110th Anniversary: Nanoparticle Mediated Drug Delivery for the

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110th Anniversary: Nanoparticle mediated drug delivery for the treatment of Alzheimer’s disease: Crossing the blood-brain barrier Marissa E Wechsler, Julia E. Vela Ramirez, and Nicholas A Peppas Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.9b02196 • Publication Date (Web): 23 Jul 2019 Downloaded from pubs.acs.org on July 24, 2019

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Industrial & Engineering Chemistry Research

110th Anniversary: Nanoparticle mediated drug delivery for the treatment of Alzheimer’s disease: Crossing the blood-brain barrier Marissa E. Wechslera,b, Julia E. Vela Ramireza,b, Nicholas A. Peppasa,b,c,d,e*

aInstitute

for Biomaterials, Drug Delivery, and Regenerative Medicine, bDepartment of

Biomedical Engineering, cMcKetta Department of Chemical Engineering, dDivision of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, and eDepartment of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, United States KEYWORDS: Alzheimer’s disease, blood-brain barrier, drug delivery, nanoparticles

ACS Paragon Plus Environment

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ABSTRACT. Alzheimer’s disease is an irreversible neurodegenerative disorder affecting approximately 6 million Americans, 90% of which are over the age of 65. The hallmarks of the disease are represented by amyloid plaques and neurofibrillary tangles. While the neuronal characteristics of Alzheimer’s disease are well known, current treatments only provide temporary relief of the disease symptoms. Many of the approved therapeutic agents for the management of cognitive impairments associated with the disease are based on neurotransmitter or enzyme modulation. However, development of new treatment strategies is limited due to failures associated with poor drug solubility, low bioavailability, and the inability to overcome obstacles present along the drug delivery route. In addition, treatment technologies must overcome the challenges presented by the blood-brain barrier. This complex and highly regulated barrier surveys the biochemical, physicochemical, and structural features of nearby molecules at the periphery, only permitting passage of select molecules into the brain. To increase drug efficacy to the brain, many nanotechnology-based platforms have been developed. These methods for assisted drug delivery employ sophisticated design strategies and offer serveral advantages over traditional methods. For example, nanoparticles are generally


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low-cost technologies, which can be used for non-invasive administrations, and formulations are highly tunable to increase drug loading, targeting, and release efficacy. These nanoscale systems can facilitate passage of drugs through the blood-brain barrier, thus improving the bioavailability, pharmacokinetics, and pharmacodynamics of therapeutic agents. Examples of such nanocarriers which are discussed herein include polymeric nanoparticles, dendrimers, and lipid-based nanoparticles.


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Alzheimer’s disease is a progressive neurodegenerative disorder which affects approximately 6 million Americans,1 is the most common disease of aging,2 the fifth leading cause of death in adults over the age of 65,1 and the cause of approximately 70% of all cases of dementia.3 The hallmarks of Alzheimer’s disease are represented by amyloid plaques and neurofibrillary tangles present within the brain tissue. Although these pathophysiological characteristics of Alzheimer’s disease are well known, current treatments only provide temporary relief to slow the progression of symptoms. Many of the approved drugs for the treatment of cognitive impairments associated with Alzheimer’s disease are based on neurotransmitter or enzyme modulation, such as acetylcholinesterase inhibitors.3 However, these treatment strategies often fail due to poor drug solubility, low bioavailability, and the inability to overcome obstacles present along the drug delivery route, specifically, when crossing the blood-brain barrier.3–5

The blood-brain barrier is the most selective barrier which the central nervous system possesses to protect itself from invading species. It is primarily composed of tightly connected endothelial cells (connected by tight junctions and adherens junctions) and a


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discontinuous layer of pericytes. The complex and highly regulated barrier surveys the biochemical, physicochemical, and structural features of nearby molecules at the periphery, only permitting passage of select molecules into the brain.6,7

Transport through the blood-brain barrier can be either paracellular transport or transcellular transport. Paracellular transport refers to the passage of solutes between endothelial cells, dependent upon a concentration gradient, while transcellular transport denotes passage of molecules through endothelial cells. The degree of permeability in a healthy blood-brain barrier is defined by the balance between paracellular and transcellular transport.6 Use of the transcellular pathway occurs in the majority of cases with passive diffusion of lipophilic molecules.6 Hydrophilic molecules, such as proteins and peptides, depend on specific protein interactions to enter the brain using active transport mechanisms.8 An example of this is in the case of glucose uptake which is transported using glucose transporter-1.

