INTRODUCTION

Alzheimer’s disease (AD) is one of the most progressive neurodegenerative disorders in individuals beyond 65 years of age resulting in loss of neurons, and eventually dementia. It is an untreatable disorder with progressive and longer duration (Goedert and Spillantini, 2006) and represents over 80% cases of dementia in the world in elderly individuals. It results in progressive loss of behavioral, mental, functional decline, and other intellectual abilities (Anand et al., 2019). Age is the most considerable risk factor; as in 2010, 38% of individuals beyond 85 years of age were troubled with AD which is anticipated to escalate to 51% by 2050 (Herbert et al., 2013). Various cardiovascular risk factors, for example, atherogenic dyslipidemia, hypertension, obesity, and diabetes are also associated with AD (Oesterling et al., 2014). Because of its constantly expanding rate and societal aging factor, AD has garnered enormous research interest.

MANAGEMENT OF AD

The overall management of AD includes pharmacological as well as non-pharmacological treatments. Non-pharmacological approach basically addresses different causes of cognitive impairment and behavioral disturbances. Pharmacological approach, which is described as symptomatic or neuroprotective is based on modulation of disease-related neurotransmitter alterations. At present, approved symptomatic treatment includes cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists, (Kumar et al., 2015) that depends on their ability to retard the clinical development of symptoms across intellectual, behavioral, and functional areas. Currently approved some of the disease modifying therapeutic drug targets are highlighted in Table 1.

Initially, pharmacological approach for AD was aimed to increase cholinergic transmission in the brain (cholinergic hypothesis). Among the various approaches utilized to raise synaptic levels of acetylcholine (ACh), hindering the disintegration of ACh by acetylcholinesterase (AChE) inhibition was proved to be successful. Inhibition of butyrylcholinesterase (BuChE) enzyme, which is present in lower amounts in normal brain, is present in greater amount in AD brain may also enhance cholinergic transmission (Thakur et al., 2018). Novel approaches of targeting the Aβ and tau-based therapeutics can be significant keys to cater the disease (Anand et al., 2014).

Figure 1. Hypothesis for pathophysiology of Alzheimer’s disease. [Click here to view]

Non-pharmacological treatments can enhance the quality of life of individuals with AD (Olazaran et al., 2010). A moderate quantity of well-organized randomized controlled trials has evidenced the advantages of different non-pharmacological strategies, such as intellectual training, intellectual rehabilitation, and intellectual stimulation treatment in AD patients (Ballard et al., 2011). Various non-pharmacological approaches were reported in Table 1.

The biomarkers manifest significant importance in drug development for AD for choosing the ideal drug candidate for large and high-cost phase-III clinical trials. Biomarkers are also significant in confirming the drug influence on the basic pathophysiology of the disease, which may be required to designate the drug as a disease-modifier (Thakur et al., 2018). Generally used biomarkers for AD are compiled in Figure 2.

Table 1. Pharmacological and non-pharmacological therapy for AD. [Click here to view]

POTENTIAL RISK FACTORS ASSOCIATED WITH AD

A few studies have exhibited that hypertension, sedentary lifestyles, and lifestyle-related disorders like type 2 diabetes mellitus and obesity can enhance possibility of AD (Jayaraman and Pike, 2014). Several genetic factors are also responsible for its outbreak and their contribution in its pathogenesis. However, there are no incidences recommending a considerable effect of occupational exposures on AD. Various physiological and other risks associated with AD are encapsulated in Table 2.

APPROVED DRUGS FOR THE TREATMENT OF AD—CURRENT STATUS

ChEIs and NMDA receptor antagonists are the drugs which are used most frequently for the treatment of AD. Donepezil, rivastigmine, galantamine, and memantine are the generally used four FDA-approved drugs; however, combination of donepezil and memantine is also used for AD therapeutics. They improve the quality of life by controlling the intellectual loss and thus motor regulation (Harilal et al., 2019). Three of these drugs including donepezil, galantamine, and rivastigmine act on CNS cholinergic pathways. All these have anticholinesterase activity, and galantamine which is a natural-product alkaloid also acts as an allosteric modulator at nicotinic acetylcholine receptors. These drugs are frequently prescribed for individuals in early predementia stage having considerable continuous memory impairment depending on intellectual testing reports (Graham et al., 2017). AChE inhibitors may cause g.i. adverse effects such as vomiting and nausea that may be reason for discontinuation of treatment (Santos et al., 2015).

