Nano astaxanthin protects the brain, eyes, skin, liver, kidneys, central nervous system

SUPPLYING NANO ASTAXANTHIN TO THE BRAIN AS A TREATMENT AGENT FOR THE NERVOUS SYSTEM
The central nervous system (CNS) contains the brain and spinal cord, the spinal cord is located inside the spine.  It is separated from other parts of the human body through the blood-brain barrier, which is the boundary between the brain’s extracellular fluid in the central nervous system and the circulating blood flow in the body ( Figure 7 A) .(114)This barrier is made up of specialized capillaries, which, unlike the normal structures in capillaries, do not have regular pores and have tight connections between cells.  Therefore, many molecules cannot pass through them through diffusion and reach the cerebrospinal fluid in the brain.(115−118)The endothelial surface of these capillaries is covered with special proteins that allow glucose enters the brain as well as gas exchange between circulating blood and the brain from the barrier.(119)This barrier results from the tight connections between endothelial cells in the CNS arteries and limits passage of solutes and substances.(120) The CNS has the ability to activate the immune system in response to several forms of injury including trauma, infection, stroke, and neurotoxins.

Hình 7. (A) Các tế bào nội mô não tạo thành hàng rào tế bào và được kết nối liên tục bằng các mối nối chặt chẽ; các mối nối chặt chẽ là cấu trúc chính của hàng rào máu não và vận chuyển có chọn lọc các chất dinh dưỡng giữa máu và não. Vai trò của tế bào ngoại vi là kiểm soát lưu lượng máu não trong khi chân cuối của tế bào hình sao chịu trách nhiệm hỗ trợ sinh hóa cho các tế bào nội mô.(122)(B) Các chiến lược khác nhau để khuếch tán qua hàng rào máu não.(127)

(NANOCMM TECHNOLOGY)

Figure 7. (A) Brain endothelial cells form a cellular barrier and are continuously connected by tight junctions;  Tight junctions are the main structure of the blood-brain barrier and selectively transport nutrients between the blood and brain.  The role of pericytes is to control cerebral blood flow while the end feet of astrocytes are responsible for biochemical support of endothelial cells.(122)(B) Different strategies for amplification diffuses across the blood-brain barrier.(127)
Neuroinflammation occurs for a variety of reasons, including infection, concussion, toxic metabolites, deformed proteins, and autoimmunity.  Microglia (innate immune cells in the central nervous system) are activated in response to these factors and initiate inflammation in nervous tissues.  Although this response is initiated to protect nerve tissue against infection, it can lead to nerve cell damage and neurological diseases if the response is severe and not well controlled. .(121)
Many drugs cannot penetrate brain cells and therefore lose their effectiveness in treating brain-related diseases.  Therefore, the following promising strategies have been proposed to deliver drugs to the brain.
(1)Temporary permeability enhancement at the blood-brain barrier: Disconnecting the tight junctions between endothelial cells using ultrasound/microbubbles and altering osmotic pressure, but this approach allows nanoparticles to penetrate uncontrolled entry into cells, disrupting the homeostatic function of the brain, causing brain toxicity.(123)
(2)Diffusion of small lipophilic molecules (<400 Da) across endothelial cells takes two forms: extracellular and transcellular.(124)Tight junctions hinder the diffusion of hydrophilic or insoluble molecules Lipid soluble via intracellular transport.  Due to the lipid nature of liposomes and deformable liposomes (solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs)), they can pass through the phospholipid bilayer of the BBB endothelial cell membrane by diffusion. lipid-mediated free diffusion (facilitated diffusion) or lipid-mediated endocytosis.
(3)The transcytosis pathway is through absorption, receptors, and different carriers ( Figure 7 B).  In absorptive transcytosis, the transfer process begins by creating electrostatic interactions between the positively charged particle and the negatively charged plasma membrane.  This pathway is not specific to the brain and is also found in the liver, kidneys or lungs.  In one study, nanoparticles were prepared using polylactide polymer linked to PEG polymer and the results showed successful adsorption of the produced nanoparticles;  The presence of PEG is intended to improve the performance of the formulation and increase the shelf life of the nanoparticles.(125,126)

