A Review Of The Common Neurodegenerative Disorders: Current Therapeutic Approaches And The Potential Role Of Nanotherapeutics Part 3

Several documented reports confirm behavioral or functional improvements in vivo when treated with nanoparticles. 

According to scientists, our internal behavior is closely related to memory. Many studies have shown that our physical state can affect our cognitive function.

First of all, physical exercise plays an extremely important role in enhancing brain function and improving memory. Exercise can not only help us release stress and reduce anxiety but also greatly improve our cardiovascular system. This can increase our blood circulation and oxygen supply, thereby improving the working efficiency of the brain. At the same time, exercise can also promote the connection between neurons, and improve the stability and connection efficiency of neurons, and these factors will also significantly improve our cognitive and memory abilities.

In addition, diet also has a great impact on our memory. Some foods, such as blueberries, walnuts, cod, chicken, etc., are rich in nutrients and fatty acids, which have a good effect on improving brain function and anti-oxidation. A balanced diet can help us better manage our blood sugar levels and enable our brain cells to obtain enough fuel and energy. These factors are essential to improve our memory and cognitive level.

In general, our physical state has an extremely important impact on our cognitive function and memory. Therefore, we should exercise more and pay attention to aspects such as diet and living habits to maximize our brain function and memory. Together, we can work to improve our physical and mental health and create a better future. It is clear that we need to improve our memory, and Cistanche can significantly improve memory because it can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives adequate nutrition and energy, thereby improving brain vitality and endurance.

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For example, Wu et al., 2020 explored that iron-oxide nanoparticle-tagged MNCs were able to migrate from the administered site to the choroid plexus and trigger a functional recovery in the ischemic-stroke brain. The author suggested that MNCs could be more beneficial if administered directly into the lateral ventricles instead of intravenously [119].

5.2. Organic Nanoparticles

Naturally occurring molecules, such as lipids and other organic molecules, can be exploited as tools for delivering nanomedicine due to their superior biocompatibility compared to inorganic materials. Moreover, a lipid nanocarrier is more effective in protecting the therapeutic moiety from degradation, reducing toxicity, and increasing biocompatibility, than the free-drug administration [116]. 

Among the different lipid carriers, liposomes have been the most extensively explored for brain-targeted delivery. Liposomes dual functionalized with mApoE and phosphatidic acid were developed to enhance delivery across the BBB and target Aβ aggregates with high affinity [120]. This liposomal formulation could disaggregate Aβ fibrils in vitro. 

The negatively charged phosphatidic acid interacts with the positively charged amino acid residues on the Aβ, while the maple interacts with the negatively charged regions of the same. In a recent study, our lab has developed surface-modified liposomes for brain-targeted delivery of ApoE2-encoding plasmid DNA [121]. 

The targeting ligand used was mannose along with a CPP (penetration and rabies virus glycoprotein peptide, RVG) to enhance brain targeting and cellular internalization, respectively. 

Similarly, liposomes modified with RVG and transferrin displayed superior uptake in brain endothelial cells, astrocytes, and neurons as compared to plain liposomes [94]. 

In a separate study by Rodriguez et al. [93], surface functionalization of liposomes with transferrin and a CPP was sufficient to improve the brain permeability of liposomes in mice after a single intravenous administration. 

In all of these studies, drug accumulation in the brain was attributed the surface functionalization. Similarly, optimized brain targeting liposomes, functionalized with mannose and either RVG, penetration, rabies-derived peptide (RDP), or CGNHPHLAKYNGT (CGN) peptide sufficiently delivered VGF (VGF nerve growth factor inducible) across in vitro BBB models and in vivo mouse models. 

In this study, the authors observed a 1.5–2.0-fold (p < 0.05) higher transfection in functionalized-liposome-treated mice compared to an untreated control-mouse group (Figure 3). Further, the formulated liposome nanoparticles were biocompatible both in vivo and in vitro [122].

Figure 3. In vivo vgf transfection in the brain and other major organs in mice. Data is shown as mean ± SD of 6 animals per group. ~, |, @, #, *, –, +, and " show statistically significant differences (p < 0.05) from control, naked DNA, plain, Pen, MAN, CGN, RVG9R, and RDP liposomes, respectively. 