Rivastigmine co-inhibits acetylcholinesterase and butyrylcholinesterase and is specific for the G1 rather than G4 form of the enzyme. As compared to other approved drugs, it does not metabolize in liver and, subsequently, does not cause adverse drug reactions of other drugs generally given to elderly individuals with AD. Galantamine shows lower AChE selectivity; vomiting and nausea are its most frequent adverse effects, which are usually self-limiting (Atri, 2019; National Institute for Health and Clinical Excellence, 2011).

In contrast to all other drugs listed above, donepezil has significant effect in AD therapeutics and is given as 5–10 mg tablets once in a day before bed, because of its longer half-life. It selectively inhibits AChE, leading to well response from AD patients with enhancement in intellectual, behavior, and general function. These may be the reason for its more frequent use as compared to other drugs mentioned above (Atri, 2019).

Figure 2. Biomarkers for Alzheimer’s disease. [Click here to view]

Table 2. Risk factors associated with Alzheimer’s disease. [Click here to view]

Table 3. Drugs approved by FDA for treatment of Alzheimer’s disease. [Click here to view]

Memantine, a recently approved drug for AD, aims to target the NMDA receptors and glutaminergic pathways. Application of memantine in chronic treatment decreases the concentration of Aβ both in aged animals and in AD models. This results in decreased Aβ production. However, in 2005, USFDA refused to extend the application of memantine for mild AD; because of significant adverse effects, e.g. confusion, dizziness, headache, and constipation (Carvalho et al., 2015). Riluzole, a glutamate release inhibitor and post synaptic glutamate receptor signaling, is under phase II trial in mild AD patients (Thakur et al., 2018).

The combination of memantine and donepezil has also been permitted by USFDA for treating moderate-to-severe AD in individuals who were on 10 mg of donepezil hydrochloride treatment. When memantine is given along with stable cholinesterase inhibitor therapy in patients with AD, a good safety profile was found (Ito et al., 2017). Table 3 compiles an overview of pharmacokinetics of drugs used in AD.

DRAWBACKS OF CONVENTIONAL THERAPY

Conventional drug delivery systems including tablet, capsules, powder, or liquid dosage forms have critical restrictions, namely requirement of high-dose, rapid/extensive first pass metabolism, and unfavorable pharmacokinetics leading to low/poor bioavailability (Mudshinge et al., 2011). In treatment of AD, drugs administered orally are expected to cross various gastrointestinal barriers, undergo effective absorption, sustain the drug in the systemic circulation, and successfully transport the drug into the blood–brain barrier (BBB), to reach the target site (Stegemann et al., 2007). Breakdown of the drug moiety in the gastrointestinal tract accelerates drug elimination, reduces half-life, and reduces bioavailability, thus mitigating the predicted beneficial effects. Additionally, sustained interaction or unpremeditated activation of drug substances at non-specific target sites resulting in several side effects, namely nausea, vomiting, gastric problems, etc. (Sainsbury et al., 2014). Few examples are memantine causes dizziness, confusion, constipation, and vomiting (Kornhuber et al., 2007). Acetylcholinesterase inhibitors are associated with vomiting and nausea which frequently leads to discontinuance of therapy (Raina et al., 2008). Owing to a short half-life of 0.5–3 hours, tacrine needs four administrations in a day (Watkins et al., 1994). Furthermore, the physicochemical properties of the drug molecule including the solubility, molecular weight, polarity, partition coefficient, and dissociation constant play an important part in therapeutic effect or drug failure (Alyautdin et al., 2014; Sainsbury et al., 2014). Furthermore, several bioactive substances like proteins, peptides, and other biological macromolecules have poor solubility and are poorly absorbed in the g.i.t, which is responsible for their lower therapeutic effectiveness and hence clinical trials (Munin and Edwards-Levy, 2011).