To increase drug delivery to the brain, many nanotechnology-based platforms have been developed to overcome limitations presented by the blood-brain barrier and opsonization


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caused by plasma proteins present in systemic circulation. These technologies for assisted drug delivery involve sophisticated design strategies and offer many advantages. For example, use of nanoparticles with a size of 1-1000 nm are generally low cost, can be non-invasive, and formulations are highly tunable to increase drug loading, targeting, and release. These nanoscale systems can facilitate passage of drugs through the bloodbrain

barrier,

thus

improving

the

bioavailability,

pharmacokinetics,

and

pharmacodynamics of drugs. Examples of such nanocarriers include dendrimers, polymeric nanoparticles, and lipid-based nanoparticles (Figure 1).3


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Figure 1. Anatomy of nanocarriers used for Alzheimer’s disease drug delivery across the blood-brain barrier. Dendrimers, polymeric nanoparticles, and liposomes are examples of nanocarriers which have been used to deliver therapeutic agents across the blood-brain barrier for the treatment of Alzheimer’s disease. To cross the blood-brain barrier, studies have shown optimal particle diameters ranging from 5-200 nm.

Alzheimer’s disease


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Alzheimer’s disease is a chronic neurodegenerative disease characterized by the impairment of memory and cognitive functions, and is one of the most common neurodegenerative diseases in the world.1,4,9 In the United States alone, approximately 6 million people are living with Alzheimer’s disease.3 By 2050, this number is expected to triple, affecting a projected 13.8 million people over the age of 65.1,3

Pathophysiology

Alzheimer’s disease is histopathologically characterized by neuronal death and a large synaptic loss in regions of the brain responsible for cognitive functions. The pathological hallmarks of the disease include the presence of amyloid plaques (accumulation of the amyloid-beta peptide) and neurofibrillary tangles (accumulation of tau protein filaments).3 The presence of amyloid plaques and neurofibrillary tangles results in shrinkage pressure within the brain causing neuronal apoptosis.4 Two hypotheses have been proposed regarding the pathophysiology of Alzheimer’s disease: (i) the hypothesis on amyloid


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cascade neurodegeneration and (ii) the hypothesis on the impairment of the cholinergic system (Figure 2).3,4

According to the amyloid cascade neurodegeneration hypothesis, Alzheimer’s disease begins with the proteolytic cleavage of the amyloid precursor protein (by disruption of homeostatic processes) which results in the overproduction of amyloid-beta, and formation of amyloid plaques.9 Environmental, genetic, and age-related factors contribute to a metabolic shift which may favor processing of the amyloid precursor protein.9 Generation of amyloid-beta peptides is obtained by cleavage of the amyloid precursor protein by beta-secretase and gamma-secretase (components of the presenilin complex). Mutations in the amyloid precursor protein and the presenilin complex have resulted in an increase of amyloid-beta deposition in patients with Alzheimer’s disease.9 The amyloid-beta (Aβ) peptide exists in isoforms of varying length and has been shown to have a critical role in the pathogenesis of Alzheimer’s disease.10 The most abundant Aβ peptide in the brain is Aβ(1-40), containing 40 amino acid residues, followed by Aβ(1-42) comprised of 42 amino acids.10,11 The biochemical properties of the amyloid-beta peptide


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favor aggregation, forming insoluble oligomers and protofibrils, leading to the potential for neurotoxicity. In addition to the aforementioned processes, clearance of the amyloid-beta peptide is reduced, leading to the extracellular accumulation of amyloid-beta. These processes result in the successive activation of neurotoxic cascades which eventually lead to neuronal cytoskeletal changes, dysfunction, and apoptosis.9

According to the cholinergic hypothesis of Alzheimer’s disease, dysregulation of the cholinergic system is related to the decrease in cognitive function associated with Alzheimer’s disease.3,4 Specifically, the original hypothesis states that the degeneration of cholinergic neurons, in addition to the loss of cholinergic neurotransmission, significantly contributes to cognitive impairment in patients with Alzheimer’s disease.12 It is now known that dysfunction of the cholinergic system may not cause cognitive impairment directly, but rather indirectly, in combination with additional processes.

Other causes of neurodegeneration in Alzheimer’s disease have been thought to be tau protein-mediated. The tau protein is a microtubule associated protein primarily located in the axons of neurons.13 The predominant function of tau is to control the stability of axonal


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microtubules. Detachment of tau from microtubules leads to an increase in unbound tau, resulting in misfolding of the protein and development of pre-tangle formations.13 Hyperphosphorylation of the tau protein caused by internal cell dysregulation then leads to the formation of neurofibrillary tangles,2,4 a hallmark of Alzheimer’s disease.