Source: Reprinted from Arora, S.; Singh, J. In vitro and in vivo optimization of liposomal nanoparticles based brain targeted of gene therapy. International Journal of Pharmaceutics 2021, 608, 121095 [122]. With permission from Elsevier.

Antioxidants can protect the neurons from amyloid-β-plaque-mediated oxidative damage. Curcumin has displayed promising antioxidant potential against various NDs [123]. 

It binds to the Aβ deposits, disrupts aggregation, and disaggregates pre-formed fibril, both in vitro and in vivo [124,125]. Besides liposomes, solid lipid nanoparticles (SLN) have also been used for brain-targeted delivery of therapeutics to manage various NDs. Rosmarinicacid-loaded SLNs were administered intranasally to ameliorate the behavioral dysfunctions and oxidative stress associated with Huntington's disease [126]. 

Nanomicelle, particularly polymeric nano micelle, has emerged as a potential vehicle to deliver diverse therapeutic agents [127,128]. Depending on their hydrophilic and hydrophobic characteristics, polymers that self-assemble to form micelles can do so at reasonably lower concentrations while maintaining a small internal diameter, sufficient to carry cargo [129]. 

More recently, some studies have demonstrated the ability of functionalized chitosan nano micelles to transfect brain cells at effective concentrations [130]. Chitosan nano micelles present the advantages of being biodegradable, nontoxic at the concentration of use, and flexible towards surface modification [131]. 

These advantages make chitosan nano micelles an excellent carrier for delivering drugs, proteins, genes, and even antibodies to the brain. Recently, Xue et al. [132], conjugated chitosan nanoparticles significantly inhibited by α-syn aggregation in vitro, as well as discovering significant neuroprotective effects in Parkinson's disease models. 

Chitosan can equally be used in conjugation with other polymers to enhance delivery across the BBB. In a separate study by Jaruszewski et al. [133], Chitosan-coated PLGA nanoparticles had a better BBB uptake compared to naked PLGA nanoparticles. 

While different polymeric formulations have been employed in the production of nanoparticles, poly D, L-(lactic-co-glycolic) acid (PLGA) has been extensively used for brain-targeted and controlled drug delivery [134]. 

This biodegradable, biocompatible polymer, with adjustable degradation rates, a high drug loading capacity, and the ability to cross through the BBB to target the brain, makes it an ideal carrier system for treating NDs. In one study, TET1 peptide-coated PLGA nanoparticles were used to encapsulate and deliver a hydrophilic drug, nattokinase, to the brain. 

The TET1 peptide demonstrated a high affinity for neurons and promoted retrograde transport. This formulation successfully improved the stability of the nattokinase protein and downregulated amyloid aggregation, proving to be a vital option for treating AD [135]. 

A separate study by Carradori et al. synthesized Anti Aβ1-42 conjugated poly (alkyl cyanoacrylate) nanoparticles directed toward Aβ1-42. When transgenic AD mice were treated with these nanoparticles, there was a significant decrease in the brain and plasma level of Aβ soluble peptide and its oligomer, resulting in corrected memory defect [136]. 

In a separate study by Safari et al., phosphatidylserine nanoliposomes also improved the memory of AD-induced rats when loaded with metformin. In this study, IL1-β, TNF-α, and TGF- β levels were found to be reduced in the hippocampal region. Neurogenesis was observed along with significantly reduced necrosis and neuroinflammation [137]. 

As we have discussed, nanoparticles are capable of initiating neurogenesis in vivo systems, but nanoparticles have also been explored to aid stem cells' differentiation into neurons. For example, polycaprolactone-lignin nanoparticles triggered neurogenesis and neurite outgrowth in PC12 and hADSCs cells. The developed nano-scaffold was biocompatible and safe. 

The author claimed that the incorporation of 15% lignin nanoparticles improved the expected outcomes: neuro-construction and regeneration [138]. Similarly, NGF-loaded chitosan nanoparticles differentiated canine mesenchymal stem cells into neuronal cells [139].

