Gerardo leyva drug discovery today 2015

Drug Discovery Today Volume 20, Number 7 July 2015

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This review presents the current status of the etiology and pathophysiology of Parkinson’s disease in addition to nanotechnology tools to design new carriers to the brain.

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Nanoparticle technology for treatment of Parkinson’s disease: the role of surface phenomena in reaching the brain Gerardo Leyva-Go´mez1,5, Herna´n Corte´s2,5, Jonathan J. Magan˜a2, Norberto Leyva-Garcı´a2, David Quintanar-Guerrero3 and Benjamı´n Flora´n4 1

Laboratory of Connective Tissue, CENIAQ, Instituto Nacional de Rehabilitacio´n (INR), Mexico City, Mexico Laboratory of Genomic Medicine, Department of Genetics, Instituto Nacional de Rehabilitacio´n (INR), Mexico City, Mexico 3 Facultad de Estudios Superiores Cuautitla´n, Universidad Nacional Auto´noma de Me´xico, Laboratorio de Posgrado en Tecnologı´a Farmace´utica, Av. 1o de mayo s/n, Cuautitla´n Izcalli, C.P. 54745, Edo de Me´xico, Mexico 4 Department of Physiology, Biophysics & Neuroscience, Centro de Investigacio´n y de Estudios Avanzados-IPN (CINVESTAV-IPN), Mexico City, Mexico 2

The absence of a definitive treatment for Parkinson’s disease has driven the emerging investigation in the search for novel therapeutic alternatives. At present, the formulation of different drugs on nanoparticles has represented several advantages over conventional treatments. This type of multifunctional carrier, owing to its size and composition, has different interactions in biological systems that can lead to a decrease in ability to cross the blood–brain barrier. Therefore, this review focuses on the latest advances in obtaining nanoparticles for Parkinson’s disease and provides an overview of technical aspects in the design of brain drug delivery of nanoparticles and an analysis of surface phenomena, a key aspect in the development of functional nanoparticles for Parkinson’s disease.

David Quintanar-Guerrero is Professor in the National Autonomous University of Mexico. He received his PhD in pharmaceutical sciences from the University of Geneva, Switzerland, and Claude Bernard University Lyon 1, France. He received the Pharmapeptides prize for the best doctoral thesis (1998) and the CANIFARMA award for the best technological development of DDS for humans (2012) and for animals (2008). He is currently national researcher recognized by the National Council of Science and Technology of Mexico. David Quintanar-Guerrero has 81 peer-reviewed articles, 35 divulgation articles, 14 patents and 320 congress presentations and conferences.

Benjamı´n Flora´n is Professor at the Center for Research and Advanced Studies (CINVESTAV) at Me´xico City. He is a member of the National Researchers System of Me´xico. He is currently Chairman of the Department of Physiology, Biophysics and Neurosciences in CINVESTAV. His team is interested in pathophysiology of Parkinson’s disease, and the pharmacological basis of drug action of L-DOPA and dopaminergic compounds, especially in the cellular and molecular mechanism of L-DOPA-induced dyskinesia. He has around 39 peer-reviewed articles, eight book chapters and 200 congress presentations and conferences.

Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide and it affects about 1–1.5% of the population over 60 years of age [1]. There are cross-cultural variations in the prevalence of PD that are potentially interesting from an etiological point of view, because they might derive from differences in environmental exposures or the distribution of susceptibility genes [2]. At present, there is no cure for PD, and current management is limited to supportive care that partially alleviates disease signs and symptoms and treatment that does not slow or halt disease progression. Pharmacological treatment has been focused on restoring dopaminergic neurotransmission [3]. The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) remains the gold standard for treatment of PD; it improves motor functions, daily living Corresponding author: Quintanar-Guerrero, D. (quintana@unam.mx) 5

These authors contributed equally to the writing of this paper.

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activities (DALY) and quality of life (QOL). However, L-DOPA and dopamine receptor agonists also have several pharmacokinetic drawbacks (notably short half-lives), their effectiveness is limited to long-term use and they are associated with tolerance and the development of debilitating hyperkinetic movements including chorea, dystonia and athetosis, collectively known as L-DOPA-induced dyskinesias (LID) [4]. Therefore, the identification of alternative strategies is crucial. Other nondopaminergic therapeutic strategies including drugs targeting adenosine, glutamate and adrenergic and serotonin receptors, as well as calcium channel blockers, iron chelators, glucagon-like peptide (GLP)-1 agonists, antiinflammatories, neurotrophic factors and gene therapies have been recently developed [5]. However, the main limitation continues to be the development of a suitable carrier for administration of multiple drugs. It is necessary to construct small molecules with appropriate charge, lipophilicity and molecular weight that will be able to diffuse from the blood into the central nervous system (CNS) through the blood–brain barrier (BBB) [6,7]. Beneficial pharmacological effects have been shown by systems involving the continuous release of specific drugs [8,9]. Thus, the development of carriers that release specific drugs effectively and efficiently comprises the challenge; therefore, nanoparticles are an attractive alternative [10,11]. In this review, we offer a detailed description of the clinical aspects of PD, its current treatment and the advances made in recent years in brain drug delivery for this disease. Previously, Linazasoro et al. published a speculative description of the potential applications of nanotechnology in the treatment of PD [12]. Subsequently, Garbayo et al. focused a review exclusively on drug delivery systems for the treatment of PD [13]. We present here an updated review of all of the nanoparticle strategies developed against PD, focusing on the considerations of the general features of nanoparticle constitution, including formation, structure and composition of the protein corona, how the protein corona depends on the synthetic identity of a material and how it influences the physiological response.

Moreover, we suggest some key considerations required before designing nanoparticles coated with polyethylene glycol (PEG) and characterize the performance properties of this product. With these considerations, we conclude by highlighting strategies for controlling protein adsorption to achieve a desired physiological response and offer a perspective on future developments in the treatment of PD.

Clinical aspects and etiology of PD PD is a neurodegenerative disorder caused by degeneration of dopamine neurons of the substantia nigra pars compacta that projects into the striatum and other nuclei within the basal ganglia. This degeneration produces a series of plastic changes in the functional organization of the basal ganglia that progressively give rise to diverse clinical manifestations, including motor and non-motor symptoms [14]. The most relevant motor abnormalities include bradykinesia, rigidity, postural instability, akinesia and resting tremor [15]. In fact, these abnormalities are considered the hallmarks of the disease. However, other features are relevant in the clinical diagnosis of PD, such as response to L-DOPA, symptom asymmetry and disease progression. Interestingly, some reports estimate that motor symptoms only appear when 50–70% of the dopaminergic neurons of the substantia nigra has degenerated.

Resting tremor affects >70% of patients with PD; it is usually

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unilateral in early disease stages, often progressing to bilateral resting tremor over time. Bradykinesia is often manifested as weakness or fatigue by patients with PD; it is commonly reported that it can appear in routine activities, such as difficulty in getting out of a chair or difficulty in opening containers. Rigidity is a clinical manifestation observed in nearly all patients with PD; it can start unilaterally and then become bilateral. Postural instability appears in patients with PD in later disease stages; these patients have an increased risk of falling. Freezing of gait (FOG) is one of the most disqualifying motor alterations in patients with PD, and it is defined as an absence or marked reduction of forward progression of the feet, notwithstanding the intention to walk, it is most frequent in later disease stages [16]. In patients with advanced PD, the most common motor complications comprise LID and motor fluctuations [17].

