Nanomedicine and Nano Formulations for Neurodegenerative Diseases

Introduction

Neurodegenerative diseases are characterized by the progressive degeneration of the structure and function of the central or peripheral nervous system that affects millions of people worldwide. The most common neurodegenerative diseases are Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), but they also include Huntington’s Disease (HD), Multiple Sclerosis (MS), brain tumor, and epilepsy. As of a 2021 report, the Alzheimer’s Disease Association estimates that the number of U.S population with Alzheimer’s disease could be as many as 6.2 million [1]. An estimated 1.2 million people in the United States could be living with Parkinson’s disease by 2030 [2]. Alzheimer’s disease is a neurodegenerative disorder that causes memory loss which interferes with mental function and daily tasks. It is a progressive disease, and the symptoms get worse over time. It is caused by an abnormal increase in some proteins around brain cells, such as amyloid and tau.

Treatments available in the market relieve the symptoms and lessen the disease’s progression but do not cure this condition. Central Nervous System (CNS) diseases are characterized by an imbalance in neurological function, which may cause neuronal death [3]. They can result from mitochondrial dysfunction, the accumulation of misfolded protein, a lack of neurotrophic factor production, endogenous antioxidant enzyme activity depletion, neurotrophin deficiency, and sometimes defects at the genetic and molecular levels. Due to the different mechanisms involved in the CNS conditions, it is challenging to have a single treatment strategy to treat these conditions. Besides, the Blood-Brain Barrier (BBB) is another obstacle that hinders potential drugs from crossing to the brain.

BBB and Challenges to Deliver Medications to the Brain

The BBB is a physiological barrier around the brain comprised of continuous tight junction responsible for the low permeability and prevention of molecules passing to the brain. It helps separate the brain from the peripheral circulation and aids protection from entry of foreign pathogens and maintains the fluid level inside the brain. Many parameters can be responsible for the passage of the drugs across the BBB, such as molecular weight, size, shape, ionization state, lipophilicity, and plasma-protein-binding affinity. The BBB only allows the passage of essential nutrients and small hydrophobic molecules less than 400 Da by passive diffusion. Thus, only a small number of drugs reach the brain. Small hydrophilic molecules are transported by carrier-mediated transport while the larger molecules are transported by adsorption-mediated endocytosis or receptor-mediated transport. The process of targeting the brain utilizing a nanocarrier is not straightforward. One of the challenges in delivering drugs is the premature release from the nanocarrier before reaching the target site.

Another challenge is the interaction with biological system components like serum proteins. These interactions can lead to aggregation, elevate the nanocarrier elimination from the body, and decrease circulation time [4]. Furthermore, targeting specific receptors in the brain may not be satisfactory as some receptors may be expressed in a different part of the body leading to off-target effects, which may cause toxicities and side effects [5]. Because of the BBB structure’s complexity and pathophysiology, it is essential to understand the transport mechanisms through BBB to improve the drug design of the formulations of neurodegenerative diseases as many of them fail to succeed due to lack of efficacy or possibility of toxicity [6].

Transport Mechanisms across BBB

There are many approaches to deliver molecules to the brain, such as passive diffusion, receptor-mediated transport, adsorptivemediated transcytosis, and carrier-mediated transcytosis. Passive diffusion is the pathway of most small-sized lipophilic essential elements to reach the brain in which the transport depends on the concentration gradient. In receptor-mediated transport, the ligand interacts with a BBB receptor, forming a complex that is taken to the cytoplasm by endocytosis. This process is a type of active transport that requires energy. In adsorptive mediated transcytosis, a positively charged ligand interacts with the negatively charged by electrostatic interaction. Thus, adsorptive-mediated brain targeting can be utilized for cationic proteins and peptides. In carrier-mediated transcytosis, essential molecules are delivered to the brain by a specific carrier. This type of transport has been used to provide medication to the brain by a modification to resemble the endogenous molecules to bind to the carrier and be transported to the brain [4].

Nanotechnology in Neurodegenerative Diseases

Nanotechnology is the design, characterization, formulation, and applications of materials by managing their size and shape in the nanoscale range (1 to 100 nm). Nanosystems are fabricated using top-down lithographic and nonlithographic fabrication techniques and content in size from micro- to nanometers. The person who initiated thinking about this field was Richard P. Feynman, who presented a talk about extreme miniaturization and manipulating things on a small scale titled “There’s Plenty of Room at the Bottom.” Afterward, nanotechnology has expanded in different fields, including medicine and engineering. As for nanomedicine, we use nanoparticles as a tool to diagnose, prevent, and treat various diseases. Nanoparticles have a high ratio of surface area to volume, which results in different optical, magnetic, and biologic properties inside the human body. Nanoparticles can be classified into organic (e.g., Liposomes) or inorganic nanoparticles (e.g., gold nanoparticles). Polymeric nanoparticles are made of polymers that are biocompatible and biodegradable and can protect the drug from degradation [7].

Besides, nanoparticles can help to deliver water-insoluble drugs which have low bioavailability. For example, micelles are nanosized colloidal dispersions prepared by amphiphilic polymers. They have a hydrophobic tail and hydrophilic head, allowing the hydrophobic core to carry hydrophobic drugs in the body. Furthermore, nanocarrier can be formulated by polymers that can control a sustained-release effect that may be beneficial in many conditions. The FDA has approved many nanoparticles for use in humans, either as nanocarriers for therapeutic applications or as contrast agents for diagnostic imaging. NPs can be modified with polymers and ligands, which improve binding affinities with the gene and can enhance their targeting capability. They also can be coated to their targeting capability. Nanoparticles have a unique size, and physicochemical properties allow them to penetrate anatomical barriers and offer sustained release action. In neurodegenerative diseases, nanotechnology focuses mainly on targeting the brain and offering the local release of drugs after crossing the BBB [8,9].

Organic Nanoparticles

Liposomes

Liposomes are nanocarriers that compose of a phospholipid bilayer with an aqueous core. They can encapsulate both hydrophilic and hydrophobic therapeutic agents. They can be either Small Unilamellar Vesicles (SUVs), Large Unilamellar Vesicles (LUVs), or Multilamellar Vesicles (MLV) [10]. Liposomes are biocompatible, biodegradable, and have low toxicity. They also can protect the encapsulated drug from degradation resulting in higher bioavailability. They can cross the BBB via active transport by binding to a specific receptor or transcytosis [11]. Another approach to bypass the BBB is the intranasal route which can reach the brain via the olfactory and trigeminal nerves. The intranasal delivery of liposomes has many advantages, including fast delivery to the brain, passing the first-pass metabolism, and avoiding systemic side effects. [12]. Arumugam et al. compared the drug delivery of rivastigmine liposomes via oral and intranasal routes to the brain. The results showed a higher level of the drug in the brain for the intranasal route indicates the higher bioavailability using that route of administration.