NANOCARRIERS IN AD THERAPEUTICS

The primary reasons for frequent therapy failure can be correlated to the adverse pharmacodynamics and pharmacokinetics of drugs, gastrointestinal instability of drugs, and toxicity (hepato-, neuro-, or renal toxicity) to the tissues (Arias, 2015; Suri et al., 2015). Currently approved drugs for AD therapeutics are based on improving neurotransmission or enzyme modulation. The drugs conventionally used to target CNS suffer from the primary constraints of the inability to cross the “BBB” or the “B-CSF barrier” efficiently; and higher drug efflux because of P-glycoprotein activity. Nanotechnology, in conjugation with therapeutics, can be used to control various obstacles faced by drug molecules in the treatment of neurodegenerative diseases. Nanotechnology based dosage forms radically regulate these characteristics of the drug molecules and enhance the therapeutic potential applying various functional aid by utilizing nanotechnology-based dosage forms (Brambilla et al., 2011; Nazem and Mansoori, 2008). Nanoformulations not only result in the improvement of pharmacodynamics and pharmacokinetics of drugs, they also have potential to minimize toxicity (Orive et al., 2003; Parveen and Sahoo, 2006). Nanoformulations overcome the obstacles by safely carrying the drug through the biological environment with enhanced permeability, thus providing maximum efficiency at a comparatively lower dose. An essential feature of nanoformulations is the controlled drug release at the target site (Safari and Zarnegar, 2014).

Substantial research reports have evidenced the capability of nanoformulations to circumvent oral and intestinal absorption barriers and carry drugs to the site of action (Ensign et al., 2012; Lundquist and Artursson, 2016). This is achievable owing to their small size (1–1,000 nm), surface charge, high surface to volume ratio (Singh and Lillard, 2009). In CNS delivery, the BBB barrier presents a great obstacle for the nanoformulations targeting neuronal systems (Misra et al., 2003). Altering the surface characteristics of nanformulations enables crossing the BBB by avoiding phagocytic opsonization, thus enhancing the drug levels in the brain (Gidwani and Singh, 2014). The nanosized dosage forms can be classified on the basis of nature of the carrier material as (i) inorganic (gold, carbon, and silica) and (ii) organic (solid-lipid NPs, dendrimers, emulsions, liposomes, and polymers).

Various nanotechnology-based strategies such as polymeric nanocarriers, carbon nanotubes, lipidic nanocarriers, liposomes, nanoemulsions, dendrimers, and metal-based nanocarriers have been evolved over the past decade, focusing on both arresting neurogeneration and neuroprotective for the treatment of AD. Herein, we discuss emerging nanodrug delivery systems for AD therapeutics.

ACROSS THE BLOOD–BRAIN BARRIER

Newly discovered drugs that might be efficacious for the AD treatment may face various hindrances that other drugs used for non-CNS systems may not confront, one of which is the –BBB. The BBB is a highly complex and specialized structure that permits only those substances which are essential for brain activity (Banks, 2012). It is made up of tight junctions in the endothelial membrane that permits just certain molecules to pass through. The tight intersections of BBB are at high transendothelial electrical resistance in comparison to other tissues. There are specialized mechanisms such as specific enzyme systems, protein receptors, and glucose transporters for transporting substances across the BBB. The BBB obstructs undesirable substances from crossing by utilizing tight intersections between cells, extra degradative enzymes, and pumps to eliminate undesirable substances that do pass. Receptors and transporters permit nutrients required for normal functioning to move through to the brain parenchyma (Oesterling et al., 2014). The BBB does not have transporters for conventional drugs and so they are generally not able to pass or are actively pumped back out after crossing. This turns into a significant issue for the therapy of neurodegenerative disorders (Edwards, 2001).