Diagnosis of PD is performed on the basis of the presence of the motor cardinal signs described previously; however, many patients with PD present other, less studied non-motor symptoms. Nonmotor abnormalities in PD most notably include sleep disorders, anxiety, depression, cognitive decline, impulse-control disorders, dementia, olfactory dysfunction, pain, hallucinations and autonomic nervous system alterations including constipation and postural hypotension [18]. Remarkably, these non-motor symptoms can appear clinically either before or after motor alterations. Nonmotor features could also be related to motor on–off alterations during treatment and can be exacerbated by improper adjustment of antiparkinsonian drugs. Non-motor manifestations can even have major clinical relevance in later stages of the disease.

The description of loss of dopamine neurons within the substantia nigra pars compacta and the formation of Lewy bodies as pathological hallmarks of PD have established this disease as a neurodegenerative process that primarily affects the dopaminergic system in the basal ganglia, later extending to other brain regions including neocortical regions and the limbic system [15]. Despite the numerous studies undertaken, the underlying cause of PD is unknown to date. It is currently thought that PD might be produced by a combination of different factors, including environmental factors and genetic susceptibility [19].

Epidemiological studies have identified risk factors for PD, such as exposure to pesticides, for example 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), trichloroethylene, paraquat and rotenone [20,21]. The exact role of these risk factors in PD remains unclear; however, the mechanism is related to mitochondrial dysfunction, oxidative stress (OS) and energy failure [15,19]. Additionally, some genes known to cause familial PD, such as DJ-1, Parkin and PINK1, have been involved in several mechanistic aspects of mitochondrial function [19]. Some studies have related PD development with mutations in several genes and polymorphisms in the SNCA gene, which encodes a-synuclein protein (Lewy bodies are formed by muted a-synuclein) [22]. In addition to environmental and genetic factors, PD is also related to other factors, such as iron metabolism and neuroinflammation [15,23,24]. Despite the limited knowledge of the disease, efforts to stop the disease have focused mainly on the restoration of dopaminergic neurons.

Current treatment strategy for PD Currently, there are many pharmacological therapies available that can dramatically alleviate clinical manifestations, improving www.drugdiscoverytoday.com

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FIGURE 1

Schematic representation of sites-of-action of current drugs for the treatment of Parkinson’s disease (PD) in the striatum. Neuronal pathways affected and action mechanisms of medication for treatment of PD are depicted. Activity of medium spiny gamma-aminobutyric acid (GABA) efferent neurons of the striatum is influenced by glutamate afferents from the cerebral cortex and thalamus, dopamine afferents from the substantia nigra pars compacta and cholinergic interneurons. Current drugs act on these neural substrates in the striatum, improving the clinical manifestations: L-3,4-dihydroxyphenylalanine (L-DOPA) is converted into dopamine, replacing the neurotransmitter deficit in PD; dopamine agonists bind to and activate dopamine receptors, producing dopamine-like effects; anticholinergic drugs bind to and block acetylcholine receptors, modulating the release of several neurotransmitters, which activate the diverse subtypes of receptors present in a variety of presynaptic afferents in the striatum, as well as in postsynaptic efferent GABA neurons; amantadine binds to and blocks N-methyl-D-aspartate (NMDA) glutamate receptors, normalizing the activity of the glutamatergic corticostriatal pathway and, additionally, the dopamine-releasing effects and inhibition of dopamine reuptake have been suggested; monoamine oxidase B (MAO-B) inhibitors avoid degradation of dopamine, elevating extracellular levels of available neurotransmitter.

the QOL of patients for several years [25]. Available antiparkinsonian drugs include L-DOPA, dopaminergic agonists, monoamine oxidase type B (MAO-B) inhibitors and amantadine (Fig. 1). These drugs replace, modulate or mimic dopamine effects, improving the motor behavior of patients with PD, although the extent of improvement depends on the compound administered.

Numerous studies have been undertaken in the search for drugs for the treatment of PD; however, current therapy focuses mainly on dopamine replacement therapy. L-DOPA remains the gold standard for the treatment of PD, because it can readily cross the BBB and is converted into dopamine by the actions of the enzyme DOPA decarboxylase [26]. Multiple clinical and experimental trials have demonstrated that L-DOPA is the most efficacious compound for controlling many clinical features of PD, and its use notably improves the motor disabilities, especially in early disease stages [26]. Unfortunately, treatment with L-DOPA is not efficacious after several years (tolerance), and its use is associated with some harmful side-effects, including response fluctuations (wearing off) and LID. These side-effects can be extremely debilitating and represent a 826

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major disadvantage of continued therapy. It has been suggested that the prevalence of LID in patients with PD increases with LDOPA treatment duration and dose, and that its severity increases over time. Because of these drawbacks, it has been suggested that medical therapy begins with dopamine agonists or MAO-B inhibitors, and L-DOPA therapy should be delayed as long as possible.

Although for patients with more severe disability L-DOPA is usually indicated [25].

Dopamine agonists are compounds that produce symptomatic improvement through the activation of dopaminergic receptors; they are divided into ergot derivatives (pergolide and cabergoline) and non-ergot derivatives (pramipexole, ropinirole and rotigotine). At present, in clinical practice, only non-ergot derivatives are recommended for initial treatment of PD, because therapy with ergot-derivative agonists is suspected of causing or promoting serious cardiac complications [27]. Non-ergot dopamine agonists are also efficacious in early PD, and some evidence showed that it is less probable than L-DOPA to cause motor alterations, particularly LID. Because age-of-onset of PD is a risk factor for LID, dopamine agonists are generally indicated as initial pharmacotherapy for patients <60 years of age. However, there is evidence that dopamine agonists can produce LID over time, and that their use is related to adverse side-effects such as psychosis, confusion, hallucinations and sleep attacks [26]. If motor symptoms are mild but require therapy, a MAO-B inhibitor (selegiline or rasagiline) can be useful before beginning treatment with L-DOPA. MAO-B inhibitors act by decreasing the catabolism of dopamine, thus elevating available extracellular dopamine levels. Different studies demonstrate that MAO-B inhibitors, particularly rasagiline, are generally well tolerated and that they have few side-effects, including mild nausea, constipation and confusion. Interestingly, in addition to symptomatic control, a potential neuroprotective effect of rasagiline has been suggested [28].

