Abbreviations

Angiotensin-converting enzyme 2 (ACE2)

Alzheimer’s disease (AD)

Aminopeptidase N (APN)

Amyloid-β (Aβ)

Blood brain barrier (BBB)

Brain-derived neurotrophic factor (BDNF)

Central nervous system (CNS)

Dopaminergic (DA-ergic)

Glial cell derived neural factor (GDNF)

Human coronavirus 229E (hCoV-229E)

Interleukin-1β (IL-1β)

Inducible nitric oxide synthase (iNOS)

Lewy bodies (LB)

Macrophages (M.s)

Monocyte chemotactic protein-1 (MCP-1)

Neural Stem cells (NSCs)

Parkinson’s disease (PD)

Polyethylene glycol (PEG)

Poly (lactic-co-glycolic acid) (PLGA)

Arg-Gly-Asp (RGD)

Reactive oxygen species (ROS)

Substantia nigra (SN)

α-Synuclein (α-syn)

Severe Acute Respiratory Syndrome (SARS)

Tumor necrosis factor-α (TNF- α)

1. Introduction

Protein aggregation is a typical phenomenon in both Parkinson’s disease (PD) and Alzheimer’s disease (AD). In particular, PD is characterized by the deposition of aggregated misfolded α-synuclein (α-syn) protein, which is known as Lewy bodies (LB) in dopaminergic neurons, and thus causes severe motor dysfunction [1]. On the other hand, AD where the cognitive process is typically lost is diagnosed with the abnormal accumulation of amyloid-β (Aβ) plaque and tau neurofibrillary tangles in the brain [2].  Supporting evidences are there to clarify the proteinopathy due to the accumulation of pathological α-syn, Aβ, and tau that spreads from cell-to-cell [3-12]. The α-syn aggregates localize in the mitochondria and induces mitochondrial fragmentation and decreased membrane potential [13-15].  In AD, the aggregation of Aβ peptide results from the oxidative stress from dysfunctional mitochondrial reactive oxygen species (ROS) [16-18]. Further, abnormal hyper-phosphorylation of microtubule-associated tau protein leads to the formation of tau tangles with prion-like activity. In both the diseases, AD and PD, expression of inflammatory cytokines have been noticed which may cause the protein aggregation and cell death. However, inhibition of amyloidosis in both AD or PD with small molecules and antibodies exhibit only a little success [19-21].

Traditional therapeutic drugs usually have off-target effects. Nanomaterial formulations can ensure targeted delivery and also can overcome the blood brain barrier (BBB) during delivery of the actives [22-25]. Additionally, composite nanomaterials can be developed to ensure the new cell growth in PD and AD [26]. In this review, we will explore the current field of nanomaterials for therapeutic application of cell-based therapies in PD and AD.

2. Present Treatment Strategy

Except some palliative treatment, like using Dopa/Dopamin, currently, there is no curative therapy for PD or AD. However, efforts are in progress to regenerate the neuronal growth, axonal extension and to repair the damaged cell in both the diseases using some neurotropic factors like BDNF, GDNF.  Nanomaterials like scaffolds, PLGA are thoughts to be used not only for targeted delivery of the neurotropic factors but also to increase their half-life and to improve the motor function and dopaminergic neuron restoration without showing any toxic effects in vivo [27-29].

Further, maturation of neurons can be done, in vitro, by using scaffolds pretreated with RGD and heparin before administration to an in vivo system [30].  In this regards, various scaffolds are being made using alternating amino acid sequences, which support neuronal growth and differentiation [31, 32].  Humanin peptide, which is known to inhibit Aβ-related cell death in AD can be delivered successfully with polymersomes (PEG-PLGA) [33].

Cell Therapy: Cell therapy of PD by transplantation of stem cells has been proposed earlier. However, there are enough demerits in that approach, like availability of enough cells for transplantation, probability of future development of carcinoma, and so many other logistic challenges including cost of the treatment. 

Neural Stem cells (NSCs) have been considered as the preferred cells for transplantation as those can produce dopamine, the active principle for PD/AD treatment [34-36].  Besides the production od Dopamine, NSCs posses the ability to control the level dopamine in the synaptic cleft as it contains the Dopamine catabolizing enzymes, and as a result offers a less probability of having future neural tube defects that can result from the excess unused floating dopamine in the Substantia Nigra (SN region). Further, NSCs can also be used as a vehicle for delivering other neuron co-stimulatory drugs, and/or chemotherapeutic agents.  In fact, NSCs have been found to deliver neurotrophic factors to the CNS and promote neuron integrity and regeneration [37-40].

