Nanotechnology for Alzheimer Disease

Send Orders for Reprints to [email protected] Current Alzheimer Research, 2017, 14, 1-8

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RESEARCH ARTICLE

Nanotechnology for Alzheimer Disease Jerzy Leszek1,#, Ghulam Md Ashraf 2,#, Wai Hei Tse3, Jin Zhang3,4, Kazimierz Gąsiorowski5, Marco Fidel Ávila-Rodriguez6, Vadim V. Tarasov7, George E. Barreto6,8, Sergey G. Klochkov9, Sergey O. Bachurin9 and Gjumrakch Aliev9,10,11,* 1

Wroclaw Medical University, Department of Psychiatry, Wroclaw, Poland; 2King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; 3University of Western Ontario, Department of Medical Biophysics, Ontario, Canada; 4University of Western Ontario, Department of Chemical and Biochemical Engineering, Ontario, Canada; 5Department of Basic Medical Sciences, Wroclaw Medical University, Wroclaw, Poland; 6Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; 7Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia; 8 Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile; 9Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, 142432, Russia; 10GALLY International Biomedical Research Consulting LLC., San Antonio, TX, 78229, USA;11School of Health Science and Healthcare Administration, University of Atlanta, Johns Creek, GA, 30097, USA

ARTICLE HISTORY Received: November 05, 2016 Revised: December 07, 2016 Accepted: January 30, 2017 DOI: 10.2174/15672050146661702031 25008

Abstract: Alzheimer’s disease (AD) typically affects behavior, memory and thinking. The change’s in brain has been reported to begin approx. 10-20 years before the appearance of actual symptoms and diagnosis of AD. An early stage diagnosis and treatment of this lethal disease is the prime challenge, which is mainly halted by the lack of validated biomarkers. Recent nanotechnological advancements have the potential to offer large scale effective diagnostic and therapeutic options. Targeted drug (e.g. Rivastigmine) delivery with the help of nanoparticles (NPs) in the range of 1-100 nm diameters can effectively cross the blood brain barrier with minimized side effects. Moreover, biocompatible nanomaterials with increased magnetic and optical properties can act as excellent alternative agents for an early diagnosis. With the high volume of research coming in support of the effective usage of NP based drug delivery in critical environment of CNS, it is quite likely that this approach can end up providing remarkable breakthroughs in early stage diagnosis and therapy of AD. In the current review, we have presented a comprehensive outlook on the current challenges in diagnosis and therapy of AD, with an emphasis on the effective options provided by biocompatible NPs as imaging contrast agents and drug carriers.

Keywords: Alzheimer’s disease, dementia, drug delivery, nanoparticles, neuroprotection. INTRODUCTION Alzheimer disease (AD) is the most prevalent neurodegenerative disorder (NDD) affecting more than 35 million people worldwide, with no full proof diagnosis apart from the post-mortem identification of neurofibrillary tangles (NFTs) and senile plaques (SP) in the brain [1, 2]. The premortem diagnosis of AD that is based primarily on neurological, cognitive and neuropsychological tests, in vivo brain imaging and patient’s clinical history has been reported to provide a maximum 85% accuracy. The soluble AD markers can be detected by two general approaches. The first approach which measures the total amyloid-β (Aβ) or tau pro*Address correspondence to this author at the “GALLY” International Biomedical Research Consulting LLC, San Antonio, TX 78229, USA; Tel: +440-263-7461; E-mail: [email protected], [email protected] # Equally contributing author 1567-2050/17 $58.00+.00

tein in the plasma or cerebrospinal fluid (CSF) has been hampered by a remarkable overlap of these markers in healthy as well as affected individuals, thus leading to not so conclusive results [3]. The second approach which utilizes the pathogenic markers like Aβ-derived diffusible ligands (ADDLs) and phosphorylated and cleaved tau protein may provide more conclusive findings, but their low CSF concentrations in early AD make it very tough to accurately identify them by ELISA or blotting assays [2, 4]. Nanotechnological advances have now started to exert a remarkable impact in neurology and neurodegeneration [5]. These approaches based on the engineering of nanoparticles (NPs) specific for brain specific endothelial cells (EC) are now gaining attention in AD diagnosis and therapy [6, 7]. The NPs which are highly specific for circulating Aβ may improve the AD condition by inducing a “sink effect” [8, 9]. The new in vitro developments related to AD diagnostics include scanning, tunnelling microscopy procedures, immu© 2017 Bentham Science Publishers