Although conventional methods are suitable for treatment of neurodegenerative disorders, they do not have optimum efficacy. This necessitates for the development of therapeutic alternatives for AD. Various approaches can be prodrug formation and the utilization of carrier-mediated transport systems, for example, carbohydrates, peptides, antibodies, gene delivery vectors, nanoparticles, micelles, and liposomes. The mechanisms by which nanocarriers can improve BBB penetration are efflux transport inhibition, nanocarrier cationization, paracellular transport enhancement pharmacologically, or using the hyperosmotic strategy and olfactory delivery of nanocarriers (Shah et al., 2013). To cross the BBB, various nanotherapeutic approaches have been adapted (Fig. 3). The approaches include

(i) The affinity and binding of lipophilic nanocarriers for endothelial cells improve the transportation of drug molecule via lipophilic transcellular pathways or endocytosis;

(ii) The adsorptive property of nanocarriers towards blood vessels provided a sustained drug release in the systemic circulation with increased possibility for transport of drug across BBB;

(iii) Additionally, functionalized nanocarriers trigger receptor mediated transcytosis and carrier protein mediated transport of drug candidates across BBB (Saraiva et al., 2016).

NANOPARTICLES IN DRUG DELIVERY SYSTEM AND ITS IMPORTANCE

Nanoparticulate drug delivery system is an advanced technology that could be applied to deliver drug substances directly into the brain and has been shown to be extremely efficacious against some CNS disorders. Nanosized systems have garnered considerable interest owing to their favorable features, namely capability to prevent chemical and enzymatic drug degradation, improve drug solubility, and facilitate its transport across the biological membranes. Targeted systems carry the drug straight to the site of action, reduce adverse reactions of the drug, and improve the therapeutic index (Mehmood et al., 2015). Various nanoparticulate systems like polymeric nanoparticles, nanoemulsions, liposomes, antibody tethered nanocarriers, dendrimers, etc., are used for drug delivery and some of them are depicted in Figure 4.

While nanoformulations have been investigated for efficacious drug delivery through various routes such as oral, parenteral, topical, vaginal, rectal, etc., they can also play an important part in diagnosis, and imaging. Nanocarriers are also amenable for nasal mucosal vaccination and nasal drug delivery. The nanocarrier systems allow the effective antigen recognition; especially nanocarriers based on the lipid and polymer are used for nasal delivery of antigen (Le et al., 2019). Nanomedicines played a vital role in the nose to brain delivery. For treating the brain related pathologies, the main focus is on the drug’s ability to cross the BBB. The nanoparticulate systems are considered efficient in to achieve brain targeting as they exhibit better penetration of the drugs in the brain. While the need for devices that can allow deposition of the dosage form to the upper part of nose is essential for nose to brain delivery, surface modification of the nanocarrier can act as a strategic approach for perfect nose to brain targeting. Several reports account for targeting of drugs to brain via different nanoparticulates. Of the various nanocarrier systems investigated for brain therapeutics and theranostics in recent years, are either polymeric or lipidic in nature. Polymeric nanoformulations include polymeric nanoparticles, polymeric micelles, and carbon based nanovehicles. Lipidic nanoformulations are liposomes, niosomes, transferosomes, solid lipid nanoparticles, and nanostructured lipid carriers. Nanogels and nanoemulsions have also garnered considerable attention of researchers for transendothelial delivery of neuropharmaceuticals (Oesterling et al., 2014).

Figure 3. Schematic representation of potential pathways involved in nanocarrier-mediated drug trafficking across BBB associated with AD-nanotherapeutics. [Click here to view]

Figure 4. Versatile nanocarriers adopted for mitigation of Alzheimer’s disease. [Click here to view]

The BBB is enriched with various transport systems which can transport substances in and out of the brain. The prominent ones are receptor-mediated transport system, transporter-mediated system, adsorptive-mediated transport system, active efflux-mediated transport system, and peptide-mediated transport approach. Mostly, molecules use either of these transport systems to enter and leave the brain with the exception of certain small lipid soluble molecules that cross the BBB transcellularly. These transport systems could serve as efficient routes for the transport of drugs to the brain by improving its permeability (Sweeney et al., 2018).