Figure 2. Overarching hypotheses of Alzheimer’s disease pathogenesis. The two hypotheses which have been proposed regarding the pathophysiology of Alzheimer’s disease are the following: (i) the hypothesis on amyloid cascade neurodegeneration and (ii) the hypothesis on the impairment of the cholinergic system.


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Current therapeutic treatments

The current treatment approach for Alzheimer’s disease is to provide symptomatic therapy and decrease the speed of disease progression by using acetylcholinesterase inhibitors and a N-methyl-D-aspartate (NMDA) antagonist. To date, there are only five drugs used to treat Alzheimer’s disease which have been approved by the United States Food and Drug Administration (Table 1).4 Acetylcholinesterase inhibitors act by preventing the action of acetylcholinesterase, thereby increasing the availability of acetylcholine for postsynaptic stimulation.3 Therapeutic agents available following this mechanism of action include donepezil, galantamine, and rivastigmine.3,4,14

Memantine is the only NMDA antagonist available for the treatment of Alzheimer’s disease. This NMDA antagonist acts on the glutamatergic system by blocking NMDA receptors, thus reducing the effects of glutamate activity on brain cells. This mechanism of action is particularly important as glutamate-related excitotoxicity is present in the pathophysiology of Alzheimer’s disease.3 Glutamate (a neurotransmitter) is beneficial for


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learning and memory when present at normal levels. However, if levels become too high, glutamate may overstimulate nerve cells causing apoptosis through excitotoxicity.3 Thus, the interaction between memantine and NMDA receptors has shown to be critical in providing symptomatic improvement in patients with Alzheimer’s disease.3

Table 1. Approved therapeutic drugs for Alzheimer’s disease management.

Generic drug

Drug class

Disease treatment stage

Administration route

Donepezil

Cholinesterase inhibitor

All stages

Oral

Galantamine


Mild to moderate stages

Oral

Rivastigmine


Mild to moderate stages

Oral

Memantine

NMDA receptor antagonist

Moderate to severe stages

Oral

Memantine + donepezil

Combination, NMDA receptor antagonist + cholinesterase inhibitor

Moderate to severe stages

Oral

Treatment shortcomings and new strategies


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Over the last decade, hundreds of compounds have been tested in clinical trials for the treatment of Alzheimer’s disease, yet, only five compounds are currently approved in the United States to delay the progression of the disease. Many of the investigated compounds reported failure as a result of low bioavailability due to restriction by the bloodbrain barrier.4,14 In addition, many of the animal models used have shown to create a “transitional gap” between animal and human studies.14 To increase the number of available effective therapies for Alzheimer’s disease, much scientific effort is needed to increase our knowledge and understanding of the involved pathways to provide a cure for the disease, as opposed to only providing symptomatic relief. In order for this to be accomplished, improved models and drug delivery systems need to be developed in an effort to overcome many of the challenges and failures which previous systems have encountered.

A major challenge in the development of treatment options for Alzheimer’s disease is the design of a system to penetrate the blood-brain barrier. A method of achieving this outcome is utilizing nanoparticle-based systems which provide a strategy to overcome


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obstacles present along the drug delivery route.3,4 By employing these nanoscale systems, passage of therapeutic agents can be facilitated through the blood-brain barrier to improve the bioavailability, pharmacokinetics, and pharmacodynamics of compounds, thereby increasing the effectiveness of a particular treatment.

Considerations of nanocarriers and examples for delivery across the blood-brain barrier

Physicochemical characteristics

Nanomedicines have a myriad of advantages and potential applications for the treatment and diagnosis of neurodegenerative disorders, such as Alzheimer’s disease. While the most critical consideration when selecting a nanocarrier for brain delivery is their safety and toxicity, it is important to carefully select the physicochemical properties of these materials (Figure 3). The rational design of nanoneuromedicines must take into consideration the characteristics of the carriers and their effects upon entry into the body.15 In particular, nanocarrier size, surface charge, shape, and surface


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functionalization must be tailored to ensure their successful delivery and enhancement of the treatment efficacy.6,16–20

Size is one of the most important design factors that must be tuned for brain delivery, since it directly impacts the uptake and transport of the nanomaterials.16,17,21 Depending on the administration route, transport mechanism, and vehicle chemistry, nanocarrier size should be optimized.6,15–19 It has been demonstrated in previous studies that nanoparticles with a size ≤ 200 nm are more efficiently internalized, have deeper brain penetration, and a longer circulation than larger particles.16,22,23 However, carriers with a diameter of ≤ 5 nm have found to be susceptible to rapid renal clearance, which in addition to their limited loading capabilities and fast drug release kinetics, make them inadequate delivery vehicles.16,17 Within this range, nanoparticles are capable to cross through biological barriers more easily, maintain their circulation, and be taken up by the desired cell targets.17