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nosensors, and ultrasensitive NP-based bio-barcodes, which are capable of detecting Aβ (1-40) and Aβ (1-42) [8, 10]. Despite these advances, some major concerns related to the initiation of NP-mediated adverse events in AD demand the engineering of precisely assembled biocompatible nanoconstructs [8]. Biocompatible nanoconstructs (Fig. 1) can be synthesized from biopolymers, chitosan [11], gelatin [11, 12], and polymers [13], or from the semi-conductive metals-gold [14] and cadmium [15] though adverse effects such as cytotoxicity or inhibition of cytokinesis, which can result from physiological applications. Quantum dots synthesized from the more commonly used cadmium are cytotoxic due to the liberation of Cd2+ ions during the deterioration of the CdSe crystal lattice [16, 17]. Others have demonstrated in vitro the disruption of tubulin orientation leading to cell cycle arrest and prevention of cytokinesis caused by the internalization of polymeric NPs as small as 10s of nanometers [18]. However, since the emergence of nanoscience and nanotechnology some 20 years ago [19], there have been many developments to counteract some of these affects. For example, the modification of quantum dots with shells have not only lowered the toxicity but also provided functional groups for ligand, DNA, or peptide bioconjugation [20, 21]. In the present discussion, the focus will be on materials with dimensions < 100 nm, which are the length scales even below the observation capacity of simple, optical or confocal microscopy. The nanosized objects are about 100 to 10000 times smaller than the size of mammalian cells. The primary structural characterization techniques at this scale include confocal/optical/fluorescence microscopy, scanning/transmission electron microscopy, nuclear magnetic resonance (NMR) and X-ray crystallography. The amyloid precursor protein (APP) for instance is an actual X-ray crystal structure visualized by visual molecular dynamics (VMD) [22]. In comparison, a potential AD therapeutic candidate dehydroevodiamine hydrochloride (DHED), is much smaller in size [23]. Micro-sized nano-microspheres can carry nanosized cargo into neurobiological systems by their ability to get readily endocytosed into the cytosol [24-26]. DIAGNOSING AD: DEVELOPMENTS

NANOTECHNOLOGY-BASED

AD pathogenesis is primarily typified as the gradual loss of neurons and synapses, thus causing gross atrophy in multiple regions of the affected brain [27]. At present, the reliable early diagnosis of AD is very tough and is often mistaken with other age/stress-related conditions. All the available clinical methods of AD diagnosis including neuropsychological testing and brain imaging can provide a maximum of 85% accuracy, and that too at a much later stage of the disease. The accurate diagnosis can only be obtained postmortem by examining the brain issue in an autopsy [28]. Early detection of the disease remains important for the reason that it can determine the treatment efficacy and help in proper evaluation of experimental treatments. The clinical symptoms (memory/cognition decline) of AD appear usually much after the beginning of deterioration of neural tissues, thus proclaiming the need of much more sensitive and reliable approaches for an early detection of neurodegeneration.

