood capillaries intercellular cleft, pinocytosis and fenestrate are virtually non-existent, and therefore components must pass transcellular. (Singh, 2013) The Blood Brain Barrier (BBB), the Blood-cerebrospinal fluid barrier (B-CSFB) and the blood-tumor barrier are the tough puzzles which make the delivery of drugs to the brain much more challenging than rest of the organs. As we pointed out in the above sentences, along with other barriers, BBB has a unique structure which may delay supply drugs to the brain, also to the spinal cord. There is a presence of very high trans-endothelial electrical resistance of >1500 Ωcm2 along the tight junction of BBB when compared to any other capillaries of the tissue, where it is just 3-30
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Ωcm2. (Ribecco-Lutkiewicz et al., 2018) Mainly because of the reasons mentioned above there is a reduction in the passive diffusion of aqueous based drugs to the brain in comparison with other organs of the body.
The impedes of drug transport is an enzymatic reaction which serves to protect the brain
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along with the physicochemical properties of drugs, these serve as an additional problem in the drug permeation across BBB. The two main types of traporters expressed in CNS are
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efflux transporters and nutrient transporters. Efflux transporters such as BCRP (Breast Cancer Resistance Protein), MRP-1 (multidrug resistance protein) and P-glycoprotein (MDRL) creates barrier to lipophilic substrates by transporting them across BBB against concentration
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gradient.(Dobbing, 1961; Lingineni et al., 2017) Polar nutrient transporters which transports glucose, amino acids, mono carboxylic acids are dependable for the delivery of polar
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compounds to the brain but their structural specificity remains as a hurdle.(SanchezCovarrubias et al., 2014) Some of the influx transport mechanisms that can be effectively utilized for drug delivery are large neutral amino acid transporter (LAT1) as in case of L-
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dopa, organic anion and cation transporters (OAT & OCT) and the choline transporters (CHT).(Mittapalli et al., 2010)
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The blood-cerebrospinal liquid obstruction (B-CSFB) is fantastic, offering one more hindrance that mindfully controls the entrance of molecules carried by the blood to the interstitial liquid of the cerebrum parenchyma and CSF attributable to the choroid plexus and the arachnoid film. At last, the blood-tumor barrier (BTB) coming about because of adjustments in cerebral microvasculature as the tumor makes it considerably more troublesome for medications to penetrate than normal brain endothelium, prompting outstandingly low additional tumoral interstitial medication and consistent development of intracranial malignancies. (M Zaki, 2012) 4
3. Different approaches used brain drug delivery Researchers used different strategies to increase the permeability of drug into the BBB. The first approach was an invasive route that finds a way through the obstacle of BBB by directly administering drug into the brain. Direct invasive route of the drug into the brain involves intracerebral and intrathecal administration it also requires a craniotomy. These dimensions have certain advantages, a wide range of small and large molecules can be delivered. Intranasal administration is also realised due to the bridge between brain and nose, known as olfactory bulb. Various compounds can be transported into the CNS through this intranasal
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path which also includes toxic agents, pathogens, viruses etc. An alternate approach involves disruption of BBB, where a hypertonic solution introduced
into the circulation via carotid artery, and the junctions open up due to the shrinking of cells. This mechanism utilises 30 minutes for a drug to administer. During this time, the tight
cellular junction between brain capillary endothelial cells have a paracellular diffusion (fig 2)
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of water-soluble drugs and solutes increased, on the other context, it also allows toxins
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present in the blood to pass through BBB.