The rivastigmine liposomes also possess sustained release action, which can reduce the frequency of the administration [13]. The same results were obtained in a later study using Electrostatic Stealth (ESS) liposomes which exhibited higher bioavailability of the drug in the brain compared to the drug solution. The liposomes also did not affect the nasal mucosa and showed a sustained release action and can be a promising intervention for AD [14]. The same intranasal approach was tested for other medications for AD, such as donepezil, due to its lower bioavailability. Al Asmari et al. developed donepezil-loaded liposomes, which had a sustained release effect compared to the drug solution and possessed good stability over three months. The intranasal administration of the liposomes did not cause any histological changes in different organs, including the olfactory nerve. It also had sufficient drug delivery to the brain, suggesting its usefulness in AD conditions [15]. Another approach to improve the therapeutic activity of therapeutic agents is to conjugate liposomes with specific ligands to enhance brain targeting. Mourtas et al. conjugated curcumin-loaded liposomes with transferrin antibody to target amyloid deposits and BBB. The decorated nanoliposomes showed better translocation across BBB and high affinity to the amyloid deposits, which shows that this formulation can be used for AD [16].

Polymeric Nanoparticles

composed of biodegradable polymers like poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA) copolymers, poly (ɛ-caprolactone) (PCL), or other natural polymers such as alginate, chitosan, gelatin, and albumin. Polymeric nanoparticles are classified to either nanosphere in which is dispersed in the polymeric matric, or nanocapsule, in which the drug is loaded into an oily core and surrounded by a polymeric membrane. Like liposomes, they can be functionalized with various ligands to enhance their targeting or protect them from the opsonization of the immune system. Like other nanoparticles, polymeric nanoparticles have many advantages, including controlled release effect, improved bioavailability, and therapeutic efficacy. They can be prepared by different methods, including solvent evaporation method, emulsification, or nanoprecipitation. Ahlschwede et al. developed PLGA modified curcumin nanoparticles for AD disease. The nanoparticles were prepared using a modified emulsion technique and then conjugated with [Gd]DTPA-chitosan.

The nanoparticles were also conjugated with anti-amyloid antibody (IgG4.1) and K16ApoE. PLGA nanoparticles successfully entrapped the curcumin, which has an anti-amyloidogenic effect and showed an entrapment efficiency of 72%. The IgG4.1 bonded to chitosan as it has amine groups, and the nanoparticles showed high binding affinity to amyloid proteins. The conjugation with K16ApoE allowed higher translocation across hCMEC/D3 endothelial cell monolayers showing that the addition of K16ApoE enhanced the uptake of the nanoparticles. The nanoparticles also offered a specific MRI contrast for amyloid plaques detection [17]. In another study, curcumin was loaded in Se-PLGA nanospheres and were tested in 5XFAD mice and were able to lower the amyloid-β load by Specific binding to Aβ plaques proposing that they can be effective nanoformulation for AD [18]. PLGA-PEG nanoparticles were also used to encapsulate curcumin and were conjugated with B6 peptide, which enhanced the permeability across BBB and enhanced the bioavailability of curcumin.

The nanoparticles were tested in APP/PS1 transgenic mice, and the results showed enhancement in the learning and memory capability. The study suggests the possibility of using these nanoparticles for AD [19]. PLGA nanoparticles were also used to load other possible therapeutic agents like EGCG, which has low bioavailability. Cano et al. developed PEGylated PLGA nanoparticles loaded with EGCG and ascorbic acid. The oral administration of these nanoparticles showed a neuroinflammation reduction and an increase in drug levels in the synapses, which improved memory and learning. Therefore, the developed nanoparticles can be a potential therapy for AD [20]. PLGA nanoparticles were also loaded with quercetin and complexed with Zn. The nanoparticles decreased Aβ fibrillogenesis and reduced related toxicity. Furthermore, the nanoparticles were associated with enhanced memory and learning capabilities, suggesting that they are candidates for AD conditions [21].

Polymeric nanoparticles were also used in PD studies to offer more specific and long-term treatment. Sridhar et al. synthesized chitosan nanoparticles loaded with selegiline in order to increase their bioavailability. The developed nanoparticles showed a 20- fold increased concentration in the brain following intranasal administration. The nanoparticles were also beneficial for increasing dopamine and glutathione concentrations in the brain, which indicates that these nanoparticles can be a promising treatment for PD [22]. PEI nanoparticles were also used for PD by complexing with siRNA. The formulation was delivered via intracerebroventricular infusion into Thy1-aSyn mice, which resulted in a decline in the neuroinflammation in the brain parenchyma and ependymocytes and a reduction of SNCA protein and SNCA mRNA expression by 50 and 65%, respectively. α-synuclein (SNCA) is a presynaptic protein that causes the accumulation of toxic oligomers in the brain leading to PD. The results of this study propose that gene therapy can be a potential therapy [23]. PLGA loaded L-dopa was also tested via intranasal administration to 6-OHDA–Wistar rats. The formulation has a long half-life and shows better bioavailability. Besides, the coordination and motor function in the nanoparticles treatment group was better than the control group showing that this nanoformulation can be a promising candidate for PD [24].

Solid Lipid Nanoparticles

Solid Lipid Nanoparticles (SLNs) have emerged as novel nanocarriers that can deliver the drugs across the BBB to the brain. They can be used through different routes of administration, such as oral, inhalational, and parenteral, to reach the brain and target neurodegenerative diseases. They consist of lipid or modified lipid (triglycerides, fatty acids, or waxes) with a 10–1000 nm diameter. Their solid hydrophobic lipid core allows dispersion of both hydrophilic and lipophilic drugs [25,26]. SLNs have various types depending on the distribution of drugs within them. They are either drug-enriched shell model, drug-enriched core model, or homogeneous matrix model. In the drug-enriched shell model, the drug is distributed around the shell, which offers burst release of the drug in the outer layer; however, the use of a low concentration of surfactants can help control the release of the drug. In the drugenriched core model, the drug is concentrated in the central core surrounded by outer lipid layer offering sustained release action.

In the homogeneous matrix model, the drug is distributed within the lipid matrix by strong molecular interactions. This type is usually used to disperse lipophilic medications without the use of surfactants [6]. SLNs provide controlled drug delivery, high efficacy, and superior targeting [27]. SLNs were developed to overcome the problems associated with polymeric Nanoparticles, such as avoiding the usage of organic solvents, therefore, reduce systemic toxicity [28]. Thus, they are among the safest and cheapest nanocarriers for drugs that enable a safe and nontoxic way to cross BBB. Their efficacy depends on their size, structure, physicochemical properties, and the method they were produced by. In recent years many researchers have been published for SLNs targeting neurodegenerative diseases. Misra et al. developed SLNs loaded with galantamine hydrobromide, an acetylcholinesterase inhibitor used in Alzheimer’s disease. This medication has poor bioavailability in the brain and can cause cholinergic side effects. The SLNs, made of biodegradable and biocompatible components, overcame these limitations by improving bioavailability and enhancing drug delivery to the brain [29].

Dhawan et al. loaded the SLNs with quercetin, a flavonoid with antioxidant activity and a drug candidate for Alzheimer’s disease. Quercetin-loaded SLNs were successfully formulated using the microemulsification technique and exhibited superior memory retention in the in-vivo experiment suggesting that they can be a potential intervention for AD [30]. In another study, Ferulic Acid (FA), which has antioxidant activity, was loaded into SLNs, which decreases ROS generation and cytochrome c release. This formulation is a promising intervention for AD as it can lower free radical generation and inhibit oxidative stress damage [31]. Kakkar et al. incorporated curcumin in SLNs to enhance its oral bioavailability and, therefore, its therapeutic effect. The SLNs could reverse brain alterations induced by AlCl3 exposure making it a potential treatment for AD [32]. Several formulations were also developed for Parkinson’s disease to enhance the drug’s bioavailability. Currently, there are many FDA-approved medications for this condition, such as levodopa, ropinirole, bromocriptine, and apomorphine; however, they have limited therapeutic efficacy to the brain.