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Being neurotoxic and hypothesized as causative agent of AD related memory loss, ADDLs have been implicated in AD pathogenesis [29, 30]. A significant difference in CSF concentrations of ADDLs in normal and AD patients proclaims them as a potentially reliable marker [30]. However, the weak signal due to low concentration of these biomarkers is not detected reliably by ELSIA, but can be detected by a newly developed ultrasensitive method called bio-barcode assay [29]. The barcode technique utilizes magnetic iron oxide core microparticles and gold NPs (attached to a large number of “barcode” DNA oligonucleotide strands) suspended in solution and conjugated with ADDL specific antibodies. The authors used the term “barcode” DNA because of the unique label specific to the target protein (ADDL in this case) [4, 31]. In procedures similar to the traditional ELISA, the particle-ADDL-particle sandwich is removed magnetically from the solution, the barcode DNA is released from the sandwich with elevated temperature and low-salt conditions and then read using standard DNA detection methods such as gel electrophoresis, fluorescent probes in real time PCR, electrochemistry, scanometric detection, etc. The high sensitivity enabled measurement of ADDL levels of about 200 aM (attomolar, 200 x 10-18 moles/L) in CSF of healthy people, whereas in AD patients, the levels were markedly higher, about 1.7 fM (femtomolar, 1.7 x 10-15 moles/L) [4]. Using this novel assay, approx. 10 times higher ADDL concentration was observed in the AD-CSF samples as compared to healthy-CSF samples [4]. The fact that CSF samples are not easily available is encouraging the researchers to investigate the possibility of adapting this method for blood samples, which would greatly simplify the effective usage of this promising diagnostic tool. The optical property named localized surface plasmon resonance (LSPR) possessed by silver and gold NPs is now being utilized in diagnostic approach targeting the ADDL biomarkers [32-34]. The systematic analysis of an assay utilizing triangular silver NPs prepared by nanospheres lithography employing UV-VIS spectroscopy exhibited noticeable shifts in the maximum excitation wavelength via changes in refractive index on the addition of even nanomolar concentrations of ADDLs; with remarkably varying responses to CSF and brain extracts from healthy and AD individuals [35]. There are many other studies utilizing nanomaterials for novel imaging methods, thus generating new in vivo ways to study and detect new pathological markers and help evaluate the clinical efficacy of new drugs in clearing the toxic plaques. POTENTIAL NANO-ENABLED ROUTES TO THERAPY FOR AD At present, there is no definitive cure available to reverse the AD induced neurodegeneration. The medications available in the market can at the most provide some degree of symptomatic relief, which can slightly improve the brain cells’ communication but cannot halt the process of degeneration. However, continuous research efforts are being made to identify and develop the “disease modifying” strategies which can catch the root cause of AD and halt neurodegeneration [35, 36]. The most obvious hurdle in the effective transfer of therapeutic agents from blood to brain is the blood brain barrier (BBB), which is a two way selective

Nanotechnology and Alzheimer Disease

Current Alzheimer Research, 2017, Vol. 14, No. 7

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Fig. (1). Example of nanoparticles constructed from biocompatible molecules. Base materials contain functional groups that will affect the carrier’s interaction with mammalian cells (A). Conversely, these same functional groups can be modified through conjugation or other modification strategies to modify the physical properties of the nanoparticles. Synthesis strategies of various materials will yield particles of different sizes as demonstrated by the TEM micrographs of gelatine (B) and chitosan (C).

filter between neural tissues and blood capillaries. BBB performs the crucial role as protective barrier for “foreign substances” like disease causing agents and toxins circulating in bloodstream and also for large active molecules which may be of good therapeutic value [37-39]. Hence, a new strategy to overcome this natural physiological barrier is quite desirable. In this attempt, a number of new options for engineering nano-carriers laced with desirable surface properties are being explored to facilitate effective, safe and targeted delivery of active molecules across BBB and their sustained release in the brain. These nanosystems could act as “Trojan horses” by masking the physicochemical properties of the encapsulated/embedded therapeutic agents, thus promoting the transport of such molecules across the BBB. Additionally, these nanocarriers can enhance the bioavailability of encapsulated molecules by shielding them against enzymatic degradation and hence enhancing their half life. These modifications would naturally enhance the efficacy of the nanocarriers, and with drastic reduction in the quantity of therapeutic agent required, any probable undesired side effect would also be minimized. Nanocarriers though biocompatible, are foreign materials to the body. Once introduced, a cascade of proteins will bind onto the foreign substances to form a protein corona [40, 41]. This corona will a) increase the size of the NP to affect crossing the BBB; and b) promote opsonization by macrophages and eventually elimination, thereby reducing the halflife of the circulating particles [42]. Several research groups have shown the surface conjugation of polyethylene glycol (PEG) of various lengths onto different NPs [e.g. polystyrene, gelatin, poly(lactic acid), etc.] which have been proven