In the third strategy, permeability is zoomed in by chemical modification to advance transcellular migration of the drug. Transcellular migration includes passive diffusion, a
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unique transport system and endocytosis. This strategy comprises minimal neurotoxicity when compared to disruption of BBB. (Roy Sandipan, 2012)
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Utilising nanoparticles as a carrier for encephalic drug delivery is an improved update of previous treatments. Moreover, nanoparticles can be guided more effectively to the olfactory nerve endings. The formulation of the drugs along with nanoparticles as a carrier creates a
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foundation of a promising approach of dosage. Formulations have proven to be reliable for application due to its liquid nature and have longer retention time due to its mucoadhesive
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and thermosensitive properties. Since the size of the nanoparticles is minute, they can directly approach the brain, and can be administered in smaller doses which helps to minimize any peripheral side effects (Abbas et al., 2018). A sort of biomimetic nanoparticles named as red platelet layer covered nanoparticles helps in holding the troublesome natural elements of cell films while displaying physicochemical properties that are reasonable for efficient drug delivery. RBC nanoparticles can achieve broadened blood distribution and exhibit minimised immunogenicity while assessing it with standard manufactured nanoscale medication delivery systems. (Chai et al., 2017) 5
Symmetric dendrimeric and non-symmetric hyperbranched polymers known as dendritic polymers are nanometre-sized, highly stretched macromolecules which comprise of a focal centre, fanning units and quite useful terminal groups that fluctuate in size from 1 to 1000 nm. The main highlight is that the bioactive compound is encapsulated in the nanocavity. Furthermore, polymers successfully established many approaches in preparing a varied choice of compounds used in the preparation of formulation and many other materials used in packaging, bottles, surgical sutures etc. Polymers consist significant amount of functional groups on their external surface, this structural feature of polymer helps in inducing powerful binding due to multivalency effect to the multiple cell receptors.
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Nanotechnology has been employed for gels in nanosize networks; that is made up of the hydrophilic polymers. These hydrophilic polymers can hold water-solvent peptides and
proteins which are therapeutics; this ability is due to the presence of cross-linked porous
networks. The extent of pores of nanogels is 10-400 nm usually. Subsequently, they are large
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enough to stay away from clearance from the course by glomerular filtration in the kidneys
while little enough to restrict freedom by the reticuloendothelial framework. Nanogels have
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likewise been perceived as vehicles for medication conveyance and its sophistication to the cerebrum and can be intended for upgrade responsive degradation and medication discharge
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(Bode et al., 2017).
Recently nano particulate systems were used in delivery of several drugs directly into brain through intra nasal routes. Such attempts included the delivery of docetaxel and loperamide
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using PLGA nanoparticles and insulin using chitosan nanoparticles. By the use of nanomedicine, the opportunity has been improved in the diagnosis and treatment of brain cancer. Several kinds of nanoparticles have been engaged as a drug delivery agent in the
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brain cancer therapy. These may include but not limited to gold nanoparticles, organic based hydrogel, polymer, gadolinium, liposomes, semi conduct quantum dots and micelles. Such
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nano substances developed often consists of targeting ligands that can help in specific penetration of the drug across the BBB. (Chai et al., 2017; Meyers et al., 2013) Delivery of insulin was successfully attempted as dry powder formulation using chitosan nanoparticles.(Dyer et al., 2002) 4. Nanotechnology in CNS disorders: Numerous amount advances have been carried out in the field of drug delivery every year to improvise treatment and understanding mainly against central nervous system (CNS) 6
disorders. Even after several efforts have been made in this particular area, it still did not meet challenges completely. The principal objective of BBB it is to maintain an environment in a constant order within CNS and to provide necessary nutrients. Although BBB is made up of tight junction of endothelial cells in the microvessels of the brain and BBB, its high restriction in the trading of outsider materials among blood and tissue parenchyma, despite everything it permits entry of proteins, for example, antibodies and so on into the cerebrum. Hence here the main challenge of a drug is to pass BBB. With the end goal to defeat previously mentioned test, enhanced medication conveyance has created by utilising colloidal drug transporters, for example, nanoparticles including liposomes, polymeric nanospheres
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and nanogels. Liposomes due to their potential drug carrier to target any specific organ including brain have gained high attention. Liposomes are tiny counterfeit vesicles of circular shape which comprise of a fluid centre composed by at least one bilayers made out of natural or synthetic, biocompatible and biodegradable lipids like organic layers. Nanoparticles can be combined with protein and peptides which help in the transfer of a drug across a biological
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membrane, in addition to that nanoparticles protect drugs against enzymatic degradation.