Tsai et al. investigated the effect on bioavailability when apomorphine is loaded to SLNs. Results demonstrated that the bioavailability increased by 12-fold with the enhancement of the therapeutic effect. Besides, the formulation was tested in a Parkinson’s disease model, suggesting that SLNs is a promising approach to delivering apomorphine orally [33]. Esposito et al. developed SLNs loaded with bromocriptine which offered prolonged release over 48 hours, stabilizing plasma drug level [34]. Other non-oral routes were also suggested as a route of administration to deliver SLNs to the brain, mainly the intranasal route. Pardeshi et al. investigated ropinirole SLNs to evaluate their therapeutic efficacy. The formulation did not affect the nasal mucosa and offered a sustained action that lowered the administration frequency and was comparable to the product available in the market [35].

Dendrimers

Dendrimers are nanosized drug carriers symmetrical, highly branched polymeric molecules consisting of a central core and repeated units attached to the center and known as generations. Dendrimers are prepared using linear polymers forming an organized structure of repeated units that encapsulate functional molecules. They are synthesized by two methods either a divergent approach in which dendrimers are assembled from the initiator core and extended outward by a series of reactions, or by a Convergent approach in which dendrimers are constructed from the periphery to the core, resulting in a third-generation dendrimer. Drugs are loaded by either covalent conjugation or electrostatic adsorption [36]. Dendrimers can have positive, negative, and neutral surface charges. The positive charge is the most toxic as it may cause low biocompatibility and cell lysis; thus, sometimes dendrimers are coated with PEG to decrease their toxicity. PAMAM dendrimers are the most well-known dendrimers synthesized and made commercially available.

Their core consists of ethylenediamine, and the branches are amide groups. PAMAM dendrimers with positively charged groups may cause cytotoxicity; however, G5 and lower generation PAMAM dendrimers are considered nontoxic [37]. Dendrimers can be used to treat neurodegenerative diseases, either bypassing the BBB or traversing the BBB. Dendrimers can also be conjugated with ligands to improve biocompatibility and to target the BBB. Lgartua et al. encapsulated carbamazepine in PAMAM dendrimers within their ethylenediamine core which offered sustained release action and was safe for administration. The formulation was stable for 90 days and reduced the toxicity of the free drug [38]. The same team also investigated the co-administration of tacrine and PAMAM dendrimer generation 4.0 and 4.5. Tacrine causes hepatotoxicity upon its oral administration; nonetheless, dual therapy did not show any toxicity effects on human red blood cells and reduced the cytotoxicity of tacrine on the Neuro-2a cell line.

This reduction was not associated with a decrease in the activity as this novel therapy had an excellent anti-acetylcholinesterase activity thus can be a potential treatment for Alzheimer’s disease [39]. In another study, low-generation dendrimers conjugated with lactoferrin were employed to deliver memantine to the brain. The nanoformulation was successfully taken in the brain model and showed a sustained release action. The treatment in the AD mice model revealed enhancement of the response, higher acetylcholinesterase (AChE) activity, and better memory which suggests that this formulation has a positive impact on AD [40]. Dendrimers were also synthesized to target Parkinson’s disease. Huang et al. prepared a poly-L-lysine (DGL)- dendrimers-based gene delivery system conjugated with angiopep, targeting brain receptors. This formulation was tested on the rotenone-induced chronic model of Parkinson’s disease and showed improved recovery, indicating its potential benefit as non-invasive gene therapy for PD [41]. In another study, Sheikh et al. employed polylysine-modified polyethylenimine (PEI-PLL) to deliver VEGF expressing plasmid. The synthesized formulation was tested on cell culture and animal PD models and exhibited a positive effect on the dopaminergic system. The results demonstrated the advantageous impacts of PEI-PLL mediated VEGF gene delivery for PD [42].

Nanoemulsion

Nanoemulsions (NEs) are colloidal dispersion consisting of the water phase and oil phase stabilized by surfactants at specific ratios. NEs have many properties, such as good biocompatibility and stability, and they can be administered by various routes. They also can incorporate both hydrophilic and hydrophobic drugs due to their nature. Shah et al. investigated rivastigmine microemulsion administration via the intranasal route to bypass BBB. In-vitro and ex-vivo data demonstrated high drug diffusion, indicating better permeation via the intranasal route [43]. Azeem et al. formulated a transdermal nanoemulsion loaded with ropinirole to improve its bioavailability. In vivo evaluation of the nanoformulation showed its safety and a significant increase in the pharmacokinetic parameters (AUC, Cmax, and Tmax), demonstrating a higher release. Besides, relative bioavailability compared to oral tablets revealed a two-fold increase reflecting enhancement in its antiparkinson activity [44]. Nanoemulsion was also tested for delivering anti-TNFα siRNA to overcome neuroinflammation of neurodegenerative conditions.

The intranasal administration of the nanoformulation had higher uptake in both in vitro and in vivo compared to siRNA alone. In addition, the nanoemulsion reduced the levels of TNFα in the LPS-induced inflammation model [45]. Another study investigated the nanoemulsion of rosmarinic acid coated with chitosan as a potential neuroprotective therapy. Results reveal that the formulation prevented cellular death and alleviated oxidative stress and neuroinflammation in vitro and in vivo [46].

Inorganic Nanoparticles

Gold Nanoparticles

Gold nanoparticles (AuNPs) are one of the widely studied metal nanoparticles due to their wide range of applications. Gold in its nano range diameters has unique properties and can be synthesized by various simple techniques. They have been employed in drug delivery, thermal ablation, radiotherapy, and diagnostic assay [47]. As the main challenge in neurodegenerative disease is crossing BBB to deliver therapeutic agents, some studies evaluated the gold nanoparticles in BBB models. Ruff et al. assessed the potential of AuNPs conjugated with β amyloid in crossing BBB in vitro model. Results demonstrate that small AuNPs improve the BBB integrity while large nanoparticles or negatively charged nanoparticles hampered BBB crossing [48]. These results agree with another study that tested different insulin coated AuNPs sized (20, 50, and 70 nm) in an in vivo model. The highest migration and accumulation in the brain was for the 20 nm AuNPs, which disclose the importance of the nanoparticle size in designing AuNPs for neurodegenerative diseases [49].

Many researchers investigated AuNPs as drug cargo to the brain. Glutathione encapsulated gold nanoparticles were developed to prevent the aggregation of Aβ amyloid in AD. These nanoparticles successfully crossed the BBB and inhibited the Aβ amyloid with no toxicity. Interestingly, this study suggests a different effect of the L and D chiral nanoparticles and highlights the importance of stereochemistry in developing nanoformulations [50]. In other studies, the antioxidant and the anti-inflammatory effect of gold nanoparticles was evaluated in the okadaic acid-induced AD model in rats. The AuNPs reduced oxidative stress and the neuroinflammation caused by okadaic acid, which indicates that they can be a potential treatment for AD [51]. Gold nanoparticles have also been exploited in gene therapy for PD to improve their targeting. Hu et al. synthesized gold nanoparticles conjugated with plasmid DNA via electrostatic adsorption. The in vitro tests showed successful transfection by endocytosis, and the in vivo PD model revealed successful transmission across BBB [52]. Furthermore, gold nanoparticles can be a helpful tool for the detection of Aβ amyloid in AD. Zhou et al. developed a quantitative colorimetric sensor that can detect Aβ aggregation based on the color change of AuNPs. The system is easy to use, has low cost, and has high sensitivity [53].