The surface charge of the developed nanomaterials plays a critical role in the safety and cytotoxicity of developed echnologies for brain delivery. While positively charged vehicles


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are desirable for the delivery of siRNA (negatively charged), previous studies have shown that nanocarriers with a positive charge (high zeta potential) might cause toxicity to the blood-brain barrier.6,18,24–26 Therefore, carriers with a neutral to negative charge have been more commonly explored for delivery across the blood-brain barrier with efficacious results.16,24,27 Nonetheless, it is important to mention that upon entry into the body, nanocarrier surface charge is impacted by protein adsorption.28 Thus, it is vital that the interactions between the nanomaterials and serum components are analyzed using adequate in vitro and in vivo models.16 Besides its impact on blood-brain barrier toxicity, surface charge also affects cellular uptake, distribution, and efficacy of nanomedicines depending on the route of administration, cell target, and activity.16,17,19 Hence, this characteristic must be taken into account in the design of nanocarriers for the treatment of Alzheimer’s disease.

Another characteristic to be examined during the development of nanosized vehicles for drug delivery across the blood-brain barrier is the carrier shape. Synthesis of nonspherical nanoparticles with different shapes and aspect ratios, has been shown to


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enhance the circulation, uptake, biodistribution, and ultimately their efficacy as drug delivery vehicles.17,18,29–31 These effects may be due to the ability of non-spherical vehicles to deviate hydrodynamic behavior in blood vessels.17,32,33 “Top down” and “bottom up” approaches have been utilized as step-by-step processes to create particles with a variety of shapes in a highly controlled manner.17 In particular, rod-like structures have demonstrated the capability to successfully penetrate the blood-brain barrier and deliver their payload to the brain.16,34,35

Altogether, these material properties determine the potential of various nanotechnology platforms to overcome the blood-brain barrier. In order to enhance these capabilities, one of the latest approaches is the inclusion of active targeting moieties on the nanoparticle surface.15,19 However, it is vital to remark that all of these characteristics must be tailored for each platform, since their chemistry, route of administration, and mechanism of action may pose additional challenges that need to be addressed to ensure the success of nanomedicine treatments for a variety of neurodegenerative disorders.


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Figure 3. Key physicochemical characteristics for the development of nanomaterial technologies to cross the blood-brain barrier for Alzheimer’s disease treatment. Size, shape, surface charge, and functionalization greatly influence the nanocarrier efficacy for drug delivery to the brain. Nanoparticles between 5-200 nm have shown to penetrate the brain more efficiently than larger particles, in addition to being efficaciously internalized by macrophages for cell-mediated delivery across the blood-brain barrier. The surface charge of the nanotechnologies used for brain delivery must be carefully controlled to minimize the potential toxicity of each platform. Furthermore, nanoparticle shape, can


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significantly enhance the circulation and uptake of nanomedicines. Finally, surface functionalization of the nanocarrier offers an extensive range of possibilities to improve brain penetration and target specific cell receptors with the use of small molecules, antibodies, or peptides.

Dendrimers

As hyperbranched polymers with complex three-dimensional architectures and highlycontrolled mass, size, shape, and surface chemistry, dendrimers have shown promising characteristics for the diagnosis and treatment of neurodegenerative diseases.36–39 These molecules are usually formed by an initiator core from which tree-like spatially arranged peripheral functional groups are attached.40 Using an iterative sequence of reaction steps, each iteration (generation) adds a subsequent layer of branching functionality (Figure 1). With each generation, the dendrimer diameter increases by 1 nm.37 The properties of these materials can be easily tailored by the selection of monomers used and by the


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degree of polymerization achieved. This versatility has driven the use of dendrimers as drug carriers.