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(Bode et al., 2017)
5. Various treatments that can be carried out using nanomedicines
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5.1. Treatment of brain cancers by using nanomedicine:
The complexity of brain cancer treatment faced is due to the presence of numerous obstacles
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which includes BBB. The WHO has classified gliomas in 3 significant classes ie; astrocytoma, oligodendroglioma and oligoastrocytoma (mixed gliomas). Astrocytomas are the most common of the three categories. Usually, astrocytomas are treated by chemotherapy,
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radiotherapy and surgical method, with a primary objective of lengthening survival time and improving health rather than curing the disease (Craciunescu et al., 2003). Tumor treatment
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can disrupt the properties of vascular endothelium, and it may also disrupt the BBB. In the early stages of a tumor, there are no changes in the structure of BBB, as the tumor progress occurs BBB remains intact which makes surgical resection inflexible or, in other words, the fast backslide of cerebrum tumors. Subsequently, conventional chemotherapeutics cannot be conveyed to the brain successfully (Hua et al., 2018). 5.2. Nanocarriers used in the treatment of epilepsy:
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Epilepsy is a most severe type neurological disorder which affects approximately 50 million people globally. It is characterised by recurrent seizures, which involves the involuntary movement of the entire body or a part of the body for a brief period. A seizure is resultant of excessive electrical discharges in cells of the brain. Even though there are some successful anti-epileptic drugs (AEDs) found in the market, but there may be chance epilepsy becoming out of control in many patients, which leads to failure of AEDs. More over oral and intravenous routes were not very effective due to the hindrance offered by blood brain barrier.(Bennewitz and Saltzman, 2009) Biodegradable nanoparticles formulated with a drug molecule encapsulated by using polymeric nanoparticles whose size range lies between 50-
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200nm, resulting in increased bioavailability. For example, chitosan nanoparticles containing antiepileptic drug through intranasal route for used brain targeting. The formulation of
chitosan nanoparticles has overcome the limitation of low bioavailability due to short halflife, degradation due to proteolysis and small drug reaching the brain (Kaur et al., 2018).
Most of the drugs which are formulated in the form of nanoparticles and having lipophilic
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nature along with small particle enhance drug uptake by increasing the retention time at the application site by its mucoadhesive property. Also, it's thermosensitivity properties which
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help in the reduction of peripheral side effects (Abbas et al., 2018).
An electro-responsive hydrogel nanoparticles were developed to facilitate the delivery of
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anticonvulsants such as phenytoin sodium. The nanopaticels modified with angiopep-2 showed a greater distribution in the CNS and were able to release phenytoin during
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seizures.(Wang et al., 2016) 5.3. Parkinson’s disease:
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Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system (CNS) that mainly affects the motor system. For the most part, side effects come gradually
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after some time. In the initial stages of the disease, it includes gradual development of shaking, unbending nature and trouble with strolling. In the advanced stages, dementia becomes common, depression and anxiety are also common. Other symptoms may include emotional problems and sleep. The aetiology behind Parkinson's is obscure. However, it is acceptable to include genetic components (Rana et al., 2015). There are many standard dosages form available in the market, but it has the disadvantage of low bioavailability. Hence parenteral route is often preferred to attain affectively. Chitosan nanoparticles can be formulated to increase uptake of the drug into the brain. Due to its method of formulation 8