Silver Nanoparticles

Silver Nanoparticles (AgNPs) are other popular metallic nanoparticles with many biomedical applications due to their distinctive physical and chemical properties. They are helpful and can be used as antibacterial, antifungal, antiviral, anti-inflammatory, and anti-cancer agents [54]. However, many studies have stated that Ag NPs can cause neural death upon their entrance to the brain. Some researchers evaluated the inflammation and the neurological effects of Ag NPs on microglia. Results of the study show that up taken Ag NPs became coated with non-reactive silver sulfide (Ag2S), and Ag NPs have an anti-inflammatory effect by reducing reactive oxygen species (ROS), nitric oxide, and TNFα. The formation of Ag2S was found to render the Ag ion toxicity [55]. On the other hand, several studies suggest that Ag NPs have a neurotoxic effect when targeting CNS. Khan et al. investigated brain endothelial cells and astrocytes after Ag NPs exposure and found an upregulation of many proteins that cause neurodegeneration and multiple inflammatory pathways. In addition, there was a downregulation of protein which maintains hemostasis [56]. These results come in agreement with another study that examined the Ag NPs effect on neural cells. After administration, there was an increase in IL-1β and C-X-C motif chemokine 13, which indicated inflammation. The was also an upregulation in amyloid-β (Aβ) plaques, the pathological characteristic of AD [57].

Silica Nanoparticles

some research asserts that silica nanoparticles cause neurotoxicity, detrimental effects on neural cells, and lead to neurodegeneration. Upon intranasal instillation of SiO2-NPs to mice model, it was found that there was cognitive damage along with an increase of the anxiety level. Furthermore, nanoparticle exposure caused neurodegenerative symptoms, including neuroinflammation, higher tau phosphorylation, and exocytosis deterioration [58]. However, a subclass of silica nanoparticles called Mesoporous Silica Nanoparticles (MSNs) got attention due to its advantages, including large surface area, high drug loading, and functionalization capability [59].

It was found that PEG–PEI functionalized MSNs can cross BBB in vitro model, and they did not have a toxic effect [60]. PEGylated quercetin-loaded silica nanoparticles were developed and tested in a copper-induced oxidative stress model. The nanoparticles showed higher antioxidant activity in neuronal culture. This neuroprotective activity suggests its usefulness in neurodegenerative diseases [61]. Silica nanoparticles were also conjugated with different ligands to enhance the uptake by BBB. Song et al. prepared PEGsilica nanoparticles conjugated with lactoferrin (Lf), a cationic iron-binding glycoprotein. This functionalization allowed higher transport of nanoparticles across the BBB in the in vitro model, suggesting that this type of conjugation may be beneficial for nanocarriers for brain conditions [62]. In another study, Karimzadeh et al. synthesized MSNs loaded with rivastigmine hydrogen tartrate and functionalized with succinic anhydride and 3-aminopropyltriethoxysilane. The formulation was able to protect the drug increasing its stability and bioavailability; nonetheless, further optimization is needed to reduce the reduction of viability associated with these nanoparticles [63].

Cerium Oxide Nanoparticles

Cerium oxide nanoparticles (CeONPs), also known as nanoceria, have an antioxidant and radical-scavenging activity which can be helpful for the treatment of neurodegenerative diseases. Small cerium oxide nanoparticles which have a size lower than 5 nm can cross BBB [64]. Nanoceria can be taken and accumulated in neural cells reducing the level of reactive nitrogen species. They can also mitigate Aβ-induced mitochondrial fragmentation and neuronal cell death, indicating their beneficial effect in AD [65]. It was also reported that nanoceria has a neuroprotective effect human Alzheimer’s disease model, which is helpful for AD [66]. Cimini and his colleagues developed PEG-coated CeONPs conjugated with an antibody targeting Aβ aggregates, and results show that nanoparticles improved neuronal survival via the BDNF signaling pathway [67].

Potential Neurodegenerative Nanomedicine in Clinical Trials

Only a few studies are testing nanoparticles for neurodegenerative diseases were found on clinical trials.gov. One is titled “31-MRS Imaging to Assess the Effects of CNM-Au8 on Impaired Neuronal Redox State in Parkinson’s Disease” which is testing the effects, safety, pharmacokinetics, and pharmacodynamics of gold nanocrystals in patients who have been diagnosed with PD. A second study titled “Study of APH-1105 in Patients with Mild to Moderate Alzheimer’s Disease” is evaluating the safety, tolerability, and efficacy of intranasal delivery of APH-1105 for the treatment of AD [68].

Challenges

Despite its many advantages, many challenges face the application of nanotechnology. Sometimes nanoparticles can cause side effects or even toxicity due to their interaction with the biological system. This interaction can depend on size, surface charge, or concentration Metal nanoparticles tend to be more toxic than organic nanoparticles. For instance, it was reported that iron Nanoparticles could cause significant cytotoxicity in the PC12 cells neuronal model, and they produced neurodegeneration and oxidative stress in mice models [69,70]. Also, zinc oxide nanoparticles induce apoptosis in neural stem cells, and manganese and Cu nanoparticles may produce reactive oxygen species (ROS) [71,72]. Another challenge is the lack of an animal model that resembles the features of neurodegenerative diseases. These models do not precisely replicate all the disease features and thus fail the translation from the preclinical to the clinical trials. The development of a perfect animal model mimicking the pathogenesis of the disease, taking into consideration all crucial characteristics, is a key for testing the new nanoformulations.

In addition, there are many hurdles to translating nanomedicine to clinics due to the lack of translational advisory organizations. Usually, the are three main areas in which the project may fail either the choice of the research area, selection of therapeutic agent, or the peer-review process. This is why translation expertise is an essential key to academic research. These hurdles need translational evaluation criteria to overcome, such as safety, technical, competitive, regulatory, reimbursement, and commercial evaluation. The safety evaluation should be concerned about the safety of the nanoparticles and if they will interact or leave any residues or cause harm for patients. Thus, nanoformulations that have not been used before in humans must have a significant advantage to be considered and translated to the market. Besides, long-term safety and biocompatibility are critical for successful nanomedicine in the market. Another technical challenge is that the nanoformulation produced in the lab will be hard to scale up for manufacturing, and large-scale production can be expensive. batch-to-batch variation can also hamper the production process. Another challenge is the competitive market. The improvement in potency or fewer side effects is not sufficient. The new drug should leave better therapeutic outcomes. The manufacturers should know where the competition is likely to be when their drugs enter the market. If the manufacturer is the first or second in the market, it will not be hard to secure a share in the market. But after that, there must be a clinical advantage to compete in the market [73,74].

Conclusion and Future Prospective

Despite the extensive research that was done for discovering an effective treatment for neurodegenerative diseases, the medication available today in the market only manages the symptoms, and there is no cure till now. Thus, exploring other possible innovative approaches for potential treatment is necessary to improve patients’ quality of life. The nanotechnology and nanomedicine field has enabled the synthesis of various nanoformulations with superior properties, which can be beneficial to neurodegenerative diseases. Around 100 novel nanoformulations were approved by the FDA including liposomes and lipid nanoparticles, PEGylated polymeric and inorganic nanoparticles are available in the market for treating different conditions. Nanoformulations have many advantages, such as protecting the drug from degradation, increasing solubility and bioavailability, improving active agents’ therapeutic effectiveness, and decreasing toxicity. Both organic and inorganic nanoparticles were investigated for neurodegenerative disease conditions.