Dendrimer-based technologies have been developed to take advantage of the characteristics of these systems. These include the ability to sustain drug levels at therapeutic levels, increase the circulation half-life of active agents, improve drug transport and stability, and enhance drug efficacy.41–43 Furthermore, the functionality of the dendrimer surface allows for the conjugation of biomolecules or contrast agents, while having high drug loading capabilities in the internal cavities. Dendrimers have demonstrated high affinity for proteins, peptides, ligands, lipids, and nucleic acids.44,45 A large variety of dendrimers have been explored for drug delivery, imaging, and theranostics. These include poly(aminoamine) (PAMAM), poly-etherhydroxylamine (PEHAM), and poly(propyleneimine) (PPI) dendrimers.37,43 Among them, PAMAM dendrimers have been the most extensively studied structures due to their chemical properties.39,46,47 A full-generation PAMAM dendrimer is polycationic, and exhibits primary amine groups on the surface. Meanwhile, a half-generation PAMAM dendrimer is


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polyanionic that displays carboxylic acid groups on the surface.37 This ability of PAMAM dendrimers offers great breadth of potential applications for these carriers.

For the treatment of Alzheimer’s disease, dendrimers have been used as antiamiloydogenic agents. For example, fourth generation PPI maltose (PPI-G4-Mal) and fifth generation PPI maltose (PPI-G5-Mal) glycodendrimers have exhibited the capability of disrupting the amyloid-beta (Aβ) peptide, specifically Aβ(1-40) fibrilization.48 Each one of these systems has different mechanisms to prevent Aβ fibrilization. While PPI-G4-Mal generates clumped fibrils at low dendrimer-peptide ratios and amorphous aggregates at high ratios, the fifth generation dendrimers hinders fibril formation by generating granular nonfibrillar amorphous aggregates.48 With these studies, it has been shown that preventing fibril clumping may be used as an effective approach to deter the progression of Alzheimer’s disease. Another strategy that has shown promise is the use of cationic phosphorous dendrimers (CPDs).39,44 These materials have proven their ability to modulate amyloidogenesis and inhibit the aggregation of tau protein.44 Specifically, CPDs (generation 3 and 4) have anti-inflammatory properties by blocking acetylcholine


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hydrolysis and possessing antioxidant properties. Working synergistically with traditional pharmacological treatments for Alzheimer’s disease, CPDs have shown that appropriate concentrations are not antagonistic to acetylcholinesterase inhibitor therapy.39

Furthermore, dendrimers have been used as carriers for drug delivery of antioxidant and anti-inflammatory agents across the blood-brain barrier. While the association of neuroinflammation and oxidative stress is linked to several neurodegenerative disorders, and not specifically to Alzheimer’s disease, the ability of dendrimers to serve as neuro therapeutic delivery vehicles which cross the blood-brain barrier presents a carrier worth further discussion. In studies performed by Kannan et al. and Moscariello et al. the abilities of dendrimers to serve as neuroinflammatory treatments have been evaluated.49,50 Using a rabbit cerebral palsy model, Kannan et al. used PAMAM dendrimers for the delivery of N-acetyl-L-cysteine, an antioxidant and anti-inflammatory agent.49 PAMAM dendrimers administered intravenously on day one resulted in significant improvement of motor function, while reducing neuroinflammation and oxidative stress five days after administration.49 In the work performed by Moscariello et


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al., PAMAM dendrimers were conjugated to a streptavidin adapter to analyze their uptake mechanisms and evaluate their transport across the blood-brain barrier using in vitro and in vivo models.50 These results demonstrated the potential of dendrimers as theranostic systems and protein delivery vehicles (i.e. growth factors) for neuroprotective applications.

Additionally, dendrimers have been used as a tool to further understand the mechanisms of Alzheimer’s disease. Specifically, dendrimers have been used for the analysis of the formation of amyloid plaques, one of the hallmarks of the onset and progression of Alzheimer’s disease.36,38 For example, one of the most important peptidic sequences involved in the formation of amyloid aggregates is the so-called KLVFF sequence, which plays a critical role in the formation of β-sheet structures. Chafekar et al. developed a KLVFF-functionalized dendrimer scaffold which showed a significant inhibitory effect on Aβ(1-42) aggregation.51 These constructs also demonstrated the ability to disassemble pre-existing amyloid aggregates. In other studies by Patel et al., a PAMAM dendrimer conjugated to sialic acid were used as membrane clusters mimetics to compete for the


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binding of Aβ.52 The synthesized materials reduced Aβ induced toxicity compared to controls. The effects of polysaccharides in the Aβ aggregation process have also been studied. As presented by Klajnert et al., third generation PAMAM dendrimers were able to modulate heparin-induced aggregation of Aβ(1-28).53 In this work, dendrimer concentration had a direct impact on peptide aggregation, with low concentrations promoting a reduction of aggregation, and the opposite effect when high dendrimer amounts were used. Overall, these findings are important for the improved design of tuned dendrimer chemistries and formulations for the efficacious treatment and diagnosis of Alzheimer’s disease in addition to other neurodegenerative diseases.