Amantadine is another drug with antiparkinsonian properties; it reduces rigidity, akinesia and tremor. Additionally, amantadine is the only agent reported to possess antidyskinetic effects [28]; however, its safety and efficacy has not yet been determined. The anti-parkinsonian and -dyskinetic properties of amantadine have not been completely elucidated; however, its effects could be mediated through a complex action mechanism that involves inhibition of synaptic dopamine reuptake and blocking of Nmethyl-D-aspartate (NMDA) receptors. Additionally, a variety of compounds are currently being explored to find novel pharmacological alternatives that allow effective control of clinical manifestations without harmful side-effects. Compounds with potentially neuroprotective effects, such as rasagiline, riluzole, creatine, trophic factors and coenzyme Q10 (CoQ10), are currently being studied [28,29]. Neuroprotective treatments such as glialcell-line-derived neurotrophic factors (GDNF) are a promising approach; however, their delivery to the brain is a problem that must be overcome [29].

At present, all of these treatment strategies have been limited; the main problems in the development of an effective treatment include crossing of the BBB by the drug targeted to the site of action and prolongation of drug delivery to prevent fluctuations in concentration. Therefore, advances in new carriers of antiparkinsonian drugs have focused on the development of biodegradable nanoparticles (NP) that can cross the BBB.

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Nanotechnology tools for delivery of therapeutic agents: nanoparticles

Polymeric nanoparticles Polymers offer versatility unmatched by any metal or ceramic material. Hence, nondegradable particles such as fullerenes, metal particles, quantum dots, carbon nanotubes and silica NP have been

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Schematic diagram showing the transport of drugs through the bloodâ&#x20AC;&#x201C;brain barrier (BBB) using nanoparticles (NP). The mechanisms of endocytosis, transcytosis and the possible inhibition of P-glycoprotein (P-gp) are predominant for explaining the crossing of the drugs encapsulated.

less employed [11]. Materials employed in NP production include: poly(lactic-co-glycolic acid) (PLGA) at different degrees of composition that determine biodegradation velocity; poly(lactic acid); poly n-butyl cyanoacrylate (PBCA), one of the polymers exhibiting the highest degradation velocity; poly(e-caprolactone), a little-used polymer but one that is low-cost and easily handled; human serum albumin; and chitosan, with the advantage that the ionic gelation method does not require organic solvents, an element necessary when peptides or proteins are incorporated. Some inconveniences associated with polymeric NP comprise residues of organic solvents, onset of polymerization and production of toxic monomers [31,32].

The use of polymers for application in PD possesses the advantage that there are several well established methods for their development and there is extensive information on the toxicity of materials.

Solid lipid nanoparticles An option that emerged recently involves the use of lipids. In relation to this type of dispersion, the term lipid is employed in a broad sense to include triglycerides, glycerides, fatty acids, steroids and waxes. In general, dispersions prepared with lipids utilize highly efficient homogenization techniques to produce solid lipid nanoparticles (SLN), a term coined to define dispersions of this type prepared by other, including chemical, methods. Characteristics of SLN include controlled release over various weeks, capacity for vectorization, stability for up to three years in some cases [33] and high drug loads. In addition, use of the high pressure homogenization method allows the omission of organic solvents while increasing lot reproducibility [34] and the viability of large-scale production [35]. Thus, SLN comprise an attractive option in part because they are physiologically acceptable, thus decreasing the potential damage caused by acute or chronic toxicity. Other important aspects include the presence of polymorphic structures in SLN, their change over time toward more stable structures, possible expulsion of the drug and a change in the zeta potential of stored liquid systems. This transformation is slower for long triglyceride chains than for shorter ones and this effect can be reduced by lyophilizing the formulation. When the process of freeze-drying is used, a short reconstitution time, a low or unmodified particle size distribution and unchanged activity of the www.drugdiscoverytoday.com

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The term nanotechnology covers all materials and systems where structures and components exhibit physical, chemical and biological properties, phenomena or significantly novel and improved processes owing to their nanoscale size. One of the major applications is aimed at pharmaceutical and medical areas. NP for pharmaceutical purposes are solid colloidal particles ranging in size from 1 to 1000 nm and consisting of macromolecular materials in which the active principle (the drug or the biologically active material) is dissolved, entrapped or encapsulated, or to which the active principle is adsorbed or attached [30]. NP offer controlled drug release, mask physicochemical properties, reduce drug toxicity, improve bioavailability and enhance therapeutic efficacy and biodistribution. Regarding usefulness in PD, it is also important to consider the prolonged-release systems and the transit of the NP into the brain to explain whether a formulation really crosses the BBB, whether it is deposited in the brain and whether the drug is released or simply adheres to the lumen. When the case is that NP cross the brain, the mechanisms involved can be useful to explain whether a reversible or irreversible opening exists. A summary of the relevant research shows that there are different possibilities and that these depend mainly on the composition of the NP that predominates: (i) A prolonged NP circulation time that leads to an increase in the adsorbed amount in brain capillaries, favoring the concentration gradient to the brain. (ii) Endocytosis by the endothelial cells, release of the drug within these cells and diffusion to the brain. (iii) Transcytosis through the endothelial cells, deposition into the cerebral compartment and release of the drug. (iv) Some surfactants, such as poloxamer 407 and polysorbate 80, can inhibit the P-glycoprotein (P-gp) that constitutes the efflux system in the BBB, which decreases or inhibits expulsion of the drug from the brain. (v) A general-effect surfactant that solubilizes lipids in endothelial cell membranes and increases the permeability of drugs across the BBB. (vi) The direct or indirect opening between tight junctions of endothelial cells. The NP could then permeate and release the drug into the brain. (vii) A possible toxic effect could be generated by the presence of certain materials or could increase their concentration in endothelial cells, which would open the BBB. (viii) Different combinations of previously mentioned considerations.

However, it is suggested that endocytosis by endothelial cells followed by release of the drugs by means of these cells, delivery to the brain and finally transcytosis through the endothelial cell layer are the dominant mechanisms involved [11] (Fig. 2), except for assembled systems with specific ligands that employ other types of transport. The use of materials used to develop NP can be classified into polymeric and lipid materials.

Brain

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encapsulated drug are desirable. During the freezing of a sample, there are regions of high concentration of particulate systems, including free surfactant, salts and unloaded drug. These regions, in addition to mechanical stress by ice crystals, can induce aggregation and fusion. It is possible to preserve the original properties by employing appropriate amounts of cryo- and lyo-protectants, and standardized parameters of the process [36]. Some principal factors to consider include the following: freezing temperature and speed; volume and sample concentration, type and concentration of cryo- and lyo-protector; type and concentration of stabilizer; vacuum pressure; and heating rate and type of resuspension (moderate or vigorous agitation). The effect of chain size can also be observed in the loading capacity of the drugs, because lipid matrices with a high composition of di- and tri-glycerides open certain spaces where the drug can be stored. One material with these characteristics is Compritol1 ATO 888. In addition, if one seeks to increase the drug-loading capacity, the main factor to consider is solubility in the melted lipid, which would equal 100% of the loading capacity. Other factors that influence this are the chemical and physical structures of the solid lipid matrix [37â&#x20AC;&#x201C;39].

It is noteworthy that, despite the advantages of SLN over other formulations, not all molecules with therapeutic applications possess the characteristics required to be incorporated efficiently into a lipid matrix. One alternative that could offer greater viability is the formation of nanocrystals followed by the application of a coating with an adequate surfactant [40].