Organic nanoparticles offer a high degree of safety as it consists of biocompatible and biodegradable polymers. They also have the advantage of the ease of preparation and can be manipulated to improve the release of the drug from its cargo. On the other hand, inorganic nanoparticles have unique physical properties and high surface area, nonetheless, have a lower safety profile as they increase the risk of oxidative stress and neuroinflammation. Additional coating with some polymers such as PEG can improve their safety. Nanoparticles can also be conjugated with nucleic acid and other ligands to enhance the targeting to the brain and enhance the translocation across the BBB. Many studies have reported that drug-loaded nanoparticles had higher concentrations in the brain, therefore, higher therapeutic efficacy against neurodegenerative. Others stated that nanoparticles had potent neuroprotective effects in the case of AD and PD. The application of this advanced technology will likely continue to improve, offering new therapeutics which provide superior clinical outcomes and enhanced patient-focused formulations. However, there are still some challenges that must be taken into consideration.

Validation of the in vitro and in vivo protocols is essential to translate these nanoformulations from the lab to clinical trials. The generation of ideal models mimicking the pathophysiology of the diseases is a crucial factor for the translation of nanoformulations. It is also necessary to set specific guidelines for the quality, safety, and efficacy evaluation of these products and perform appropriate clinical trials to ensure the lowest side effects to facilitate marketing these nanoformulations successfully. These models should emphasize on the long-term effect of nanocarriers on different organs in the human body as well as the environment. Besides, cost-effectiveness in developing nanoformulations must be taken into consideration for commercial success in the market.

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The Skin Aging Process and Anti-Aging Strategies

Introduction

Appearances play a vital role in society as it is how one communicates to others their identity and it strongly influences how one is perceived. Moreover, when living in the age of social media, influencers, and photoshop, the average person is now exceedingly aware of their physical appearance. It is easy to fall victim to setting unrealistic expectations for oneself, especially when comparing the average person to the meticulously retouched images of celebrities posted to the public. Filters used to smooth out wrinkles on Instagram posts, fillers injected to plump up tissue to diminish laugh lines, [1] and makeup to cover up any sunspots that have developed all show a marked aversion to aging in their picture-perfect society. In 2012, a survey conducted by the market research company NPD Group found that women between the ages of 18 and 24 found that fewer than 20% considered anti-aging skin care to be important. However, a survey of the same demographics in 2018 by beauty consumer analysts discovered that this statistic rose to more than 50% of women adding products in their routine to defy wrinkles [2] (Graph 1). The notable 150% increase in utilizing preventive skin care is reflective of the generation’s growing unwillingness to show the physical signs of aging. Nonetheless this attempt to delay the aging process is not unique to Millennials or Gen Z.

Graph 1.

As early as 30 BC, Cleopatra was known to take daily baths in donkey-milk for the anti-aging and skin-softening properties of the hydroxy acids in the milk and during the Tang-dynasty, Empress Wu Zlitan maintained her famed beauty through the years by washing her face with powdered Chinese motherwort and cold water [3] Since then, science and technology has advanced to be able to identify the specific active compounds that made these treatments effective. In doing so, these compounds are able to be purified for higher efficacy in treatment. Furthermore, the development of new treatment methods for the purpose of anti-aging have taken the world by a storm. A study done by the American Society of Plastic Surgeons reported that 3.4 million injections of soft tissue filler were done in 2020 alone. This value is second only to Botox injections being the most popular minimally invasive cosmetic procedure with a total of 4.4 million procedures done. In addition to fillers, other popular anti-aging methods include serums, resurfacing creams, “vampire facials’’ and more that claim to help create a smoother and fuller appearance of the skin.

As concerns about the physical manifestation of aging grow and people continue to take an active role in either the prevention or reversion of aging skin, treatment methods have become more accessible and normalized in the modern world. While anti-aging claims are an effective marketing tool in drawing consumers to a product or procedure, these claims must be backed up with actual mechanisms that work to rejuvenate the skin - whether it is through stimulation of collagen production or the removal of damaging reactive oxidative species. There are so many products on the market with varying ingredients and price points, so it is important to know which ones are actually effective in producing anti-aging results and which ones are pointless. While there is not yet a proven effective product capable of eliminating all signs of aging, there are products and treatments that are clinically proven to have wrinklereducing effects and work to visibly reduce signs of aging.

Aging Process

Graying hair, shrinking stature, and cracking joints are all telltale signs of aging everyone hopes to escape, with the most famous indication being the appearance of fine lines and wrinkles on the skin. Wrinkles are the creases and folds that form in the skin as a by-product of the aging process as the skin loses its elasticity over time. As the separation of the body from the outside environment, the skin is impacted by aging factors that are both intrinsic and extrinsic. Intrinsic aging is determined genetically and describes the unavoidable physiological process resulting in the development of fine wrinkles in thin, dry skin. Extrinsic aging factors encompass environmental factors such as sun exposure, air pollution, and smoking that produce rough textured skin and the formation of deeper, coarse wrinkles [4]. To protect from these external factors, the skin has multiple layers to serve as a defense against pathogens, UV light, physical injuries, and more. The 3 most commonly known layers of the skin are the epidermis, dermis, and hypodermis - all varying in structure and function. Lesser known is that each of these layers has several sublayers aiding in the functionalities of the skin.

The outermost layer, the epidermis, is divided into the stratum Basale, stratum spinosum, stratum granulosum, stratum lucidum, and the stratum corneum [5]. Of these, the skin barrier has been located primarily at the intercellular lipid matrix of the uppermost layer of the epidermis, the stratum corneum. The stratum corneum consists of 20-30 cell layers of keratin and horny scales (made up of anucleate squamous cells, or dead keratinocytes) as well as the crucial lipid matrix containing cholesterol, free fatty acids, and ceramides. These compounds making up the lipid matrix are together known as a “natural moisturizing factor” as they function to keep the deeper layers of skin, such as the dermis and hypodermis, well-nourished and hydrated. The primary purpose of the skin barrier is to remain as tight as possible and in doing so, it plays three vital roles. First, it protects the body from external stressors such as UV radiation, pollution, and chemicals. Second, the barrier functions to retain water in the skin and maintain healthy levels of hydration through the prevention of excessive trans epidermal water. Trans epidermal water loss refers to the amount of water that passively evaporates via the surface of the skin, and it is a good measure of effectiveness of the skin barrier system [6].

Third, the skin barrier is responsible for transporting nutrients through itself and into the skin to preserve the health of the major organ. Ultimately, these tasks in conjunction operate to maintain homeostasis among the body’s many systems [7]. If the skin barrier does not work as, it should, the epidermis will become vulnerable to damage and unable to fight off external aggressors, such as free radicals that can result in the formation of discoloration and premature wrinkles. In fact, up to 90% of visible skin aging is due to environmental factors, such as sun exposure [8]. Over time, with improper care, the skin barrier will become impaired and result in less hydrated skin that is more susceptible to harm. With normal, healthy skin, the top layer is continually shed as it is being renewed by a self-replenishing pool of stem cells existing in the basal layer. However, as people age, this pool of stem cells becomes diminished resulting in slower cell turnover rates [9]. This slowing divide of cells causes the dermis layer to thin. The dermis consists of interwoven elastin and collagen fibers, offering support and elasticity. As the interconnected fibers loosen with time, depressions are created on the skin surface that are unable to heal, resulting in the development of wrinkles [10].