Biological therapeutic agents such as nucleic acids, peptides, proteins, and monoclonal antibodies are being aggressively researched since they have potential to restore the damaged cells and decelerate the progression of AD (Sharma et al., 2012). Researchers have developed vaccines for AD and some of them are under clinical trial. Most of the vaccines act on the tau protein in the AD which prevents the functional damage in the brain. Of lately, nano-vaccines (antigen loaded in the nanoparticles as vehicles) have emerged that confer protection to the antigen and result in enhanced efficacy (Wisniewski et al., 2016). The drug delivery systems mediated by nanotechnology are primarily based on the brain’s transportation of therapeutic agents. Currently the focus is on both specific and non-specific processes for mechanisms to target research of brain locations.

Magnetic nanoparticles

In the recent years, magnetic NPs have been extensively explored and are applied for both diagnosis and therapeutic reasons. Their inert nature associated with low toxicity suggests implications in brain pathologies including AD. Kong et al. (2012) in an experiment in a mouse model suggested that magnetic NPs can permeate the normal BBB when an external magnetic field is applied. On systemic administration, an applied strategic external magnetic field navigates the magnetic nanoparticles to cross the BBB and aggregate in a perivascular zone of the brain parenchyma. Internalization by endothelial cells was suggestive of transcellular trafficking as the BBB crossing mechanism. Furthermore, remote radio frequency magnetic field can be utilized to release drug from silica coated magnetic nanocapsules. In conjunction, the results suggest a meticulous approach for manipulating the biodistribution of MNPs in the brain via an external magnetic field.

Figure 5. Schematic illustration of composition of SLN and its interaction with LDL receptors. [Click here to view]

Table 4. SLNs for the treatment of AD. [Click here to view]

In a strategic approach, an electromagnetic actuator was designed for guiding magnetite containing drugs (Do et al., 2016). These magnetic nanoparticles were capable to cross BBB after applying external electromagnetic fields [28 mT (0.43 T/m)]. Additionally, the brain uptake and transport rates of magnetic nanoparticles were considerably improved by applying a pulsed magnetic field. The localization of NPs monitored using fluorescent magnetic nanoparticles demonstrated the feasibility of the magnetic nanocontainers as valuable targeting system for AD diagnosis and therapy.

Cubosomes

These are liquid crystalline nanostructured particles consisting of biocompatible carriers. A cubosome is comprised of a three dimensionally organized bicontinuous curved lipid bilayer separated by two aqueous channels within which the bioactive ingredients and proteins come into contact (Fig. 6) Their distinguishing characteristics are that they can encapsulate substances that are hydrophobic, hydrophilic, and amphiphilic, maintain controlled release of the drug and bioadhesion, are thermodynamically stable, and are promising vehicles for various drug administration routes (Karami and Hamidi, 2016).

Table 5. Research highlights of few nano-conjugates developed for treatment of Alzheimer’s disease. [Click here to view]

Figure 6. Composition of cubosome drug delivery system. [Click here to view]

Wu et al. (2012) developed lectin modified non-immunogenic odorranalectin (small peptide) cubosomes. The system was conjugated with streptavidin through incorporating maleimide PEG oleate and aimed for effective nose to brain drug delivery. The relative uptake of odorranalectin cubosomes was 3.46 times higher compared to the bare cubosomes in brain tissues. Pharmacodynamic study on rats after intranasal administration revealed enhanced efficacy of streptavidin conjugated odorranalectin cubosomes for the mitigation of Alzheimer’s disorder that suggested a potential non-invasive peptide and protein delivery approach in brain tissues.

Piperine, a memory enhancing natural alkaloid, was used for developing novel oral cubosomal delivery system by Elnaggar et al. (2015) for the treatment of neurological AD. Various bioactive surfactants (Tween, cremophore, and poloxamer) modified crystalline cubosomes were evaluated for pharmacokinetic and pharmacodynamics assessments. Among them, Tween 80 modified piperine cubosomes exhibited effective anti-apoptosis and prominent anti-inflammatory activity performed through Caspase-3 assay. Nanoscaled dimension (~167 nm), low polydispersity index (0.18), and optimum zeta potential of developed cubosomes exhibited high entrapment efficiency (~88.7%) and superior stability. Developed novel oral cubosomes depicted potential for inhibition of AD progression.