Similarly, RA-NPs improved neuronal cell differentiation, survival, and viability in neural stem cells after the ischemic effect [113].

6. Nanomedicines under Clinical Trial

There is an utmost need to develop novel treatment strategies against neurodegenerative disorders, that pause neurodegeneration rather than provide symptomatic relief. 

Several studies on nanoparticles, show promise of an effective drug delivery approach, which can be a ray of hope against neurodegenerative disorders. A recent search in ongoing clinical trials revealed less than 10 nanoparticle-based formulations under different phases of clinical trials against NDs (Table 2). Only one clinical trial of a lipid nanoparticle-based formulation for transthyretin-mediated amyloidosis has been completed and approved for sale in public. While a (CRISPR)/Cas9 gene-based study is in the clinical trial phase I, lipid nanoparticles are being used as a drug delivery platform for this study. 

An exciting approach of nanoparticle-mediated delivery of APH-1105 against mild-to-moderate AD is enlisted; this clinical trial will be started in 2023. However, a gold nanoparticle-mediated CNM-Au8 delivery approach is in the clinical trial phase 2. On the other hand, multiple studies of CNM-Au8-gold nanocrystals-based studies are in phase 1 and phase 2 of clinical trials against ALS.

7. Challenges, Future Prospects and Conclusions

Neuronal death is the primary characteristic of NDs, i.e., AD and Parkinson's. Therefore, neurogenesis is the most envisioned treatment strategy for these disorders. However, drug delivery to the brain is still a challenge due to multiple crucial factors, including the BBB, lipophilicity, the molecular weight of the drug, etc. 

These factors limit the therapeutic potency of drugs and make NDs more challenging to treat. Thus, nanoparticle-mediated targeted drug delivery to the brain has been explored in recent years for neurogenesis, and it provides a promising platform for improving treatment strategies. 

Despite these potential advantages, nanocarrier-mediated drug delivery has some challenging aspects, including safety, production, and regulations.

The toxicity of nanoparticles primarily depends on size, surface charge, ionic dissolutions, and shape. These features should be considered for developing nanoparticle-based drug-delivery systems as per the official nanotoxicity guidelines [140]. 

Additionally, the approval of these nanocarriers should be critically examined, including the effects on health and the environment [141]. A great pool of literature suggests several amendments to minimize the toxicity associated with the size and charge, such as surface modification with biodegradable- or bio-molecules of intrinsic origin [142,143]. 

As far as the production of nanocarriers is concerned, they should maintain batch-to-batch uniformity in terms of their size and content. There are multiple methods documented for nanoparticle production, including high-pressure homogenization, microemulsion, extrusion, etc. Furthermore, the pharmacokinetic properties of the nanotherapeutics greatly impact its efficacy and toxicity. 

Therefore, it is crucial to investigate the pharmacokinetic parameters of nanotherapeutics in a relevant animal model. In this regard, Pharmacokinetic and more advanced physiologically based pharmacokinetic models can be utilized as a potential tool to predict the in vivo nature of nanotherapeutics [144]. Additionally, regulatory requirements for the clinical acceptance of nanotherapeutics should be considered critically [145]. 

Nanomedicine is a ray of hope for NDs, and it can be an effective tool to overrule the barriers of current and traditional treatment approaches [146]. We highlighted nanoparticle-based reports against various NDs, which may open the prospect of nanomedicine. 

Understandably, the development of curative treatment is not an immediate process, but preliminary research in the field may lead to a stepping stone that can help eradicate NDs. However, to prove the efficacy against NDs, the generation of more in vitro and in vivo data is needed. 

Furthermore, thorough in vitro and in vivo investigations and their correlation establishment are required to assess the efficacy of nanoparticles. This would help the research fraternity to extend or identify effective nanoparticles for diagnostic or therapeutic applications.

Author Contributions: All authors (R.N.L.L., B.C., R.T., A.G., B.L., and J.S.) contributed to drafting and editing the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported by the National Institute of Health grants RO1 AG051574 and RF1 AG068034. B.L. also acknowledges support from the NIGMS COBRE award 1P20 GM109024 and DaCCoTA CTR pilot feasibility grant U54GM128729.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

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