Polymeric nanoparticles

Polymeric nanoparticles range in size from 1-1000 nm and are highly versatile and tunable systems. In contrast to many other materials, polymers have a unique combination of characteristics enabling these materials to be used for various drug delivery applications. Due to their polymeric nature, these materials provide opportunity


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to control and modulate particle stability, loading efficiencies, release kinetics, and surface modification capabilities.7,54

Polymeric nanoparticles have been synthesized from either pre-formed polymers (Figure 1) or monomer(s) using a variety of polymerization techniques, as well as many other methods such as, ionic gelation, solvent diffusion, nanoprecipitation, and spray drying.3 In addition, these nanoparticles can be prepared from both natural and synthetic polymers. Examples of polymers used for delivery of therapeutic compounds to the central nervous system include polysaccharides, poly(ethylenimines), poly(alkyl cyanoacrylates), poly(methylidene malonates), and polyesters.54

The first polymer-based nanoparticle system used to deliver therapeutic compounds to the central nervous system was polybutylcyanoacrylate (PBCA).55 PBCA nanoparticles were synthesized via emulsion polymerization of polyalkylcyanoacrylates.7 In these studies, dalargin (an opioid peptide) loaded PBCA nanoparticles were coated with polysorbate 80 (Tween 80) and delivered intravenously.54–56 The overall goal of this work was to obtain therapeutic levels of dalargin present in the central nervous system,


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indicating drug passage through the blood-brain barrier. Subsequent studies showed that in the absence of the nanoparticle coating with polysorbate 80, PBCA nanoparticles loaded with radiolabeled dalargin resulted in a decrease in the number of nanoparticles which crossed the blood-brain barrier.57 Since then, this work and several others have shown that polysorbate 80 appears to enhance the penetration of polymeric nanoparticles through the blood-brain barrier.

Nanoparticles present in the bloodstream are often quickly captured by the reticuloendothelial system by opsonization. To prolong nanoparticle residence time in circulation, a decrease in particle size and/or adsorption of surfactants (e.g. polysorbate 80) on the surface have shown to be effective. Specifically, adsorption of the surfactant polysorbate 80 on nanoparticles has seemingly been showed to act by decreasing the clearance of nanoparticles by the reticuloendothelial system, interacting with endothelial receptors of the blood-brain barrier, and potentially modulating tight junctions and efflux transporters.3,54,56


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PBCA nanoparticles coated with polysorbate 80 have also been used to deliver small molecules and growth factors for the treatment of Alzheimer’s disease. Rivastigmine is an acetylcholinesterase inhibitor used for the current treatment of Alzheimer’s disease. In a previous study, delivery of rivastigmine loaded PBCA nanoparticles coated with polysorbate 80 was compared to loaded nanoparticles in the absence of the coating, and free rivastigmine.58 Results showed greater accumulation of rivastigmine loaded PBCA nanoparticles coated with polysorbate 80 in the brain, compared to loaded nanoparticles in the absence of the coating and free rivastigmine.58 In addition, the polysorbate 80 coating of the nanoparticles resulted in decreased accumulation in the liver, compared to uncoated nanoparticles.58 Moreover, administration of growth factors naturally present in the brain has been shown to improve the pathophysiology of Alzheimer’s disease in animal models.59 PBCA nanoparticles coated with polysorbate 80 were used for the adsorption of nerve growth factor (a growth factor important for the survival central cholinergic neurons).60 Administration of the nanoparticles intravenously in a mouse model of scopolamine-induced amnesia resulted in increased levels of the growth factor


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in the brain parenchyma, and enhanced recognition and memory function of the animals.60

Other polymeric nanoparticles used for drug delivery to the central nervous system include polyesters, such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymer, poly(lactic-co-glycolic acid) (PLGA). These nanoparticles have been designed for intranasal administration in order bypass the blood-brain barrier. Intranasal injection is a favorable administration route for nanoparticles due to its large surface area, close proximity to the brain, and high capillary density.4 In a previous study, basic fibroblast growth factor was entrapped in lectin-modified poly(ethylene glycol) (PEG) PLGA nanoparticles.61 Specifically, Solanum tuberosum lectin, which selectively binds to Nacetylglucosamine on the nasal epithelial membrane for the delivery to the brain, was used to conjugate PEG-PLGA nanoparticles.61 Intranasal administration of lectin modified nanoparticles to Alzheimer’s disease presenting rats resulted in increased levels of basic fibroblast growth factor in the brain compared to those administered intravenously. In


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addition, improvement of spatial learning and memory capabilities of the rats was observed.