Antibody-tethered nanoparticles

Of lately, researchers from University of Cambridge have disclosed a methodology that demonstrates designing of an antibody that can recognize and quantify toxic particles (amyloid beta oligomers) associated with destruction of human healthy brain tissues/cells. Antibodies are proteinaceous molecules that identify and neutralize pathogens/microbes by the virtue of their affinity towards oligomers (Fig. 7). This innovation in healthcare sector would pave of management strategy against the AD (Francesco et al., 2020).

Antibody conjugated novel delivery approach is considered as promising clinical strategy for mitigation of AD. These antibody tethered systems reduce amyloid protein/plaque deposition at the presynaptic phase of the neurological disorder and hence facilitate retrieval of diminished memory cells of brain. In this context, monoclonal antibodies (MAb) have displayed satisfactory capability to target amyloid β peptides in AD affected transgenic mice and human brain tissues. Numerous MAbs, i.e., solanezumab, bapineuzumab, and crenezumab have been explored for the evolution of brain drug delivery systems (Watt et al., 2014).

Figure 7. Monoclonal antibody-oligomer interaction to neutralize amyloid plaque. [Click here to view]

MAbs sweep away undesirable amyloid protein either by passive immunization or through complement activation and check neurodegeneration process. Although, solanezumab and bapinezumab were reported to non-specifically target the amyloid protein and delayed the AD treatment time comparative to crenezumab monoclonal antibody (Prins et al., 2015).

Rosse (2017) presented a series of conjugates composed of antibody-drug to combat wide range of inflammatory diseases, namely, AD, atherosclerosis, Parkinson’s disease, rheumatoid arthritis, etc. These conjugates were fabricated through phosphate-based linkers associating immunoglobulin proteins (CD74/CD163) and therapeutics as steroids (Rosse, 2017).

Another, antibody tethered PBD-C06 formulation (anti-pGlu3-Aβantibody) has been developed through grafting murine antigens on light and heavy chains of antibody. This immunotherapeutic approach was designed to target pGlu3-Aβepitope to mitigate the pathology of AD. Developed PBD-C06 has affinity for oligomers, monomers, fibrils, and clustered Aβpeptide that efficiently targeted neurotoxic peptides at site. Significant reduction of inflammation in the intracellular cells was reported that suggested potential clinical application in vasogenic edema (Hettman et al., 2020).

Dendrimers

The three dimensional, spherical, branched architectural entities (dendrimers) are emerging pharmaceutical nanocarriers, widely worked out for designing numerous targeted drug delivery system owing to their versatile properties, i.e., nanosize, low polydispersity index, high payload efficiency, improved solubility, less viscosity, biocompatibility, non-immunogenicity, and stability. The morphology of dendrimers is comprised of functional groups containing linkers attached with therapeutic agents on their periphery (Fig. 9). Their specific structure facilitates site specific drug delivery. For the effective treatment of neurogenerative disorders, extensive research and formulations based on dendrimers are reported. Presence of multiple functional groups or polyvalent recognition sites enable high pay load of therapeutics (Abbasi et al., 2014).

Figure 8. Nanocarrier: liposomes and its salient features. [Click here to view]

Figure 9. Drug loaded dendrimers for treatment of AD. [Click here to view]

In AD, several molecular mechanisms are involved such as apoptosis, inflammation, and oxidative stress. These processes should be targeted through designing nanoengineered dendrimers. Numerous bioactive agents, i.e. peptides/protein, nucleic acids, genes, and biosensors are frequently loaded in dendrimers for brain delivery (Aliev et al., 2019).

Katare et al. (2015) stated that drug delivery to the brain is challenging because of the low aqueous solubility and bioavailability. The haloperidol dendrimer was delivered to the brain through the nasal route of administration. The developed preparation showed hundred times high aqueous solubility. Cataleptic and locomotor studies were evaluated after intraperitoneal injection administration of haloperidol dendrimers. Haloperidol response given through nasal and intraperitoneal route was compared. It was mentioned that 6.7 times less dose was required for nasal delivery to obtain same behavioral response compared to intraperitoneal route. The study suggested improvement in aqueous solubility of poorly soluble drug through dendrimers for the amplified locomotors action in AD cases. The study confirmed that the dendrimers given via nasal route is suitable delivery for targeting brain for poorly aqueous soluble drugs.