Although certain perspectives continue to view the efficacy of SLN as controversial, improvements in pharmacokinetic parameters, the reduction of adverse effects and, especially, increased permeation in in vitro models of immortalized cell lines from the BBB all show irrefutable results. The use of lipids for the preparation of NP for the treatment of PD has been scarcely explored and might also offer potential benefits. This comprises an alternative to the polymeric NP; if a higher drug-loading capacity is required, different chain-length triglycerides, diglycerides or a mixture of both could be selected.

Parameter assessment for nanoparticle design In addition, it is important to consider at least three important parameters for the development of an effective nanocarrier system: drug loading, particle size and zeta potential.

Drug loading Loading capacity is an important parameter for the use of nanocarrier systems, because it is preferable to transport high-potency drugs using high-capacity loading systems, even in matrices that do not possess sufficient affinity but that are utilized for vectorization because they offer low toxicity. By contrast, low-potency drugs should be transported in systems with high loading capacities because low-capacity systems must be administered at high concentrations, a fact that in the majority of cases compromises the toxic levels of the NP matrix.

For PD, a high load is suitable to ensure prolonged release with a low amount of matrix NP to avoid compromising toxicity levels, as in the case mentioned above [41,42].

Particle size In a new era of nanocarrier system development, the conditional rule that functionality is related to small size has lessened in 828

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importance, and the focus has shifted toward surface properties.

The use of larger particles has permitted the utilization of more combinations of materials and different applications. In this regard, if a functional effect is demonstrated, if the toxic effects can be minimized, if it is viable to increase production to industrial scale and if there is a good cost:benefit ratio, then the stage is set and smaller is not necessarily better [43]. Whereas some physiological parameters, such as extracellular space in the order of 64 nm [44] or 20 nm pore size in the extracellular space [45], have been used as references in designing nanocarriers, studies have demonstrated that even 345 nm NP can cross the BBB [43,46,47].

Yet the permeation, distribution and half-life depend on surface phenomena, although it must be taken into account that higher particle sizes offer a greater amount of drug encapsulated. Thus, there is no strict parameter from the technological point of view, but it is necessary to work with in vitro and in vivo models to demonstrate the NP functionality. Examples of formulations in exceptional cases target the brain with large particles that are PBCA NP of >400 nm to cross the bloodâ&#x20AC;&#x201C;retinal barrier (BRB) [43] and caspase-3 inhibitor encapsulated in NP of chitosan covered with PEG [48], among others. This concept enlarges the range of NP useful in the preparation of formulations for the treatment of PD and can increase the development of NP with greater drug-loading capacity by addressing larger sizes.

Zeta potential Specifying the zeta potential has two objectives in the technological sense. The first is related to the stability of the NP: C > j20 mVj could guarantee adequate dispersion in solution, through either a steric mechanism or charge repulsion. The second objective concerns the in vivo distribution associated with negative, neutral or positive charges. To date, there is no consensus concerning the choice of best-charge ranges, as we have observed, because zeta potential is not the exclusive parameter on which the transport effect toward the BBB depends, and there is variation in results found with NP directed at the brain. For example, one observation is that negative and positive charges can have the same transport efficacy in NP, in contrast to low efficiency of neutral particles.

Therefore, another important point to bear in mind is the effect of the first or second case. For SLN, neutral or low quantities of negatively charged particles (10 mg/ml) exert no disruptive effect on the BBB, whereas large quantities of particles with a negative charge (20 mg/ml) or particles with a positive charge significantly increase BBB disruption. Thus, it would appear to be better to employ negative particles at low concentrations rather than positive charges [49]. Then it appears that, in the development of formulations for the treatment of PD, there is no strict rule regarding an increase or decrease in crossing the BBB based on the charge, because this depends on other factors. But it does appear that the answer is affirmative in terms of the impact on the integrity of the BBB, after the NP formulation is administered to an in vivo system the distribution could change.

The corona: a special phenomenon to consider When NP come into contact with biological fluids and different proteins, they acquire diverse macromolecules and a formation of a first fixed layer and a diffuse layer later is produced. The interaction of the diffuse layer with the bulk solution determines the

main interactions of the carriers and their in vivo distribution [50] (Fig. 3). Formation of the fixed layer depends on the interaction between stabilizing agents on the NP surface and proteins exhibiting high affinity toward this charge type, charge density, surface area, morphology and environmental conditions (e.g. pH, ionic strength). The diffuse layer is supported by the fixed layer and can change constantly according to the composition of the surrounding environment. In this manner, the specific integrity of the NP changes according to the complexity of that environment; therefore, studies on the adsorption of biological macromolecules onto NP are of special interest [51,52]. By contrast, adsorbed macromolecules can also undergo changes in their native structure, thus in their activity, and can eventually produce inflammatory responses [53].

It has been shown that formation of the corona through contact with plasmatic proteins confers a 21–35 nm increase in thickness owing to NP adsorption [54]. If we consider that the hydrodynamic diameters of the plasma proteins are 3–15 nm [55], we can infer

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that 2–11 layers could form (Fig. 4). In addition, the net negative charge of the proteins to plasma pH will give the corona a zeta potential that is also negative and that ranges between 10 mV and 20 mV, regardless of the NP matrix [56] (Fig. 5). Protein affinity is greater toward hydrophobic nanomaterials or to charged surfaces compared with hydrophilic or neutral ones [57]. Another observation is that nanomaterials with hydrophobic surfaces have an affinity for adsorbing apolipoproteins, albumin and fibrinogen, whereas hydrophilic surfaces bind a lesser proportion of these proteins [58]. For this reason, NP coated with hydrophilic polymers are not completely able to avoid plasmatic protein absorption; this would depend on the composition. Therefore, in order to take partial control of the corona formation, it is possible to adhere materials with a nearly neutral charge on the surface of the nanomaterials, or to interweave highly hydrophilic polymers through crosslinking; however, if the protein adhesion is completely avoided it could turn toxic the NP. The coupling of PEG to control protein adsorption has proven effective in a dose-dependent manner.

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Formation of the nanoparticle (NP)–corona complex in a biological medium. Depending on the composition of the NP surface, the proteins present in the biological environment will be attracted to form a fixed layer and, subsequently, with lower affinity, a diffuse layer, a constantly exchanged layer according to the protein composition of the surrounding medium. www.drugdiscoverytoday.com

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FIGURE 4

Schematic diagram showing different possible formations of corona layers according to the size of the adsorbed protein. (a) Formation of three layers of human serum albumin (diameter of each protein: 7 nm). (b) Formation of five layers of fibrinogen (diameter of each protein: 5 nm). (c) Formation of three layers of IgG (diameter of each protein: 11 nm).