entrapment efficiency increases and further coating with nanoparticles helps in the effective conveyance of the medication to the cerebrum. For example, Ropinirole hydrochloride (RHCl) is non-ergoline dopamine (D2) receptor agonist used in combination therapy with levodopa to treat Parkinson’s disease. Numerous other methodologies have been produced to transfer medication to the cerebrum with the assistance of poly (lactic-co-glycolic corrosive) [PLGA] nanoparticles, nanostructured lipid transporter situated in situ gel and so on. The parenteral course is a lone alternative with the end goal to bypass hepatic first-pass metabolism (Ray et al., 2018). According to several researchers nose to brain transport of nanoparticles is an effective
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method for brain drug delivery. Chitosan, PLGA, solid lipid nanoparticles etc are often employed for this purose.(Kulkarni et al., 2015) recent studies have shown that gold
nanoclusters are effective in Parkinson’s therapy. They found to prevent α-Synuclein (α-Syn) fibrillation demonstrating good neuroprotective effects in Parkinson’s disease cell models in
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vitro.(Gao et al., 2019)
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5.4. Migraine treatment:
An intense, cerebral headache is the most widely recognised neurological, vascular ailment
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which causes a throbbing and throbbing agony around the head. Generally, neurological, vascular impairment includes odd affectability of supply routes in the cerebrum causing in triggers, which for the most part prompts quick changes in the vein breadth. Therefore,
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different courses in the mind and scalp expand bringing about appalling torment in the head. The patients who are suffering from such neurological disease has an extreme vomiting,
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gastric stasis and nausea. Oral treatment mostly unsuccessful during migraine attacks because of its unpredictable absorption and delayed gastric emptying from the gastrointestinal tract. Hence the alternate technique involves nasal drug delivery transporting, helps in direct transport of the medication to the brain given by olfactory or potentially trigeminal nerve framework present between the olfactory epithelium and the cerebrum. This method comprises a few disadvantages of rapid clearance of the medication by the nasal mucosal layer cilia, the concentration of the drug, dosage form, and others. Nanoformulation modification of intranasal route helps in delaying rapid clearance, and adequate amount 9
reaches the targeted site in the brain (Abdou et al., 2017). Rizatriptan benzoate nano emulsions were prepared for anti-migrane therapy. The emulsions were incorporated into a mucoadhesive gel form for better retention and prolonged release of the medicament.(Bhanushali et al., 2009; Harjot et al., 2016) In another study rizatriptan benzoate solid lipid nanoparticles were formulated and its pharmacokinetics was studied in wistar rats. Smooth surfaced particles ranging from a particle size of 145 to 298 nm which release the drug in 8 hrs were used for the study. The drug analysed in cerebrospinal fluid and in blood following an oral as well as intravenous administration. The formulation showed increased Cmax and AUC which was superior to marketed oral product and I.V. administered
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drug solution. (Singh et al., 2015) 5.5. Cerebrovascular disease:
Cerebrovascular disease is a medical condition that affects the blood vessels of the brain and cerebral circulation. Arteries with the function of supplying oxygen and nutrients to the brain
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are often damaged or deformed. The cerebrovascular disease results in the change in the structure of blood vessels and causes atherosclerosis. Atherosclerosis is a process where
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blood vessels in the brain become narrow, resulting in a reduction of cerebral perfusion. The most common way to represent cerebrovascular disease is an ischemic stroke or mini-stroke
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and sometimes, a haemorrhagic stroke. Hypertension (high blood pressure) gives an essential contribution to stokes; other risk factors contribute strokes are smoking and diabetes. (Yamamoto, 1994) Due to the difficulties in the transport of drug to the brain due to BBB,
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various attempts have discovered to overcome the problem such as carrier-mediated transport (CMD), receptor-mediated transport (RMT) and nano-sized system that includes nanosuspension, nanoparticles and micelles with different administration route. Intranasal
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route is often used administered drug for brain targeting since it has high bioavailability and avoids first-pass hepatic metabolism. (Ding et al., 2015) Ultrasmall superparamagnetic iron