Aging and Role of Collagen

Collagen is the most abundant protein present in mammalians, serving as one of the main building blocks for a range of tissue types including bones, skin, muscles, and hair. The 3 parallel polypeptide strands are found in a left-handed, polyproline II-type helical formation with a one-residue stagger forming a right-handed triple helix [11]. This stagger contains a special amino acid sequence specifying that every third amino acid must be glycine while the 2 remaining residues are often either proline or hydroxyproline [12]. This structure results in incredible stability and versatility of the protein, allowing it to play key roles throughout the body in various forms. In the skin, collagen fibers are found in the dermis layer to form fibroblasts where new cells can grow in addition to playing a role in replacing and restoring dead skin cells [13]. As one ages not only does the body produce less collagen, causing a decline in the structural integrity of the skin, but this process can be hastened by exposure to harmful extrinsic factors like ultraviolet rays and smoking. The breakdown of the complex network of fibers leads to wrinkles as the layers underneath the epidermis lose their firmness. This is visualized in the diagram below through the comparison of the many layers shown as the collagen-elastin network progresses from younger skin to aging skin [14] (Figure 1).

Figure 1.

Not only is overall collagen production reduced, but the type of collagen being also produced is different in aging skin as well. Currently, there are a total of 28 different forms of collagen in the body including both fibril-forming as well as non-fibril forming proteins. Of these, the most predominant types of collagens are Type I, Type II, and Type III. Type I is the most common type of collagen, making up 80-90% of skin, hair, and nails and is composed of two ⍺1 chains and one ⍺2 chain coiled around each other [15]. Type II is mainly found in cartilage to support joint health and it contains three identical ⍺1-polypeptide chains of 1,060 amino acid residues [16]. Type III supports Type I collagen in maintaining skin and bone health and it is made of three ⍺1(III) chains supercoiled in a right-handed triple helix to form a homotrimer. In older skin, the collagen structure will look irregular as the proportion of collagen types in the skin changes with age. While young skin is composed of 80% Type I collagen and 15% Type III collagen, aging skin has shown an increase in the ratio of Type III to Type I collagen - largely due to the loss of Type III collagen [17]. With age, overall collagen content per unit area of skin surface is said to decline at a rate of approximately 1% per year as fibroblasts become less active [13]. In fact, a study conducted by MINERVA Research Labs reported that peak collagen content was identified between the ages of 25-34, followed by a gradual decline over the coming decades [18] (Graph 2).

Graph 2.

This, created by MINERVA Research Labs depicts the increase of collagen content until the mid-20s. Shortly after begins the progressive loss of collagen equating to an almost 25% decrease over the span of 4 decades. The synthesis of collagen fibers is primarily done by the fibroblasts of the skin, meaning that the rejuvenation of this biomatrix can only be efficiently improved with a supply of supplemental nutrients via the bloodstream. As the skin’s natural collagen supply diminishes, the introduction of collagen via injection, topical treatment, or oral ingestion can work to replenish the collagen that has been lost or even stimulate the production of more collagen after absorption. A randomized, placebo-controlled, blind study by Bloke was used to investigate the effects of drinking a test product containing a blend of 2.5 grams of collagen peptides, acerola fruit extract, biotin, vitamin C, and other compounds. Performed on women 35 years and older, this study, in conjunction with others totaling a pool of 805 patients, demonstrated that collagen supplements are effective in increasing hydration, dermal collagen density, and elasticity of the skin [19]. Another study done by Porsche et al. reported that the intake of 2.5 grams of collagen a day over an 8 week period produced an increase in procollagen Type I as well as elastin, leading to a significant reduction in eye wrinkle volume [20]. Although the formation of wrinkles is inevitable as a byproduct of the aging process, researchers are actively working to find ways to minimize the appearance of these fine lines. While there are developing treatment methods, a second way to combat wrinkles is through preventive measures.

Preventive Measure as Anti-Aging Efforts

A popular preventive measure for reducing or delaying the appearance of wrinkles is through nutrition to combat the effects of reactive oxygen species (ROS). Reactive oxygen species are generated as by-products when molecular oxygen is utilized by aerobic organisms to perform essential metabolic reactions within the body. ROS is a term used to define any oxygen-containing reactive including hydrogen peroxide (H2O2), hydroxyl radicals (˙OH), peroxyl radicals (LOO˙), and more [21]. In addition to involvement in metabolic processes, ROS also play important roles in wound healing, inflammatory responses, and apoptosis. As the skin functions as a barrier to protect from external harmful agents, when the skin becomes inflamed high levels of ROS are generated for the purpose of removing and destroying invading microorganisms and breaking down any damaged tissue. As mediators of inflammatory responses, ROS activate cell signaling to increase the production and release of proinflammatory cytokines to instigate inflammatory responses.

In the presence of nitric oxide, calcium, and pathogens within human cells, the balance between oxidant and antioxidants is affected and results in the generation and accumulation of ROS in cells. The resulting imbalance between oxidative and antioxidative events induces oxidative stress, leading to oxidative reactions. ROS are reactive species that show molecular aggregation and are capable of causing serious damage to biomolecules including lipids, nucleic acids and proteins. This deterioration to DNA and other biomolecules can also induce other structural and functional damages leading to cell and tissue injury. As DNA, lipid, and protein structures are altered, there is a resulting dysregulation of cellsignaling pathways that trigger downstream signaling cascades to alter cytokine release. As the cytokines are not released regularly, the induced inflammatory response is prolonged and causes tissue damage and the exacerbation of inflammatory skin diseases [22]. To defend against these attacks, a series of antioxidant defenses have been developed to protect vital biomolecules from ROS damage. Antioxidants perform their duties by 3 major modes of action:

(a) Directly scavenging already-formed ROS,

(b) Inhibit formation of ROS from cellular sources,

(c) Remove or repair harm caused by ROS.

To reduce the risk of oxidative stress-related issues one could implement a plant-based diet with high volumes of intake of fruits, vegetables, and other foods rich in antioxidants. A meatbased diet is low in antioxidants while plant-based foods are antioxidant rich due to the presence of thousands of bioactive food constituents. These constituents - including flavonoids, tannins, stilbenes, phenolic acids, and lignans - are called phytochemicals that are redox active molecules and function as antioxidants. When comparing the meats versus plant-based foods, plants have 5 to 33 times higher mean antioxidant content when compared to the values for animal-based foods [23]. Long-term exposure to UV radiation is also a major cause of skin aging that can be reduced through preventive measures. Photoaging causes alterations in the structure of skin such as epidermal stratum corneum integrity, skin thickness, hydration and lipidation leading to the development of wrinkles and skin relaxation. UV exposure can lead to the generation of excess ROS in the skin that then in turn activate pathways related to skin aging including: “MMP1-mediated aging, MAPK/AP-1/NF-kB/tumor necrosis factor (TNF)-⍺/IL-6-mediated inflammation-induced aging, and p53/BAX/cleaved caspase-3/ cytochrome c-mediated apoptosis-induced aging [24].