Whereas at a concentration of 2% (w/w) it reduces the presence of plasma proteins in the corona by 10%, a concentration of 5% (w/w) causes a reduction of the same proteins by as much as 70% [59]. Covalent coupling ensures that there is no desorption of (a) Protein

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Effect of the negative charge of protein on the zeta potential of the nanoparticles (NP). According to blood pH, the proteins human serum albumin, fibrinogen and IgG with PI of 4.9, 4.9 and 6.4, respectively, provide an additional negative charge. In this case, if the pH is greater than IP there is a major contribution of the negative charge (a) Effect on a negatively charged NP, (b) effect on positively charged NP and (c) effect on a neutrally charged NP. The arrows indicate only the interaction between proteins and nanoparticles.

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PEG, even if during formation of the NP there is nearly complete migration of PEG chains toward the surface to form the PEG brush coating, as has been demonstrated in the reduction of one-half of the proteins in the corona utilizing a concentration of 0.5% (w/w) [59]. A schematic representation of the best conditions for adequate repulsion of the different proteins is presented in Fig. 6, which considers a PEG concentration of 5% (w/w), an effective mechanism that ensures the administration of stealth NP. The composition and structure of the corona is important for understanding the functional reach of NP and reducing undesired effects in the treatment of PD.

Potential applications of PEGylated nanoparticles in PD

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FIGURE 6

Effective distance of polyethylene glycol (PEG) chains to repulsion. A 1 nm distance between chains is sufficient to repel proteins with a 2 nm diameter, whereas 1.5 nm is enough to repel larger proteins (6 nm diameter).

PEG is an excipient utilized as a base for suppositories and ointments, as a lubricant in tablets and as a plastifier [60]. It is a polyether with hydrophilic properties, including being nonbiodegradable, biocompatible, inexpensive and FDA-approved for many applications [61]. The concept of PEGylation refers to adding PEG chains with different molecular weights to the NP surface to produce a hydration layer that impedes protein binding. As mentioned previously, this addition can be accomplished through adsorption or covalently. PEG chains modify the NP interface and increase circulation time in the bloodstream, basically avoiding the opsonization process by reducing the recognition of monocytes and macrophages [62] and tissue and serum proteins, all of which confer stealth-like behavior [63].

This stealth effect is, in turn, based on a decrease in surface energy and van der Waals attraction forces, with an increase in hydrophilicity due to the formation of hydrogen bridges between ether units and the aqueous medium [63]. PEGylation slightly increases particle size, which is detectable in measuring equipment that utilizes dynamic light scattering or microscopy.

The conformation of PEG chains is a function of the thickness of a grafted PEG layer and the proximity among polymer chains. The so-called ‘mushroom’ conformation is produced when the distance between two chains s is greater than twice the radius of the polymer. By contrast, the ‘brush’ conformation occurs when

(a)

(b)

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FIGURE 7

Schematic diagram of polyethylene glycol (PEG) mushroom and brush configurations for polymer grafted onto the surface. (a) The mushroom conformation occurs when the distance between chains s is greater than twice the radius of PEG. (b) The brush conformation is produced when s<2r and the PEG chains are in an elongated shape on the surface.

s < 2r, where the chains stretch to occupy less space on the surface and allow a larger number of exposed monomers [64] (Fig. 7).

The Flory radius is used to estimate the size of a polymer coil, F ¼ ‘N 35, where ‘ is the monomer length and N is number of monomers. As the value of s approaches F , it is possible to record a change from ‘brush-like’ to ‘mushroom-like’ [65], changes that might occur, for example, in cases of PEG adsorption. It is noteworthy that the brush conformation involves longer circulation times owing to increased density [66], but in ‘ it conceals the NP from Reticuloendothelial System (RES) better to provide an effective stealth system. With respect to the use of different molecular weights of PEG, if the substrate is small as a protein, it is preferable to add a high-molecular-weight PEG, but if they are bigger as NP then a lower-molecular-weight PEG is used. If a high-molecularweight PEG was used with NP it is unlikely that the stealth effect would be achieved. Moreover, with respect to absorption, this decreases at the intestinal level as the molar mass increases [61].

Regardless of whether PEG is added as part of the matrix during NP formation or applied directly to the surface, it is possible for the entire amount of PEG not to be exposed to the exterior, because a fraction might remain in the nucleus in the form of molecular dispersion or by forming cavities with hydrophilic nuclei. This internalization effect can reduce PEG density and displace the coating toward mushroom-like expression, which increases protein binding [67] and reduces the stealth effect.

Once we understand that PEG coating exerts an effect on all interactions toward the exterior, it is reasonable to think that a suitable amount of PEG could produce higher drug encapsulation and modify its release pattern [68]. For NP made of materials with polymorphic structures and, as a result, with structural rearrangements closer to forms with greater stability and a plausible exit for the drug, PEG coating can be an option that prevents release of the active ingredient. It is noteworthy that, although PEG has been employed for three decades, there is no consensus to date on the relationship between molecular weight and optimal density of the coating or its conformation [69], perhaps because adequate analytical measuring techniques have not yet been developed [70]. PEGylation reduces opsonization and elimination of NP, thus increasing blood circulation time, and prolonged release is favored, increasing the probability that the drug will reach the brain before being recognized as foreign and being cleared from the body. The first data on the extension of circulation time periods referred to 12–48 h for PEGylated albumin [71]. Today, with the help of the carriers and PEG, the stealth effect can be extended to several weeks, which facilitates the different drug

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treatments in PD for reducing fluctuations in blood drug concentration caused by multiple administrations and avoiding side-effects, such as LID and the on–off phenomenon.

Although PEG has been widely utilized to generate a stealth effect in nanocarriers, it is important to maintain certain considerations, such as collateral effects that might be present in in vivo systems; for example, PEG might emerge as an immunogenic material owing to activation of the complement and antibodies [61]. Also, materials with PEG can present the phenomenon of accelerated blood clearance (ABC), possibly as a result of the formation of anti-PEG IgM antibodies by the spleen after initial administration, because IgM binds to PEG, activating opsonization with C3 fragments and uptake by Kupffer cells, which in turn affects the medication’s bioavailability [72]. If one needs to utilize an alternative material to PEG, the poly(amino acid)s have no significant effect on the ABC phenomenon, are used as thickeners in foods and cosmetics and used as moisturizing agents in cosmetics [73]. Additionally, they degrade in vivo into their corresponding amino acids and then ingress into different metabolic pathways.

Much attention is focused on the notion that the second administration produces a pronounced ABC phenomenon. Today, 30 years after the first report on ABC [74], various factors have been described that attenuate the magnitude of this phenomenon, including time interval between administrations, dosage and the physicochemical properties of NP [75]. With respect to the time effect, studies have demonstrated that it is during the interval from day 4 to day 7 after the first dose that the most pronounced ABC phenomenon appears [76], whereas for days 1–3 and 8–28 there is not such a great influence. Findings also show that the effect of the third dose reduces the ABC phenomenon [77]. With respect to density on the PEG surface, an increase in surface density correlates well with an increase in circulation time but likewise with an increase in the presence of anti-PEG IgM and the ABC phenomenon.