Nazem and Mansoori (2011) described various biomedical applications of dendrimers due to their shape and size. The anti-myeloid strategy was recommended for the dendrimers. The strategy was designed in such a way that the peptide monomer was attached to the end of fibrils which resulted in the prevention of cytotoxic effects. The most frequently researched dendrimers for the therapy of brain diseases are polyamidoamine (PAMAM) dendrimers. The effect of PAMAM dendrimers on prion peptide PrP185-208 and Alzheimer’s peptide Aβ1-28 was assessed using thioflavin T dye. Outcomes of the fluorescence and electron microscopy revealed high degree of amyloid aggregation and signs of fibril disruption. The interaction of globular and branched dendrimers with amyloid proteins showed inhibition of fibril formation in AD (Klajnert et al., 2006).

Another anti-inflammatory and antioxidant therapeutic N-acetyl-l-cysteine was explored for the synthesis of poly (amidoamine) (PAMAM) dendrimers. The synthesized system was capable of intracellular drug delivery at the site of inflammation. Presence of detachable disulfide bonds in the integrity of dendrimers enabled linking with intracellular glutathione and microglial cells. Higher payload facilitated desirable amount of drug release at local cells and exhibited improved antioxidant activity (Navath et al., 2006).

Klementieva (2019) discussed exclusive brain cell protective activity of poly propyl imine (PPI) dendrimers functionalized with maltose in transgenic mice. PPI dendrimers modified with maltose got bound with amyloid proteins, hindered their aggregation and checked fibril deposition at brain cells. The study revealed that unmodified PPI dendrimers cause cellular toxicity, whereas maltose modified dendrimers did not show intrinsic toxicity. The research highlighted that polysaccharide coated dendrimers were non-toxic to the neuroblastoma cells. Dendrimers containing cationic PAMAM and phosphorous have been fabricated through polymerization technique to investigate efficacy against deposited amyloid peptides over neuroblastoma cells. The intrinsic toxicity due to positive charge of PAMAM restricted the performance of dendrimers. Biocompatible sugar coated glycodendrimers have also been reported. The modified dendrimers were capable of interacting with amyloid proteins with minimum cell toxicity. The developed sugar coated glycodendrimers were taken account for symptomatic relief in AD owing to their high surface group density over protofibrils G4 of brain cells (Benseny-Cases et al., 2012).

RECENT UPDATES ON PATENTS AND CLINICAL TRIALS ON ALZHEIMER’S TREATMENT

Nanotechnology based dosage forms are being the most explored area for efficient delivery of the drugs for AD. The USFDA has recently approved Tauvid (flortaucipir F18) for i.v. injection, the first drug used to help image a distinctive characteristic of AD in the brain called tau pathology. Tauvid is a radioactive diagnostic agent for adult patients with intellectual impairment and is being evaluated for AD. Tauvid is suggested for positron emission tomography imaging of the brain to determine the distribution and density of aggregated tau NFTs, a primary marker of AD (USFDA, 2020). Luthman et al. (2019) patented methods for bringing down clinical reduction in an individual having early AD, methods of converting an amyloid positive individual during initial stages to amyloid negative, methods for lowering brain amyloid level in an individual, and methods of preventing AD, the methods comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. Gelmont et al. (2019) have been assigned a patent which provides, among other aspects, methods for the treating AD in individuals in need thereof, the method including administration of a therapeutically effective amount of a pooled human immunoglobulin G (IgG) and/or an anti-beta amyloid monoclonal antibody composition to an individual having moderately severe AD.