to reduce opsonization [30] and enhance cellular uptake in vitro as well as in vivo [13, 43, 44]. Similar reports of surface modifications with antibodies have demonstrated enhanced cellular internalization and specificity (Fig. 2A). Though at the nano level, such functionalized particles would only be effective if they are small enough to cross the BBB. Endogenous receptor-mediated transcytosis has been used for its efficient and site-specific drug transport through the brain. This method exploits the brain EC receptors for recognizing and transferring special ligands and low-density lipoprotein to trigger receptor-mediated endocytosis to transport drugs across the BBB. One such case demonstrated the conjugation of lactoferrin (ligand) to cyclodextrin, thus greatly improving the transport efficiency across the BBB [45]. In the past few years, emphasis has been placed on developing MRI guided and focused ultrasound to selectively and focally disrupt the BBB to increase its permeability to macromolecules (Fig. 2A). The MRI provides non-invasive real-time tracking of NPs. Etame et al. demonstrated the potential of this enhanced delivery system with PEG thiolated onto 50 nm gold NPs in a rat model [46]. Similarly, Marty et al. quantified the maximum gap between EC of rat BBB generated by the ultrasound was ~65 nm with the aid of various ultra small superparamagnetic iron oxide NPs and gadolinium-based MRI contrast agents [47]. The functionalized drug carrier would have to be less than 65 nm in diameter to be compatible with this method. A small enough model carrier hybridized with MRI compatible quantum dots and bioconjugated antibodies would provide the means to confirm the delivery of the NPs as well as increase the specific-


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ity and interaction with target cells (Fig. 2B). Highly specific antibodies and extensive modification would be required to ensure high specificity with specific type of cells. As a result of this modification strategy, the interior of the NP can be retained for drug encapsulation. In the next section, we present investigations on nanoparticulate systems and nano-related approaches having a direct implication on the management of AD. NANO-MEDIATED DRUG DELIVERY Rivastigmine is one of the few drugs which are used for the alleviation of symptoms related to mild to moderate dementia, making it a target candidate for NP-mediated drug delivery in brain [48]. A 3.82 fold enhanced uptake was observed when rivastigmine bound to Poly(n-butylcyanoacrylate) (PnBCA) coated with chemical polysorbate 80 was injected intravenously. This in turn could be attributed to the binding of blood lipoproteins to the surface of NPs [49]. In another pharmacodynamics study on amnesic mice, rivastigmine bound to PnBCA-NPs and poly(lactide-coglycolide) (PLGA)-NPs induced faster memory reversal in AD patients, thus indicating an enhanced delivery in mouse brain [50]. Based on the use of single wall carbon nanotubes (SWCNTs) as carrier, a new approach has been proposed to deliver acetylcholine (ACh) to brain to alleviate the disrupted cholinergic neurotransmission in AD patients [51]. Indeed, many other anti-ACHE or AChEI have been encapsulated in NPs to improve its brain delivery [52]. Earlier studies have raised concerns regarding the toxicity of SWCNTs towards the mitochondria in cells, but this study demonstrated that a safer delivery of Ach to target organelles is possible by carefully monitoring the dosage [23]. Moreover, the functionalization of carbon nanotubes with biomolecules like branched Polyethylene glycol (PEG) chains provides an enhanced suitability and biocompatibility as a drug delivery vehicle [53].

and aggravating neurodegeneration [54-61]. Oxidative stress induced by Aβ has been reported to contribute remarkably in AD neurodegeneration and other brain related complications [60, 62-65]. The deposition of amyloid has been reported to cause mitochondrial dysfunction, thus resulting in generation of free radicals, which in turn can initiate apoptotic pathway [66]. Thus, nanocarriers may provide sound alternative for the efficient transport of antioxidants into brain which can neutralize free radicals, hence providing protection against their damaging actions in AD. One potential antioxidant approach is the use of curcumin found in the spice turmeric, which plays pivotal role in ayurvedic treatment for variety of ailments. The presence of curcumin endows it with valuable well established medicinal properties [67]. In vivo as well as in vitro studies have demonstrated the remarkable beneficial effects of curcumin in AD pathology; especially its ability to interact with metal ions and prevent metal induced Aβ aggregation, inhibit Aβ formation and destabilize preformed Aβ fibrils [68, 69], and its strong antioxidant activity [67, 70]. Hence, curcumin administration could be a potential preventive and therapeutic strategy against AD [47, 54, 55, 71].