Specifically, there are reports that low-surface (<5 mol%) and highsurface (>5 mol%) density PEG reduces the ABC phenomenon [78], although this particular report dealt with liposomes; thus, there might be a slight variation in the parameters established for other formulations. But what is important, in any case, is to take the reference values into account. With regard to particle size, a 31.5 nm limit has been proposed to define a notable effect in relation to the ABC phenomenon: sizes of <31.5 nm decrease the ABC effect, whereas those of >31.5 nm increase it [79]. Another relevant factor is velocity of administration, in that low infusion velocity favors an increase in captures by antibodies and ABC, whereas, by contrast, faster administration velocity does not enter into contact with sufficient levels of IgM [75]. As mentioned above, the use of PEGylation continues to have limitations set by the number of models used, especially for PD, and this is a factor that should be considered for exploring further information on interaction with the immune system, decreasing the ABC phenomenon and its subsequent adaptation in clinical trials. The use of PEGylation can preserve a greater circulation time and also maintain a prolonged concentration gradient to the brain. The use of tools for drug targeting actively increases the possibility of directing the NP toward the CNS.

Active targeting mechanisms To enhance NP bioavailability, NP can be coated and/or modified by the addition of specific ligands on the outer surface, such as www.drugdiscoverytoday.com

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antigens, antibodies or receptor ligands, therefore facilitating drug delivery to the target in PD patients. Several endogenous BBB receptors used for brain-targeted drug delivery include receptors for iron transferrin, insulin, glutathione, low-density lipoprotein (LDL), LDL receptor-related protein (LRP)-1 and LRP-2 [11,80].

Whether employing simple or complex techniques, one classic proposal for increasing the flow of drugs across the BBB using NP involves adding Tween1 80 to reduce apoCII adsorption and macrophage recognition [81]. By contrast, a specific approach would be the anchoring of apolipoprotein A-I, B or E, which interact with the receptor class B type I (SR-BI for apo A-I) [82,83] or with LRP-1 for apo E and B [84].

Other examples of specific approaches for increasing the flow of drugs include conjugating NP with transferrin, a glycoprotein that transports iron in the plasma [85]. In addition, the anti-transferrin receptor monoclonal antibodies (e.g. OX26 or R17217) also use the transferrin receptor for the delivery of drugs to the brain [86]. In a similar way, lactoferrin covalently conjugated to NP can facilitate the transport across the BBB [87]. Other receptors for drug transport include the use of insulin receptor, insulin or anti-insulin receptor monoclonal antibody (29B4) or monoclonal antibody 8314, an insulin-like peptidomimetic with high affinity for a subunit of the human insulin receptor in the capillaries of the brain [88] can be covalently coupled to NP. Another choice for drug targeting is the anchoring of beta hydroxybutyric acid on the surface of the NP, which has a special transporter in the BBB – the mono carboxylic acid transporter – and which is expressed in the endothelial cells of the brain [89].

Finally, some peptides such as angiopep (Thr-Phe-Phe-Tyr-GlyGly-Ser-Arg-Gly-Lys-Arg-Asn-Asn-Phe-Lys-Thr-Glu-Glu-Tyr) [90] or H-2N-Gly-1-Phe-D-Thr-Gly-1-Phe-1-Leu-1-Ser-O-b-D-glucoseCONH2 similar to opioid peptides can be used [91]. Angiopep is recognized by LRP-1 present in the brain capillary endothelia and also in neurons [92]. Other examples of peptides include: Gly-1[93]; Phe-D-Thr-Gly-1-Phe-1-Leu-1-Ser(O-b-D-glucose)-CONH2 Thr-His-Arg-Pro-Met-Ser-Pro-Val-Trp-Pro protein (can be used to target the transferrin receptor) [94]; Tet-1 peptide, a 12-amino-acid peptide that possesses affinity to motor neurons and retrograde delivery to cell soma [95]; VH0445, a cyclic 8-mer peptide ligand for LDL receptor; the antigen p97 (melanotransferrin) [96]; and the peptide T7 (sequenced as HAIYPRH), which is recognized by the transferrin receptor with an affinity comparable to that of transferrin [97].

Regardless of the composition of the matrix of the NP, the same strategies can be employed in the case of SLN or polymeric materials. Remarkably, all of these approaches are potentially useful for PD treatment for the delivery across the BBB of promising molecules that are unable to cross it in current therapy.

Current therapeutic advances in PD At present, several attempts have been described in the literature and multiple drugs have been delivered in PD models.

Dopamine delivery systems Trapani et al. [98] encapsulated dopamine in chitosan NP; the drug was adsorbed (bear in mind that few formulations make use of this drug transport type owing to bulk phase during release) and evaluation in rats exhibited an increase in striatal dopamine 832

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production and high transportation across the MDCKII-MDR1 cell line. In another study, to minimize the peripheral side-effects of oral therapy for PD, Pillay et al. [99] designed an intracranial nano-enabled scaffold device for the site-specific delivery of dopamine. After performing in vitro and in vivo studies, the authors showed that their device enhanced dopamine concentrations in cerebral spinal fluid versus systemic concentrations. Finally, they concluded that their strategy could serve as a platform for sitespecific delivery of dopamine in the chronic management of PD.

Dopamine agonist delivery systems Esposito et al. [100] worked with bromocriptine, a dopamine receptor agonist. The drug was encapsulated in nanostructured lipid carriers that were composed of a solid lipid matrix with a certain content of a liquid–lipid phase in contrast to SLN. The nanostructured lipid was made of tristearin/miglyol mixture and poloxamer 188 as stabilizer. The formulation, administered intraperitoneally (i.p.), attenuated motor deficit in 6-OHDA hemilesioned rats by prolonging the half-life of bromocriptine in vivo.

Other effective results were proposed by Md et al. [101] with bromocriptine using chitosan NP following intranasal (i.n.) administration. The formulation showed a reversal in catalepsy and akinesia behavior in a model of haloperidol-induced PD in mice, suggesting direct nose-to-brain carrying. In addition, Tsai et al.

[102] formulated apomorphine, a dopamine receptor agonist; the drug was incorporated into SLN of glyceryl monostearate to increase oral bioavailability and brain regional distribution in rats with 6-OHDA-induced lesions. The formulation increased 12-fold in terms of higher bioavailability than the drug solution, and total rotation number increased from 20 to 94. Wen et al. [103] encapsulated apomorphine in liposomes to decrease uptake by the liver and enhance brain targeting. The formulation was injected i.v. into mice. An increase in brain concentration was demonstrated, complementary to images showing intact carriers in the brain that are associated with high drug targeting. Hsu et al. [104] encapsulated apomorphine into nanostructured lipid carriers, which was administered i.v. in rats. In vivo results exhibited an increase in brain fluorescence using this type of NP, indicating high targeting.

Similarly, Liu et al. [105] incorporated diisobutyryl apomorphine into nanostructured lipid carriers using sesame oil/cetyl palmitate and PEG. The NP controlled the hydrolysis of the prodrug and targeted to the brain, demonstrated by a high fluorescence in the brain. In an interesting manner, Hwang et al. [106] encapsulated apomorphine in perfluorocarbon nanobubbles with the aim of increasing stability and decreasing the number of injections.