Macrophages, another possible therapeutic cells against PD/AD: PD is believed to be the result of chronic inflammation [41, 42]. MFs, the main regulatory immune cells that acts in the periphery have the ability to polarize either to its M1 type or to M2 type under the influence of environmental factors [43].  M1 type of MFs while is pro-inflammatory, and releases several chemokines, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF- α), and monocyte chemotactic protein-1 (MCP-1), and iNOS, the M2- MFs produce anti-inflammatory cytokines, like IL- 10, IL-4, IL-13, and promote tissue repair [44-47]. During the inflammatory disease progression, M2-MFs are gradually replaced by M1-type [48]. With the similar note it is believed that somehow in the brain MFs are polarizes to M1-type during the pathogenesis of PD. In fact, MFs and neutrophils are able to cross the blood brain barrier, and secrete proinflammatory cytokines (e.g, ILs, TNFa, IFN-g), which can cause the development of PD development [49].

Use of Nanotechnology for Targeted Tissue Delivery:

As an extension of the targeted cell therapy, the use of nanovehicles to carry NSCs along with the neurotropic factors across the Blood-Brian Barrier (BBB) have been proposed [50-53].

1. Liposomes: Liposomes are capable to encapsulate both the hydrophobic and hydrophilic drugs into its hollow core and deliver them to the disease sites [54-56]. Long-circulating liposomes, like PEGylated liposomes, can also be prepared by coating with polyethylenglycol [58].  In clinical trials with the treatment of histoplasmosis, meningitis, and neutropenia, PEGylated liposomes showed better efficacy with less side effects [59].
2. Polymeric Micelles: Amphilic polymeric micelles are made up of PEG-.-PCL), poly(styrene) or PLGA [60]. This type of block copolymers are, indeed, approved by FDA for the targeted drug delivery [60]. In that hydrophilic shell, hydrophobic drugs can stay protected from the surrounding environment. By designing the cell-specific ligands and attached to the polymer can make the polymer to be directed towards the specific cell types [61].
3. Nanoviricide^®: is comprised of a polyethylene glycol (PEG) and alkyl pendants. The alkyl chains while make a flexible core the PEG forms the hydrophilic shell and imparts non-immunogenicity. The resulting polymeric materials form stable micelles with chemical groups that are uniformly distributed along the polymer chain. This polymeric chain attaches with the virus-specific ligands like chemical moieties, peptides, antibody fragments or other proteins (Fig. 1). Recently, NV-CoV-2, a biopolymer designed and made by Nanoviricide^® (Shelton, CT) are potentially active against many viruses including Corona virus [62].  In the antiviral therapy of corona virus, NV-CoV-2 is covalently bonded with antiviral small chemical ligands similar to S-protein which binds to the cognate cellular receptor, ACE2. NV-CoV-2 also can bind the other SARS receptor, Aminopeptidase N (APN), and showed inhibitory activities against the the human coronavirus 229E (hCoV-229E) which uses APN receptor for binding to the cell.[62].

Figure 1A: Key Players for AD Pathogenesis

Figure 1B: Key players of PD

Conclusions and Future Perspectives:

The treatment of PD is still controversial as there is no defined diagnostic tool for the early detection of the disease and also their pathological pathway. Pharmacological therapy, in fact actually starts when the patient notices the difficult motor activities, and at that point 50-70% of dopaminergic neurons actually have already been lost which makes it practically impossible to cure [62]. Current therapies mainly focusing palliative treatment and/or slowing down and reversing the abnormal motor symptoms.

Figure 2: Schematic Design of Nanoviricide Biopolymer

Figure 3: Reprogrammimg Macrophages to its M2 type for AD/PD Theraphy

Figure 4: Step# 1: Macrophage Repolarisation to it M2-type in cell culture dishes in Presence of reprogramming cytokines. Grow the cell until enough amount of M2-Mφs are obtained.

Step#2: Cell-Cell interaction between M2 type Mφs an hNSCs to get an unique cell which should express anti inflammatory cytokines, as well as need-based dopamine.

Several studies have demonstrated that nanosystems could potentiate sustained release of the repurposed PD drugs with no side-effects, and increase the effectiveness of the therapeutic agents.  Moreover, they can be used for effective delivery to the target across the BBB.  Great efforts are still in the process to develop new effective PD therapeutics, like salfinamide and opicapone which may decrease motor fluctuations [63-66], a.syn target therapies [67], and neural stem cell transplantation therapies, and gene therapy [68]. Our Plan of Action is to create a Novel Therapeutic Module for PD and AD. Accumulation of M1 type of macrophages in the brain is the key player of PD onset [69].  Repolarization to its M2-type by cytokines, nanoparticles or both could be the effective the strategy that could be deployed for PD therapy (Fig. 2). The DA-ergic NSC cells while will replenish the loss of neural cells the anti-inflammatory cytokines can also be the used as a vehicle of the M2 polarizing cytokines (IFNg-GMCSF, IL-10, IL-4, TGF-b, IL-12, etc.) to re-educate M1 type to M2 type.  Thus, in combination, therapeutic benefits could be achieved for the PD victims.

Acknowledgements:

We acknowledge all our colleagues for their help during the preparation of the manuscript by providing all the relevant information.

Funding:

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Consent for Publications: Both the authors have agreed to submit this paper for publication.

Ethical Approval: Not applicable

Conflict of Interest Statement: The authors declare no conflict of interests.

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