AP-

Other important potential antioxidant-based therapy is the Fullerene. Owing to its potent antioxidant activity, the well known buckminsterfullerene (C60) has been referred as “free radical sponge” [72]. However, the native C60 has been reported to be soluble only in few biologically unattractive solvents like benzene and toluene. As a preferred alternative, the water soluble carboxyfullerene (carboxylic acid functionalized forms of C60) are being investigated for their neuroprotection ability against free radicals [73]. In a study on cultured cortical neurons, the malonic acid derivative C60 was reported to eliminate hydroxyl radical as well as superoxide anion, thus diminishing the AD-Aβ (1-42) induced neuronal cell death [74]. Fullerenols, the water soluble hydroxyl derivative of fullerene, (fullerenols) are another species with the ability to scavenge free radicals and exert neuroprotective effect on cortical cell cultures [75, 76].

An enhanced presence of oxidative mediated free radicals has been vastly reported to play causative role in triggering

Another promising antioxidant therapy is chelation therapy. Increasing evidences have provided a strong link between unusual concentration of some metals in brain and the

NANO-ENABLED NEUROPROTECTIVE PROACHES: ANTIOXIDANTS

Fig. (2). Optimal drug delivery parameters. MRI-guided ultrasound is a technique-in-development for simultaneous tracking of MRI responsive nanoparticles’ movement across the BBB through tight junctions as it is disrupted by ultrasound waves (A). Nanoparticles < 65 nm will easily permeate through the BBB with the aid of ultrasound waves. An ideal drug carrier for this method should be able to encapsulate pharmaceuticals, have a mode of delivery confirmation (ie MRI responsive quantum dots), and a method of increasing specificity for its target (ie antibodies). Figure 2B, illustrates the external conjugation of antibodies and quantum dots to maximize the intracarrier space for drug encapsulation.

Nanotechnology and Alzheimer Disease

AD associated neurodegeneration. The accumulation of redox active metal ions like iron may act as the source of toxic free radicals inciting oxidative damage [77, 78]. Aβ metal redox reactions generated by ROS have been hypothesized as a crucial mechanism for the neurotoxicity of Aβ oligomers. In AD brains, a gradual accumulation of metals has been reported during the progression of disease from moderate to severe stage [79]. In vitro studies have suggested that biometals may bind to Aβ to promote its aggregation and formation of insoluble deposits [77, 80-83], with a consistent possibility of enhanced levels of metals like Fe, Zn and Cu observed in the diseased brain [84]. These findings suggest that the use of metal chelating compounds to correct the metal imbalance in brain and attenuate metal induced toxic effects could be a potential approach for neuroprotection and therapy in AD patients [85]. However, questions regarding the translocation of such chelating agents to the brain and efficient expulsion of the resulting metal-chelator conjugates remain unanswered. This has resulted in new studies on NP mediated delivery of agents for overcoming the limitations of metal chelating agents for brain treatment. DIRECT INTERACTION OF NANOSTRUCTURES WITH Aβ PEPTIDE The application of nanoconstructs in AD is not only limited to carrying active agents across the BBB and delivering them to the brain, but many studies also aim at engineering brain specific NPs with Aβ peptides. Such nanomaterials can interact directly with the Aβ peptides to either break the already existing amyloid aggregates or suppress the selfassembly into fibrillar plaques or toxic oligomers, thus eliminating their deleterious effects. Aβ self-assembly has reported to be inhibited by PEGylated phospholipid nanomicelles by inducing a conformational change which makes the peptide reluctant to aggregation; a diminished neurotoxicity was observed in cytotoxic studies on human neuroblastoma cells [50]. The complexes of polyampholyte and fluorinated dodecanoic acid (fluorinated NPs) were also found to inhibit the formation of Aβ fibrils [86, 87]. Nanoconstructs formed by sulfation and sulfonation of polystyrene were also reported to exhibit similar inhibitory effect [88]. The studies utilizing fairly low concentrations of quantum dot nanocrystals capped with appropriate organic compounds like dihydrolipoeic acid and Nacetyl-L-cysteine have also been reported to be quite effective in inhibiting the formation of amyloid fibrils [89, 90]. Recently, an interesting technique has been proposed to selectively and remotely dissolve the fibrillar deposits by utilizing concentrated thermal energy generated by a mixture of gold NPs-Aβ and weak microwave fields (6 times weaker than conventional mobile phones) [91, 92]. The gold NPs were preferred and selected because of their high mobility, biocompatibility and high surface:volume ratio. However, this approach is associated with the probability of oligomer formation after the fibril breakdowns, which are neurotoxic as well. Hence, further improvement is desirable to attain enhanced safety and efficacy of this strategy, which might be achieved by a modification where smaller oligomers could be targeted for disaggregation.