”The activation of transcription factors like NF-kB promote inflammation-induced signaling and create oxidative stress by increasing ROS production to lead to skin cell apoptosis [25]. UVB-induced ROS generation is capable of activating the MAPK pathway leading to the expression of MMPs. MMPs are able for the degradation of the extracellular matrix in the skin, leading to the formation of wrinkles [26]. As the risks that come with overexposure to UV radiation become abundantly clear, so is the importance of using protection against the sun’s rays. It is recommended to stay out of the sun from 10:00 am to 2:00 pm when the sun’s rays are the strongest, and when going outside, one should dress to protect by wearing covering materials such as a long-sleeved shirt, a hat, and sunglasses. On skin that is not covered, the FDA recommends to wear a sunscreen offering broad-spectrum protection that is SPF 30 or higher [27]. Sunscreens can be made with organic filters that absorb UV radiation energy to convert into unnoticeable infrared energy. The structure responsible for this absorption is chromophore, consisting of electrons engaged in multiple bond sequences between atoms. Upon absorption, the UV photon holds enough energy to result in an electron transfer to a higher energy orbit within the chromophore molecule [28]. From this excited state, different relaxation processes occur dependent on the ability of the UV filter to convert the absorbed energy in order to bring it down to the ground state energy. Inorganic filters are also used in sunscreens as pigment grade powders of metal oxides like zinc oxide in conjunction with organic filters to enhance sun protection. Unlike organic filters, these metal oxides work by reflecting and diffusing UV radiation so that it only reaches the skin, rather than becoming absorbed past it [29].

Changing the Perception

When considering anti-aging, there are two ways of looking at it: perception versus making real changes to the skin. To simply change perception, multiple methods can be used such as filters for a blurring effect or the use of makeup like foundation and concealers to lessen the appearance of any unwanted fine lines. It is important to note that many makeup brands will advertise their products as having the ability to “reduce the appearance of wrinkles” which is important to distinguish from “will reduce wrinkles”. The difference is that the former is a cosmetic claim whereas the latter is a drug claim. The FDA defines cosmetics as “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced to, or otherwise applied to the human body...for cleansing, beautifying, promoting attractiveness, or altering the appearance” [30]. For example, mica is an earth-derived silicate mineral that is included in many cosmetic products to provide a shimmering effect on the skin surface. In doing so, it not only provides protection against the sun’s rays, but it also diffuses reflected light off of the skin so that wrinkle lines are not as pronounced [31]. While mica is able to fulfill the cosmetic claim of reducing the appearance of wrinkles, there are other treatment options that work to reduce the physical presence of wrinkles. One such example is Botulinum Toxin (BTX).

While it cannot entirely discontinue the aging process of the skin, regular injections are able to slow down the visible effects of aging by helping manage the further stimulation of dynamic wrinkles. BTX-subtype A (BTX-A) is a potent neurotoxin that blocks the presynaptic release of acetylcholine at the neuro-muscular junction to produce temporary chemical denervation [32]. The toxin binds to presynaptic neurons of the pre-selected muscles within an hour and clinically reversible chemical denervation and paralysis begin after 24 to 48 hours of the injection [33]. It is only on Day 28 that the nerve sprouts are able to mediate partial restoration and new neuro-muscular junctions begin to form near the site of the old junction and by Day 62-91 there is complete recovery of muscle function. As the muscular changes achieved through BTX-A are completely reversible, treatment should be repeated every 3 to 4 months to maintain results [34]. Like Botox, dermal fillers can be injected, but they differ in function by adding fullness to areas that have thinned due to age. Biodegradable fillers, like collagen and Hyaluronic Acid (HA) fillers are reabsorbed by the body and typically have effects lasting 6 to 18 months [35].

The duration of the filler is dependent on the source and extent of cross-linking, as well as the concentration and size of each product. As hyaluronic acids are linear polymeric dimers of N-acetyl glucosamine and glucuronic acid, the degree and methods of chain cross-linking, the uniformity and size of particles, and concentration of particles will all vary and impact the clinical effects of the filler. With greater cross-linking and concentration, the viscosity, elasticity, and resistance to degradation all increase. Additionally, larger particle products in high concentrations will absorb more water and increase the degree of tissue swelling following injection [36]. Unlike biodegradable fillers, nonbiodegradable fillers work by provoking a foreign body reaction to stimulate the fibroblastic deposition of collagen surrounding nonabsorbable microspheres. One example of this type of filler is SilikonⓇ1000 which is a medical-grade pure form of silicon - upon injection, the body will form collagen around these silicone particles to increase volume in the tissue [37]. However, owing to the permanent nature of these fillers, complications are much more difficult to treat. Another treatment that is a popular treatment for skin rejuvenation is Autologous Platelet-rich Plasma (PRP).

PRP is made from fresh whole blood containing high concentrations of platelets. In these platelets there are ⍺-granules that secrete various growth factors including transforming growth factor (TGF), insulin-like growth factor (GF), and platelet-derived growth factor (PDGF) [38]. These factors are responsible for regulating processes such as cell migration, proliferation and differentiation, and promoting extracellular matrix accumulation. In this way, PRP is also capable of inducing collagen synthesis by stimulating the activation of fibroblasts, which can then in turn rejuvenate the skin [39].

Some of the Useful Approved Drugs

The Food and Drug Administration defines a drug as “articles (other than food) intended to affect the structure or any function of the body of man or other animals” [30]. To do so, active ingredients are used to produce desired biological or chemical effects. For example, retinoids vitamin A derivatives that have been proven clinically to reduce acne, prevent wrinkles, reverse the effects of sun damage, and more. As lipophilic molecules, retinoids are able to diffuse through phospholipid membranes such as the cell membrane where it is able to bind to various receptors. The resulting ligand-receptor complexes are able to directly bind to specific DNA sequences called “retinoic acid response elements” (RARE) as transcription factors or by indirectly repressing the transcription factor AP-1.31-33 [40]. The activation of RARE and the repression of AP-1 expression allows retinoids to act as powerful agents able to regulate gene expression to influence cellular differentiation and proliferation. Following treatment with retinol and retinoic acid, there is a resulting epidermal thickening due to the inhibition of collagen degradation and an increase in collagen synthesis. To determine the molecular mechanism for these changes, the expression of 12 genes were determined.

After retinol and retinoic acid treatment, there were increases in the gene expression of COL1A1 and COL3A1 responsible for the production of procollagen I and procollagen III proteins. The retinol treatment resulted in a 1.34-fold increase in COL1A1 gene expression and a 1.43-fold increase in COL3A1. After retinoic acid treatment, there was a 2.48-fold increase in the expression of the COL1A1 gene and a 2.77-fold increase for COL3A1. A facial wrinkle analysis conducted after 12 weeks of treatment showed a significant reduction in wrinkle scores: at the cheeks the scores were reduced by 63.74% and the eye areas were reduced by 38.74% [41]. Vitamin C is another compound that can be found in serums, as topical creams, or ingested to play a metabolic role in collagen synthesis and as an antioxidant. Ascorbic acid (AA) is an alpha-keto lactone that exists as a monovalent hydroxyl anion at physiologic pH levels. As an antioxidant, ascorbate undergoes a stepwise donation of 2 electrons where the intermediate compound following the donation of 1 electron is the ascorbate free radical. This radical functions as an effective free radical scavenger and suppresses matrix-metalloproteinases associated with collagen degradation [42]. AA also functions as a cofactor in the production of 2 enzymes required for collagen synthesis. Prolyl hydroxylase stabilizes the collagen molecule while lysis hydroxylase gives structural strength via intermolecular cross-linking - AA is consumed non stoichiometrically during translation within ribosomes for the formation of both of these enzymes [43].