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oxide particles found conjugating with vascular cell adhesion molecule‐ 1 making it possible to detect cerebral ischemia by MRI imaging.(Ajetunmobi et al., 2014; Fréchou et al., 2013) PLGA nanoparticles containing antioxidant enzymes such as superoxide dismutase produced promising results in preclinical testing in ischemic stroke models. Metal nanoparticles such as cerium oxide, platinum and selenium were able to reduce infarct volume above 50% when tested in rodent models.(Poellmann et al., 2018) 6. Brain targeting nanomaterials: 10
Different types of nanoformulations are prepared, such as polymer-based nanoparticles, metallic nanoparticles, carbon-based nanoparticles, lipid-based nanoparticles, ceramic nanoparticles, and semiconductor nanoparticles. Polymer-Based nanoparticles are those which are made up of polymer cores or matrix. These polymers are biocompatible and hydrolytically degradable, resulting their use in encapsulating and delivering several types of therapeutic molecules, including large biological macromolecules such as proteins and nucleic acids. (Rao and Geckeler, 2011) There two classes of polymers which are used in the preparation of nanoparticles, i.e. synthetic and a natural polymers. Several naturally derived polymers are used in the synthesis of polymeric nanoparticles, such as chitosan, gelatin,
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sodium alginate, albumin etc. Some of the synthetic polymers are polylactides (PLA), polyglycolide (PGA), poly (lactide-co-glycolides) (PLGA), polyanhydrides, polyorthoesters, polycyanoacrylates, polycaprolactone, poly-glutamic acid, poly malic acid, poly (N-vinyl pyrrolidone), poly (methyl methacrylate), poly (vinyl alcohol), poly (acrylic acid), poly
acrylamide, poly (ethylene glycol), poly (methacrylic acid). (Mallakpour and Behranvand,
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2016; Nagavarma et al., 2012)
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Carbon-based nanoparticles (CBNs) has a one-of-a-kind blend of chemical and physical properties practically, i.e., warm and electrical conductivity, high mechanical quality and optical properties which are known as multi-utilitarian natures. Because of these
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advantageous properties, it has been highly investigated in the industry for biomedical engineering, and it has been applied to biomedical purpose. One of the most tested and most
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broadly utilised normal carbon graphite customarily known as pencil lead, it is generally utilised in a few huge scale industries for various purpose like steelmaking, battery electrodes. Due to the high consumption of natural based, synthetic graphite based have been
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increased significantly. (Chaenyung Cha, Su Ryon Shin, Nasim Annabi, Mehmet R. Dokmeci and Khademhosseini, 2013; Zahid et al., 2018)
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Metal nanoparticles, the term used to describe metals of nanosizes (1-100nm) of dimensions are used as catalysts, absorbents, ferrofluids and sensors; they can be applied in electronic, magnetic and optical devices. Different materials are used in the preparation in metal nanoparticles as a precursor, for example, a metal anode, palladium chloride, potassium tetrachloroplatinate II, silver nitrate, chloroauric acid, rhodium chloride. Some of the polymers used in the formulation of metal nanoparticles are polyvinyl pyrrolidone and polyvinyl alcohol which act as stabilisers. A portion of the reducing agents is also used like
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hydrogen, sodium citrate, citric acid, carbon monoxide, methanol, formaldehyde, hydrogen peroxide. (Yonezawa, 2018) Semiconductor nanoparticles are widely used in medical purposes, such as quantum dots (QDs) are used as biosensors since it has attracted the attention of many scientists work because of their long-term photostability, makes real-time and continuous monitoring possible. A nanosensor model has been the development of immune chromatographic test strips; test strips are already an accessible tool in the market, for instance, pregnancy test strips. Semiconductor nanoparticles (NPs) referred to as II-VI, III-V or IV-VI semiconductor nanocrystals are produced using a scope of various compounds. Based on the groups in the
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periodic table into which these elements are formed they are numbered. For example, silicon and germanium are group IV, GaN, GaP, GaAs, InP and InAs are III-V, while those of ZnO, ZnS, CdS, CdSe and CdTe are II-VI semiconductors. (Hirai et al., 2000; Suresh, 2013)