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TOWARDS REGENERATIVE THERAPY The limited regeneration ability of central nervous system makes the gradual loss of brain cells (caused by toxic amyloid species) irreversible, thus limiting the potential of medical therapies targeting amyloid aggregation. However, some novel approaches based on stem cells and tissue engineering offers some hope for the reversal of neural loss [9395]. A plethora of nanotechnology based applications have emerged, which include the development of nano-scaffolds mimicking the extracellular matrix to promote and support the growth and controlled differentiation of neural progenitor cells in vivo to repair the damages [7, 96-101]. One such recent development is stem cell therapy, which utilizes few stem cells harvested from the patients and grown in laboratory to generate a good volume to initiate the process of tissue regeneration by re-injection inside the patients’ body. However, the tendency of stem cells (in culturing process on standard plastic surface) to spontaneously differentiate into other cells and thus lose their regenerative ability, has been a major drawback of this method. A recent study on the use of a novel surface patterned with an ordered arrangement of nanoscale pits (prepared by injection moulding + electron beam lithography) was found to be quite effective in permitting the stem cells to proliferate while maintaining their original properties over long period for therapeutic usage [96]. Such nano-patterned surfaces may provide the basis for a large scale stem cell culture “factories”, which may enable therapy for various NDDs. RECAPITULATION AND FUTURE DIRECTIONS Nanotechnological approaches are being used for designing and engineering novel nano-scale devices and materials with controllable functional characteristics. It is also noteworthy that many NPs having the theranostics characteristics have been effectively used in AD diagnosis and drug delivery/therapy. The nanoconstructs can provide new ways to efficiently carry and deliver drugs/neuroprotective/ therapeutic molecules to the brain, and can also be tailored to counter and eliminate the AD pathogenic factors. The nanomaterials are now being used as the basis for approaching the challenges of early and sensitive detection of AD. More recently, the use of non-invasive diagnostic imaging has been assessed. For example, the use of probes targeting amyloid fibrils by positron emission tomography might represent a powerful tool to assess early-stage of AD onset. With many promising results mentioned above now being obtained by in vitro studies, it has become important to confirm the efficacy of these nanotechnology based approaches in representative in vivo AD models. LIST OF ABBREVIATIONS Aβ AD ADDLs CSF ELISA PD

= = = = = =

Amyloid beta Alzheimer disease Amyloid β derived diffusible ligands Cerebral spinal fluid Enzyme-linked immune sorbent assays Parkinson's disease


CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.

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ACKNOWLEDGMENTS This work was supported by the grant from the Russian Science Foundation (RSCF: No. 14-23-00160). Ghulam Md Ashraf gratefully acknowledges the facilities provided by King Fahd Medical Research Center (KFMRC) and Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, Saudi Arabia.

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