Polymeric nanoparticles with high positive charge densities have been shown to cross the blood-brain barrier.4 An example of this is the use of chitosan, a natural, biodegradable, and biocompatible polysaccharide. Previous studies have shown the use of chitosan nanoparticles for the intranasal delivery of estradiol, resulting in increased levels of estradiol in the central nervous system.4 In addition, systemic administration of chitosan nanoparticles have been used to deliver amyloid-beta peptides, dopamine, and caspase inhibitors to the central nervous system.4

Overall, the capability of polymeric nanoparticles to penetrate the blood-brain barrier depends highly on surface modifications. The use of surfactants or ligands to induce modifications may induce receptor-mediated endocytosis, while adsorptive-mediated endocytosis can be enhanced due to the presence of positive surface charges.54 These aspects, as well as many others, must be taken into consideration when developing


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nanoparticle based systems for drug delivery across the blood-brain barrier for the treatment of Alzheimer’s disease, in addition to other neurodegenerative diseases.

Liposomes

Liposomes are vesicles composed of at least one lipid bilayer which surrounds an internal aqueous compartment (Figure 1). Typically, liposomes consist of phospholipids which can form uni- and multi-lamellar structures. In order to prepare liposomes, simple processes such as, sonication, extrusion, reverse-phase evaporation, or high-pressure homogenization are commonly used.3 There is a considerable interest in the use of liposomes due to their preparation simplicity, high bioavailability, biocompatibility, and low toxicity. In addition, these vesicles enable the capability to deliver hydrophilic, hydrophobic, and lipophilic drugs. Although liposomes display many favorable characteristics, their use as a transport system is limited due to their quick uptake by the reticuloendothelial system. In order to prolong the circulation duration of liposomes, the vesicle size is commonly decreased to a nano-scale range, and their surfaces are often


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modified using PEG.3,56 The delivery of liposomes to the brain can be accomplished via penetration of the blood-brain barrier by transport lipid-mediated free diffusion or lipidmediated endocytosis, or via the intranasal route thus bypassing the blood-brain barrier.3

Liposomes used for the treatment of Alzheimer’s disease have focused on targeting the Aβ peptides to prevent the formation of senile plaques. A previous study showed that incorporation of phosphatidic acid and cardiolipin into liposomes increased the in vitro affinity to Aβ oligomers (the most toxic species of Aβ forms).62 In another study, PEG coated liposomes were functionalized using anti-Aβ monoclonal antibodies.63 Significant binding of the liposomes to Aβ monomers was reported in vitro, in addition to binding of liposomes to Aβ deposits in post mortem Alzheimer’s disease brain samples.63

To overcome challenges associated with existing systems for transport to the central nervous system, surface modification of liposomes using peptides, specifically cellpenetrating peptides, have been employed. The incorporation of these peptides have shown to promote liposomal penetration through the blood-brain barrier, however, the mechanisms which enable this action remain unknown.56 In a previous study, cell-


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penetrating peptide modified liposomes were formulated with the acetylcholinesterase inhibitor, rivastigmine, in an effort to improve the distribution of the drug in the brain via intranasal administration.64 The results showed that the concentration of rivastigmine in brain was higher following intranasal administration of the modified liposomes, in addition to higher levels reported after 15 and 60 minutes following administration.64 These results suggest that cell-penetrating peptide modified liposomes have the ability to improve drug delivery to the brain and enhance pharmacodynamics of currently approved agents for the treatment of Alzheimer’s disease.

Natural compounds such as curcumin (a substance found in turmeric plants) and quercetin (a flavonoid from fruits and vegetables) display anti-inflammatory, antioxidant, anticancer properties, and have been shown to be used for the treatment and protection of Alzheimer’s disease.4 Curcumin conjugated liposomes were previously shown to have in vitro affinity to Aβ fibrils.65 In contrast, intranasal administration of quercetin containing liposomes resulted in the inhibition of hippocampal neuronal degradation a rat model of


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Alzheimer’s disease.66 These results show the promise of utilizing naturally existing compounds for the treatment of Alzheimer’s disease through liposomal delivery methods.

Outlook and future challenges

Great strides in the development of nanoneuromedicines have expanded the breadth of applications of nanotechnology for the diagnosis and treatment of neurodegenerative diseases (Table 2). For Alzheimer’s disease specifically, there is a present need for the development of technologies for efficacious drug delivery across the blood-brain barrier and into the desired cellular targets. In particular, novel nanocarriers offer exciting possibilities for safe, targeted, and efficacious treatments, due to their plasticity and control.