Nanobubbles had coconut oil and perfluoropentane as the inner phase and phospholipids and cholesterol as the outer phase. This formulation protected apomorphine from degradation and showed delayed and sustained release profiles and, specifically, as for ultrasound (US) studies, when insonation at 1 MHz is applied to nanobubbles, the drug release increases. In addition, Pardeshi et al. [107] encapsulated ropinirole, a potent dopamine receptor agonist with high relative specificity and full intrinsic activity to the D2/D3 receptors. This drug was incorporated into a novel surface-modified polymer–lipid hybrid NP for i.n. delivery in mice.

The formulation showed satisfactory bioadhesion, and equivalent pharmacodynamic parameters between nasal and oral administration were obtained, drug efficiency increased and concentration

fluctuations were decreased, which could lead to reduced sideeffects.

Dopamine precursor delivery systems Kondrasheva et al. [108] designed a novel carrier for L-DOPA. The formulation consisted of PLGA NP for nasal administration, providing lasting motor function recovery and improving drug efficacy in a PD rat model. Recently, Gambaryan et al. [109] also incorporated LDOPA into the same formulation as Kondrasheva et al. [108] and the authors described that L-DOPA applied i.n. at a dose of 0.35 mg/kg was effective only in the single-use format, whereas NP increased the motor function in the 6-OHDA rat model along the entire treatment period (112 days), demonstrating a prolonged effect even one week after discontinuation of the drug. In another paper, Ngwuluka et al.

[110] used a methacrylate copolymer–lipid nanoparticulate (MCN) system for oral drug delivery of L-DOPA. The NP were manufactured employing multicrosslinking technology and characterized for several properties. The authors found that their NP had sustained release of L-DOPA and concluded that their developed delivery system could find applications in oral, sustained and localized drug delivery. Also, Sharma et al. [111] encapsulated L-DOPA in chitosan NP and incorporated these into a thermo-reversible gel prepared using poloxamer 407. Administration was nasally in rat. In vivo studies indicated a higher L-DOPA concentration in the brain using NP; however, the use of a high viscosity gel would decrease the uptake of NP and migration rate. In addition, Sadigh-Eteghad et al.

[112] also incorporated L-DOPA into chitosan NP and demonstrated this formulation as a neuroprotective agent in neural cells (Pc-12), with decreasing caspase-3 as an indicator of apoptosis, and cell viability increased compared with the drug alone. In another study, Yang et al. [113] encapsulated L-DOPA in PLGA NP, the formulation was administered subcutaneously (s.c.) in rats and this study showed a decrease in LID using NP as indicative of the neuroprotective effect.

Antioxidant delivery systems With regard to antioxidant activity, CoQ10 has shown the ability to inhibit paraquat- and rotenone-induced mitochondrial dysfunction and neurodegeneration in rat mesencephalic primary neurons [114]; therefore, CoQ10 has been encapsulated in PLGA NP, nanostructured lipid carriers, nanocrystals and PEG complex for controlled release, improving pharmacokinetic parameters [115–117].

Cholinesterase inhibitor delivery system With a different mechanism, Joshi et al. [118] worked with rivastigmine tartrate, a reversible cholinesterase inhibitor employed for the treatment of Alzheimer’s disease and also in clinical trials of PD. The formulation was prepared using PLGA NP with poloxamer 407 as stabilizer and, by contrast, PBCA NP with poloxamer 188, both formulations were administered intravenously, and they produced faster memory recovery in amnesic mice as a result of appropriate drug transport to the brain. It is interesting to bear in mind that these stabilizers decrease the expression of P-gp at the BBB level.

Another option for rivastigmine includes chitosan NP [119].

Neurotrophic factor delivery systems hGDNF was incorporated into the polyamidoamine dendrimer and functionalized with PEG. After 6-OHDA lesion, the formulation

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administered i.v. improved locomotor activity, reduced dopaminergic neuronal loss and enhanced monoamine levels [120]. In another study, GDNF was encapsulated in liposomes and administered i.n. with a neuroprotective effect also found [121]. In another interesting study, Martı´nez-Fong et al. [122] prepared Neurotensin (NTS)-polyplex, a carrier system with an efficient, cell-specific and sustained strategy non-viral vector for transgene expression in dopaminergic neurons. This nanocomplex consists of NTS-poly-Llysine electrostatic binding to plasmid DNA, incorporating a fusogenic peptide and a karyophilic peptide to promote endocytosis and nuclear localization, respectively, in dopamine neurons, to avoid endosomes and to enhance transfection efficiency. In this respect, neurotrophic factors GDNF, Neurturin (NRTN) and Brain-derived Neurotrophic Factor (BDNF) play substantial roles in the growth, differentiation and survival of dopaminergic neurons. Such factors have been complexed in NTS-polyplex with successfully reduced motor impairment and a restorative effect on the dopaminergic nigrostriatal system in rats.

Other delivery systems Tiwari et al. [123] used nicotine-encapsulated PLGA NP and polyvinyl alcohol as the stabilizer. This system offers i.p. neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice by improving the viability of tyrosine hydroxylase immunoreactive neurons, its mRNA expression and fiber extension.

In addition, NP modulate dopamine levels, increase microglial activation and the expression of Glutathione S-transferase alpha-4 (GSTA4-4), inducible Nitric Oxide Synthase, Metallothionein-3 (MT-III), Heme oxygenase-1, Transformation related protein 53 (p53) caspase-3 and nitrite levels, thereby improving neuroprotection and modulating OS and apoptosis indicators. Hu et al. [124] developed lactoferrin-conjugated PEG-poly(lactic-co-glycolic) NP for i.v. administration into mice with urocortin, a corticotrophin-releasing hormone-related peptide associated with a cytoprotector effect for GABAergic neurons. The NP were localized in the cortex, substantia nigra and striatum region with a 2.49-times increase in the area under the curve (AUC) after striatum lesion caused by 6-OHDA. This is an example of the combination of the effect of lactoferrin and PEG for drug delivery to the brain. In a similar manner, but by a nose-to-brain delivery system, Wen et al. [125] prepared odorranalectin-conjugated PEG-poly(lactic-co-glycolic) NP for urocortin delivery in rats, with a 9.1-fold increase in dopamine level and more tyrosine-hydroxylasepositive neurons. In another study, Muthu and Singh [126] incorporated risperidone into poly epsilon-caprolactone, risperidone is also used in the treatment of dopamine-induced psychosis in PD, this type of NP aimed to reduce the dose-dependent extrapyramidal sideeffects of the drug. In vivo results in mice showed a significant prolonged antipsychotic effect and a decrease in side-effects and dose reduction. In a similar manner, Muthu et al. [127] encapsulated risperidone in PLGA NP and mixed this with a thermal-responsive in situ gel of poloxamer 407. The formulation was administered s.c. in mice. In vivo results showed reduced dose-dependent extrapyramidal side-effects, a prolonged antipsychotic effect and a dose reduction. By contrast, recombinant human erythropoietin is a hematopoietic cytokine glycoprotein that has also demonstrated a neuroprotective effect, improving long-term potentiation, memory function and a stimulatory effect on dopamine and acetylcholine release. There are different NP for recombinant human erythropoietin, such as chitosan www.drugdiscoverytoday.com