While the use of vitamin C alone functions to remove ROS, combining the additional active ingredient vitamin E can provide maximal anti-aging and brightening effects. When vitamin C and E work synergistically, the elimination of free radicals is much more efficient as vitamin C is able to regenerate oxidized vitamin E into its reduced form. Furthermore, vitamin E possesses lipid-soluble properties allowing it to pass down via sebaceous gland secretions into the deepest layers of the stratum corneum to occupy cell membranes and provide protection from oxidative stress [44]. The effectiveness of this synergistic anti-aging process is proven as the topical use of 15% L-ascorbic acid with 1% alpha-tocopherol provides significantly more protection withstanding sunburn cell formation when compared to the use of either active ingredient alone [45]. Peptides are amino acids that structure the specific proteins necessary for the skin. Studies have shown that the ingestion of collagen peptides with other active compounds can rejuvenate skin and other damaged tissues. As peptides travel throughout the body, they will encounter sites with fibroblasts, stimulating them to produce more compounds like collagen, elastin, and hyaluronic acid. With long term use, there is noticeable improvement in skin elasticity and hydration leading to more youthful, firmer-looking skin [15].

Antiaging Cosmeceuticals

While active ingredients are proven to work, they are only as effective as how far they are going into the skin. Topical treatments are meant to reduce systematic exposure and the ingredients mainly only go as deep as the epidermis to address whatever issue must be solved. However, when creating products with the purpose of anti-aging the problem with topical presentation is getting enough of the active ingredient past the top layers of the skin and to the target tissue. The penetration of actives further into the skin or penetration to a specified layer of the skin can maximize the effectiveness of these active ingredients. Derma zone is a cosmeceutical company that integrates its nanotechnology platform and science to perform transformative skin care through more effective delivery of active compounds [46]. As a cosmeceutical company, beyond the transient appearance of skin enhancement Derma zone formulas contain pure and potent bioactive ingredients to provide in-depth penetration of the epidermis and make true changes to the biochemical processes to impact the mechanisms of aging. Derma zone technology provides innovative delivery and deeper penetration of these active ingredients and botanicals. Transdermal drugs describe a vast category of drugs that serve as vessels for delivering drugs for both local and systemic mechanisms [47].

Figure 2.

True transdermal medication is the application of a drug through the skin with the intent to drive the compound into the bloodstream to promote systemic exposure across the skin. However instead of driving the active ingredients through the epidermal layer and into the bloodstream, Derma zone transdermal technology seeks to transport ingredients to the depths of the epidermis to depot there for a slow release rather than breaking into the dermis. At this layer, the capsule is broken to release the active compounds that are now free to interact with viable cells [48]. In the transportation of active compounds, Derma zone uses materials that are bioavailable to the skin to encapsulate the active ingredients in a lipophilic outer membrane that is able to efficiently penetrate the skin and be delivered to the target area. For this purpose, Derma zone has developed Nano-Lipidic Particle (NLP) nanotechnology to serve as transport. The process of making this patented NLP nanotechnology can be done in 3 phases. In Phase I, there is the development of an NLP precursor, to which water and ethanol are added to complete Phase II. Then in Phase III, the NLP liposome is completely formed with the addition of water and the active ingredient it is meant to transport (Figure 2) [49]. When fully formed, the NLP liposome will look like the illustration below. With this technology, Derma zone is able to encapsulate almost any compound. Not only are the ingredients to form NLP natural to biological organisms, it is also easily incorporated into existing processes of manufacturing and yields a more efficient and economic delivery of active ingredients. The only limitation is that the capsules are less than 200 nm, so compounds larger than a few thousand Dalton are unable to fit in the NLP liposome. Nonetheless, active ingredients such as acetyl hexapeptide-8, vitamin C, geranium maculatum oil, octanoate, and many others are able to be encapsulated and are used in the products sold through Derma zone’s brands including CleomeⓇ, Kara VitaⓇ, and Hyssop HealthⓇ [50].

Conclusion

As the largest organ and a physical barrier between the internal human body and harmful microbes and chemicals, the skin plays an essential role as the body’s first line of defense and in maintaining homeostasis among the many systems and biological mechanisms that keep us alive. Not only is it impacted by intrinsic factors that change as the aging process advances, but it must also bear the damage inflicted by years of exposure to unavoidable damaging external factors producing visible blemishes like wrinkles, age spots, and rough patches of skin. Furthermore, as people age the slowing of cell turnover rates and reduction in collagen production result in thinner skin with irregular depressions as the elastin-collagen network of fibers breaks down and loses its structural integrity. To combat these effects, both preventive and treatment measures can be undertaken to minimize the appearance of wrinkles. As vital metabolic reactions proceed within the body and UV radiation infiltrates from outside the body, reactive oxygen species are generated that have the ability to degrade biomolecules like DNA when produced in excess leading to oxidative stress. Preventive methods like consuming a healthy diet rich in antioxidants and minimizing sun exposure by covering up and the application of daily sunscreen can reduce the negative effects of excess ROS. While reflective creams and cosmetic foundation can be used to hide the perception of aging externally, minimally invasive cosmetic treatments like Botox, dermal fillers, and platelet-rich plasma each work in unique ways to lessen the appearance of wrinkles internally [51]. Even more effective in treating aging skin is the use of drugs that are capable of affecting the behavior of cells and processes within the body to reverse aging at a cellular level which manifests in a physical form of more pliable skin, better barrier integrity, and reduction of fine lines. Such compounds include retinoids, vitamins, and peptides. To be effective defenses against skin aging at a cellular level, these compounds must first be able to penetrate the living and nonliving layers of skin to interact with target molecules and processes. To move further than topical treatment, transdermal drugs like the NLP liposome, can be utilized to transport active ingredients and aid in deeper penetration for higher efficacy in reducing the effects of the aging processes.

Future Trends

The maintenance of cellular health is coordinated by generegulatory pathways and a number of cell biological processes. It was once thought that aging is an inevitable process and the natural result of entropy on the cells, tissues, and organs of the body, bringing about the gradual decline of many bodily functions [52] Now, rather than seeing aging as a process of life, scientists are beginning to view physical aging as a disease process. Both the cellular and molecular mechanisms by which aging occurs reveal intricate series of signals and pathways that are responsible for the monitoring and control of lifespan of a cell as it ages. This information reveals that the breakdown of cellular processes is in fact the result of a programmatic decision by the cell to either continue or discontinue maintenance procedures with age. As a result, it only makes sense that cellular reprogramming can be used to reverse the aging leading to the decline in activities and function of mesenchymal stem/stromal cells (MSCs). Through the in-depth studying of these molecular events and pathways, the science of antiaging will be furthered and come another step closer to reversing the aging process. In fact, Dr. Wan-Ju Li is the lead of one such study. When comparing non-rejuvenated parental MSCs to reprogrammed MSCs, scientists were able to recognize the GATA6/SHH/FOXP1 pathway as a key mechanism in the regulation of MSC aging and rejuvenation [53]. The continuation of identifying the underlying mechanisms controlling cell aging-related activities will help improve understanding of the causes of aging and play significant roles in the future of regenerative medicine.

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