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Table 2. Summary of nanocarriers used for brain delivery.

Nanocarrier

Material modifications

Therapeutic agent

Model

Result

Reference

Disrupted amyloid-beta peptide fibrilization

48

Dendrimer

PPI-maltose dendrimers

-

Neuroendocrine cell model and a neuronal neuroblastoma model

Dendrimer

PAMAM dendrimers

N-acetyl-Lcysteine

Rabbit cerebral palsy model

Reduced neuroinflammation and oxidative stress

49

Dendrimer

Cysteine dendrimer

KLVFF peptide

Fibrillar samples

Disrupted amyloid-beta peptide aggregation

51

Polymeric nanoparticle

Polysorbate 80 coated PBCA

Rivastigmine

Rat model

Increased accumulation of rivastigmine in the brain

58


Polysorbate 80 coated PBCA

Nerve growth factor

Mouse scopolamineinduced amnesia model

Increased levels of nerve growth factor in the brain and enhanced recognition and memory function

60

61


PEG PLGA

Fibroblast growth factor

Rat Alzheimer’s disease model

Increased levels of basic fibroblast growth factor in the brain and improved spatial learning and memory capabilities

Liposome

PEG coated liposomes

Anti-amyloidbeta monoclonal antibodies

Post mortem Alzheimer’s disease brain samples

Significant binding of the liposomes to amyloid-beta monomers

63

Liposome

Cell-penetrating peptide modified liposomes

Rivastigmine

Mouse brain microvascular endothelial cells model

Increased drug transport across the blood-brain barrier

64


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Rational design of these platforms requires consideration of particle toxicity, targeting ligands, dosing, administration route, and nanomedicine release. Based on these factors in addition to many others, the physicochemical characteristics of the delivery vehicle can be defined. These features must also be examined during the development of diagnostic and theranostic systems. Furthermore, while nanotechnologies have successfully been evaluated using different animal models, it is critical to assess their capabilities as effective therapies in clinical trials as the next step in the progression of nanoneuromedicines.

Alzheimer’s disease treatment is a challenge that demands creative and versatile solutions. The use of nanomaterials for Alzheimer’s disease treatment offers innumerable therapeutic possibilities, and even though this area is still in the early stages, the promise of it calls for greater research efforts to unveil its full potential.


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AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected]


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Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENTS Research reported in this publication was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under award number R01EB022025. In addition, N.A.P. acknowledges support from the Cockrell Family Chair Foundation, the office of the Dean of the Cockrell School of Engineering at the University of Texas at Austin (UT) for the Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, and the UT-Portugal Collaborative Research Program. During this work, M.E.W. was supported by a National Science Foundation Graduate Research Fellowship (DGE-1610403).


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Figure 1. Anatomy of nanocarriers used for Alzheimer’s disease drug delivery across the blood-brain barrier. Dendrimers, polymeric nanoparticles, and liposomes are examples of nanocarriers which have been used to deliver therapeutic agents across the blood-brain barrier for the treatment of Alzheimer’s disease. To cross the blood-brain barrier, studies have shown optimal particle diameters ranging from 5-200 nm. 339x163mm (150 x 150 DPI)



Figure 2. Overarching hypotheses of Alzheimer’s disease pathogenesis. The two hypotheses which have been proposed regarding the pathophysiology of Alzheimer’s disease are the following: (i) the hypothesis on amyloid cascade neurodegeneration and (ii) the hypothesis on the impairment of the cholinergic system. 283x202mm (150 x 150 DPI)


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Figure 3. Key physicochemical characteristics for the development of nanomaterial technologies to cross the blood-brain barrier for Alzheimer’s disease treatment. Size, shape, surface charge, and functionalization greatly influence the nanocarrier efficacy for drug delivery to the brain. Nanoparticles between 5-200 nm have shown to penetrate the brain more efficiently than larger particles, in addition to being efficaciously internalized by macrophages for cell-mediated delivery across the blood-brain barrier. The surface charge of the nanotechnologies used for brain delivery must be carefully controlled to minimize the potential toxicity of each platform. Furthermore, nanoparticle shape, can significantly enhance the circulation and uptake of nanomedicines. Finally, surface functionalization of the nanocarrier offers an extensive range of possibilities to improve brain penetration and target specific cell receptors with the use of small molecules, antibodies, or peptides. 242x147mm (150 x 150 DPI)



82x44mm (150 x 150 DPI)


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110th Anniversary: Nanoparticle Mediated Drug Delivery for the

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