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TABLE 1

Studies using systemic drug delivery systems for Parkinson’s disease treatment

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Drug

Particle size

Dose

Side effects/toxicity

Refs

Dopamine

<150 nm

1 dose

No

[98]

Dopamine

197 nm

1 dose (device implantation)

No

[99]

Bromocriptine

<200 nm

1 dose

N/D

[100]

Bromocriptine

161 4 nm

1 dose

N/D

[101]

Apomorphine

63–155 nm

1 dose

N/D

[102]

Apomorphine

142 nm

1 dose

N/D

[103]

Ropinirole

98–287 nm

1 dose

No

[107]

L-DOPA

250–400 nm

22 doses

No

[108]

L-DOPA

250 50 nm

91 doses

N/D

[109]

L-DOPA

152–321 nm

N/A

N/A

[110]

L-DOPA

164.5 3.4 nm

1 dose

N/D

[111]

L-DOPA

250 nm

1 dose

No

[112]

L-DOPA

500 nm

3 doses

N/D

[113]

Antioxidants

N/A

N/A

N/D

[114]

Rivastigmine

<150 nm

1 dose

N/D

[118]

GDNF

149 11 nm

1 dose or 3 doses

N/D

[121]

GDNF

N/A

1 dose

N/D

[122]

Nicotine

300 nm

28 doses

No

[123]

Urocortin

<150 nm

1 dose

No

[124]

Urocortin

<120 nm

5 doses

N/D

[125]

Erythropoietin

100–400 nm

N/A

N/A

[128]

Abbreviations: GDNF, glial-cell-derived neurotrophic factor; N/A, not applicable or not available; N/D, not determined.

and PLGA, where pharmacokinetic parameters are improved [128].

However, there are no direct applications in terms of PD to date.

Despite the previously mentioned evidence in recent developments, for prolonged release to be extended for a longer period it is necessary to increase the release time with the purpose of reducing fluctuations in the drug and its pulsatile stimulation of receptors, higher capacity of drug loading and more-efficient surface functionalization to confer vectoring and stealth properties. Additionally, few in vitro studies show evidence demonstrating no disruption of the BBB, and there is no description of possible interactions with proteins and corona formation. As observed in the majority of the previously noted examples, there is an absence of registration of long-term adverse effects and there is a match in a single administration (Table 1). Significantly, studies examining long-term adverse effects and chronic administrations have not found undesirable results. However, this involves an area of opportunity for new tasks that include such assessments and that also ensure the development of future clinical trials. Therefore, there are new challenges for the development of innovative drugs, considering the different aspects analyzed in this review.

Therapeutic perspectives: new carrier systems The proposal for future research is to orient therapeutics toward noninvasive treatments, pharmaceutical systems with the capacity to cross the BBB, prolonged release, sufficient loading capacity, biodegradability and low toxicity. In this sense, it is necessary to 834

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emphasize that, because PD therapy is chronic, oral administration of medication is highly needed. Therefore, new NP formulations should be able to have a suitable oral drug absorption and then overcome the BBB and produce prolonged release after oral ingestion. The majority of studies reported in relation to PD include systems containing only one drug, but it is possible to design multidrug systems, either in combination with only one nucleus or in layers. Another important factor is to functionalize the surface with high-specificity ligands to achieve stealth effects and prolong circulation. The present review has focused on nanoparticulate systems, but it is noteworthy that porous systems (i.e. microparticles or membranes) for protein transport have proved to be an effective innovation that guarantees the integrity of their structure and controlled release. Indeed, it might even be possible to include NP to control the release of active ingredients from porous channels, whereas these same NP could also function as carriers of other active ingredients.

Turning now to another aspect, to date the standard medications employed for PD do not improve cognitive problems, and antipsychotic drugs exhibit severe adverse effects. Cholinesterase inhibitors are one option, because PD is correlated with extensive cholinergic deficits; thus, there is interest in using cholinesterase inhibitors in these patients to treat dementia [129]. However, these substances have certain drawbacks such as nausea and vomiting that are currently controlled by applying skin patches. This is an area where new formulations of rivastigmine could be developed, alone or in combination with other drugs to reduce adverse effects.

Several non-viral options are technically available, but are lesswell-suited from a clinical point of view for treating a chronic neurodegenerative disorder such as PD, owing to short duration of gene expression and low transfection rates, circumstances entailing the need for multiple dose regimens [130]. Although release time might not be exact at first, high loading capacity could overcome this disadvantage.

Another option would be to introduce transgene-encoding enzymes or cell signaling proteins involved in dopamine production or regulation. Some notable examples of such enzymes are tyrosine hydroxylase (to convert L-DOPA from L-tyrosine), aromatic amino acid decarboxylase (to produce dopamine from L-DOPA) and GTP-cyclohydrolase-1 (a rate-limiting enzyme in the synthesis of the tetrahydrobiopterin cofactor for tyrosine hydroxylase, a deficient process in PD). Meanwhile, delivery of the gene-encoding glutamic acid decarboxylase (for GABA synthesis) decreases hyperactivity in the subthalamic nucleus. Also, parkin gene (an E3 ubiquitin-protein ligase) therapy is related to potential efficacy in alpha-synuclein overexpression and for correcting neuronal degeneration in the substantia nigra and striatum [131]. RNA interference techniques could be utilized to silence the expression of mutations, for example alleles containing leucine-rich repeat kinase 2 (LRRK2) mutations. The key idea is to identify the specific genetic mechanisms associated with PD and to target a specific therapy.

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prolonged release and sufficient drug loading are the properties required. Thus, we described diverse polymeric materials and NP types that possess the characteristics for an excellent delivery system. According to particle size, the idea that has been established for a long period of time was that NP targeted to the brain should be 100–200 nm, or preferably lower; however, particle size has been changed, and it is now possible to use formulations of a larger size ( 345 nm), provided that functionality, in vitro and in vivo correlation and low toxicity are ensured. With respect to the zeta potential, evidence suggests the use of NP that are negatively charged at low concentrations to guarantee non-disruption of the BBB. Regarding surface phenomena, corona formation is a field of study to define the different complexes formed, the mode of action in biological systems, supporting more evidence on nanotoxicological aspects and the design of new surface types. The use of PEG represents advantages for PD in decreasing corona formation and increasing circulation time. There are multiple applications at present; however, special attention to possible adverse reactions is required. Finally, the application of nanotechnology in the area of PD could offer greater benefits if new drugs are used and if the carrier surface is functionalized.

Conflict of interest The authors declare no conflict of interest. This work is consistent with the Journal’s guidelines for ethical publication.

Concluding remarks In the search for novel therapies for PD, noninvasive and biodegradable therapeutic treatments, pharmaceutical systems with the ability to cross the BBB and delivery to the site-of-action,

Acknowledgments This study was partially supported by PAPIIT (UNAM-Me´xico) project IT201914 and CONACyT (Me´xico) CB-221629.

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