Various patents have been granted/published in this field depending on the nanocarrier systems, including multiple dosage forms, liposomes, nanoparticles, solid lipid nanoparticles, nano-emulsion, etc., (Patel et al., 2017) which are compiled in Table 6. Castor et al. (2019) got patented an AD drug candidate, APH-1104, a potent analog of Bryostatin-1, and is neuroprotective by α-secretase activation via novel protein kinase C (PKC) isoforms, down-regulation of pro-inflammatory and angiogenic processes, and the substitution of β-amyloid for its soluble and harmless relative, sAPP-α at concentrations which are orders of magnitude lower than conventional APP modulators. These nanoparticles protect Bryostatin-1 in its transit to the stomach, are resistant to stomach acids, and increase residence time and efficacy once transported to the circulation system in the duodenum. Castor (2020) has been assigned a patent for the combination therapeutic consisting of nanospheres co-encapsulating Bryostatin-1 and a Retinoid to improve synergistically α-secretase production and reduce β-amyloid plaque generation. Bryostatin-1 stimulates the production of some isoforms of PKC which enhances the production of α-secretase resulting in soluble amyloid precursor protein, and inhibits the formation of β amyloid plaques. Retinoids such as all-trans retinoic acid (ATRA, retinoic acid) enhance α-secretase activity via increased levels of expressed ADAM10 protein.

Improvement in therapeutic mediation for treating individuals with AD is of prime importance for both clinicians and pharmaceutical industries. Hence collection and investigation of clinical information is required for designing new protocols and/or the advancement of upgraded therapeutics for treating the disorder. Table 7 presents a compilation of the drugs that are in phase III clinical trials, while the drugs utilized in phase II clinical trials are summarized in Table 8 (Romano, 2018).

FUTURE PERSPECTIVE

Nanocarriers seem to offer a novel way of facilitating research attempts by explicitly regulating various pathways in focused areas. An interesting target for the development of better AD therapeutics can be mitochondrial dysfunction. Magnetic NPs are a productive area for research and have numerous existing as well as potential technological applications. Dendrimers and nanoemulsions are also two classifications of nanoparticulate systems which ought to be investigated additionally for transport of CNS drug. A few issues are required to be resolved before nanomedicines for AD comes to clinical setting. They are (i) the general and the biggest hurdle is low targeting efficiency, which may restrict the therapeutic effect and cause harm to other organs and (ii) another concern is the distribution of nanomaterials into the brain. To attain specific targeting in the brain, sequentially targeted nanomaterials require consideration. Objective should be to target not only BBB, but to also target the diseased site, to prevent distribution in whole brain.

Various in vitro investigations have reported the potential adequacy of nanocarriers; however, future in vivo studies of these nanocarriers can possibly disclose a long-term systemic efficacy or potential toxicity in biological systems which can be correlated with in vitro systems. Despite the fact that the registration of patents related to nanotechnology-based systems is presently rising, clinical studies are required to assess their clinical efficacy and potential toxicological effects in humans. A detailed focus on the stability and safety in terms of biological retention, exposure time, nanocarrier size, dose, and metabolites of various polymers of the nanocarriers is also required. Subsequently, an assessment of the safety and adequacy of appropriate nanocarriers by conducting clinical studies in humans can result in encouraging cost-effective AD therapeutics.

Table 6. Patents on drug delivery systems based on nanotechnology for treatment of AD. [Click here to view]

Table 7. Drugs used in phase III clinical studies for the treatment of AD patients. [Click here to view]

Table 8. Drugs used in phase II clinical studies for the treatment of AD patients. [Click here to view]

CONCLUSION

Significant advancement has been achieved in AD therapeutics, but the entire currently available approaches target on mitigating symptoms instead of curing, implying that AD can still be considered as an unresolvable neurodegenerative disorder and needs interim advancement. Nanotechnological applications offer a lucrative efficient strategy for the AD treatment. A plethora of nanocarriers have been developed that have ability to cater to the limitations of conventional therapy, can assist in preliminary diagnosis, enhance therapeutic efficacy and bioavailability, offer negligible cytotoxicity in animal models, and present newer possibilities for development of superior formulations of potent drugs intended for AD therapeutics.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.

FUNDING

There is no funding to report.

CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

ETHICAL APPROVALS

Not applicable.

PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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