Magnetic nanoparticles and ultrasmall superparamagnetic iron oxide are capable of serving as
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an aid in MRI imaging with their ability to concentrate in ischemic stroke
regions.(Ajetunmobi et al., 2014; Fréchou et al., 2013) metallic nanoparticles are also tested
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as drug carriers and as therapeutic options in various CNS disorders.(Poellmann et al., 2018) Lipid-based nanoparticles bear the benefit of being the slightest dangerous, flexible,
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biocompatible and biodegradable for in vivo applications. Considerable advancement has been made in the region of DNA/RNA and medication conveyance utilising lipid-based nanoassemblies. Phosphatidylcholine and phosphatidylethanolamine are vesicles of bilayer
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phospholipid; this helps in the formation of lipid-based nanoparticles. Commonly phospholipids are found in natural surroundings, for example, cholesterol and hydrophilic polymers which are also made up of bilayer vesicle. One of a critical part in the formation of
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liposomes is cholesterol because it supports lowering the fluidity, diminish the permeability of water-solvent particles through liposomal film bilayer which builds the strength in organic
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fluid, for example, blood and synovial fluid of the liposomal layer. (Buse J, 2010; Chuang et al., 2018; Puri et al., 2009) 7. Possible mechanisms of nanoparticles entering into the brain. The primary function of the nanoparticles is to deliver drug moiety to the desired target site. The shape, size and the surface properties of nanoparticles will help in increasing the bioavailability, blood retention and effective drug delivery. Recent studies are proving their employability in cancer therapy. The mechanism of the nanoparticles, crossing BBB, divided 12
into passive and active transport. The passive transport routes are energy independent, for example, diffusion. The passive diffusion of drugs mainly applies in tumor cells through the improved penetrability and retention effect. The active transport mechanism involves the receptor mediated endocytosis and carrier proteins mediated transport where the energy is utilised in the form of ATPs. Various mechanisms are listed and classified in figure 3.(Zhou et al., 2018) Passive diffusion is considered to be the mechanism of entry of gold nanoparticles into the brain crossing BBB.(Zhou et al., 2018) The passive diffusion of nanoparticles through BBB can be enhanced by altered permeability of the barrier. Several osmotic agents
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such as mannitol which are delivered along with nanoparticles can increase the permeability of BBB, thereby increasing the nanoparticle accumulation in brain. Permeability modification is also possible by using focused ultrasound at low intensities.(Poellmann et al., 2018)
Carried mediated transport such as transcytosis of nanoparticles across the BBB is achieved
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by surface modifications using various biological or similar materials. Particles such as
liposomes bearing positive charge on their surface may adhere to the endothelium and may
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get transported.(Poellmann et al., 2018; Zhou et al., 2018) Surface functionalization of nanoparticles using polysorbate 80 caused the binding of Apolipoproteins (ApoE and ApoB) thus the particles are reported by LDL tranport mechanism.(Chacko et al., 2018; Wilson,
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2009; Zhou et al., 2018) addition of ligands such as rabies virus glycoprotein and adenosine to PLGA nanoparticles is found to increase the BBB penetration. Study conducted on carbon
8. Conclusion
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quantum dots proposed a GLUT1 and ACST2 proteins assisted transport across BBB.
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Nanomaterials have expanded the surface zone, and nanoscale impacts are utilised as a promising approach for the brain drug delivery, gene delivery, biomedical imaging and as the
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analytical biosensors. Nanomaterials have exceptional physiochemical and organic properties when contrasted with their more prominent partners. The properties of nanomaterials will impact their connections with biomolecules and cells by their size, solubility, shape, surface structure, charge and agglomeration.
Conflict of interest: None 13
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