During receptor-mediated transcytosis, various ligands placed on the surface of the nanoparticle bind to cell surface receptors and are endocytosed by the cell, with receptors and activators transfer used as targets, including GLUT1, LfR and TfR.(128,129)One of the most effective techniques is the use of transferrin, which is highly expressed on the blood-brain barrier and facilitates nanoparticle delivery. penetrate this barrier.(130)A recent study took advantage of transferrin to facilitate the penetration of Fe 3 O 4 -polyethylene glycol-coated NANO ASTAXANTHIN nanoparticles across the blood-brain barrier to treat hemorrhage under the spider.  The Transferrin ligand consists of two domains, one of which is α-helices and one of which is ß-sheets, and the ligand has high affinity for its receptor.  Cellular uptake of transferrin-conjugated nanoparticles through primary cortical neurons was significantly better than that of unmodified nanoparticles.  Furthermore, after exposure to oxyhemoglobin, a ROS donor, neuronal survival improved and apoptosis markers were reduced due to the release of NANO ASTAXANTHIN.(131)Figure 8 illustrates the effect of transferrin-modified and unmodified nanoparticles for subarachnoid hemorrhage (stroke caused by bleeding into the space between the arachnoid membrane and the pia mater surrounding the brain and spinal cord).

Hình 8. (A) Sơ đồ cơ chế xâm nhập của các hạt nano được biến đổi và không biến đổi bằng transferrin vào tế bào thần kinh thông qua trung gian thụ thể, sau đó là sự phân hủy của các hạt nano và giải phóng ASTAXANTHIN. 

Figure 8. (A) Schematic diagram of receptor-mediated entry of transferrin-modified and unmodified nanoparticles into neurons, followed by degradation of the nanoparticles and release ASTAXANTHIN.  (B) Evaluation of neurological damage after oxyhemoglobin exposure for purified NANO ASTAXANTHIN and transferrin-modified NANO ASTAXANTHIN loaded nanoparticles as follows: (i) Western blot, (ii) relative intensity analysis of Bax/ß-actin, Bcl-2/ß-actin and cleaved caspase-3 (CC3)/ß-actin ratio and (iii) Bax/Bcl-2 for different samples.  (C) Cell apoptosis results after exposure to oxyhemoglobin.  (D) Apoptotic rate of cells involved in each group.  # p < 0.05 compared to the control group;  p < 0.05 compared with subarachnoid hemorrhage (SAH) group;  p < 0.01 compared to the SAH group.  Reprinted from ref (131)with permission from Frontiers.
Various strategies have been developed to increase drug permeability across the blood-brain barrier.(132−134)There are mainly two types of drug delivery to the brain, one is invasive and the other is noninvasive.  Invasive methods, such as intracerebroventricular injection, disruption of the blood-brain barrier by ultrasound and osmosis, and convection-enhanced delivery, help deliver drugs directly to the desired site in the brain.  Using intracerebral injection, the drug is injected directly into the cerebrospinal fluid.(135−137)Convection-enhanced delivery is used to facilitate targeted drug delivery to the Brain Tumor.  In this procedure, a small hole is made in the patient’s skull to place one or more thin tubes (catheters) into the tumor site from different angles.  The drug is then pumped into the tumor through the catheter.  In ultrasound technology, microscopic bubbles are injected into the blood.  Using MRI scans, the injection is precisely injected into a specific area of the brain.  The ultrasound is then delivered to the same point through a cap placed on the head.  These waves vibrate the bubbles, which gently open the tight junctions and allow the drug to enter the brain through the created pathway.(138−140)In addition, different mechanisms include deposition Aβ in cerebral vascular cells ( Figure 9 ) can increase the effectiveness of NANO ASTAXANTHIN to reduce the side effects of some drugs as well as increase the expression of some essential genes in the brain.(141)Disorders Osmosis is an invasive pathway through which hypertonic fluid causes contraction of the endothelial cells of the cerebral arteries, followed by disruption of the tight junctions of the blood-brain barrier ( Figure 10 ) .(127,142)Another way to deliver drugs to the brain is through the respiratory tract, but due to the limited absorption by the olfactory bulb, the wrong amount of drug molecules may reach the target;(117,143,144)ratio Successful drug delivery through these methods is believed to be ineffective.(145,146)Opening tight junctions by osmotic pressure may allow toxins and other unwanted substances to enter the brain along with medicine.  For this reason, much research has turned to noninvasive methods.  By increasing the lipophilicity of small drug molecules, the likelihood of their delivery into the brain is increased.  As lipophilicity increases, drug metabolism and distribution in the body also increases, thereby increasing drug dosage, thereby increasing side effects.(147−149)Large molecules, e.g. like peptides, proteins or genes, cannot cross the blood-brain barrier.  In addition, these compounds are less stable in the environment, so they are metabolized quickly and are not released into the brain.  Furthermore, many drugs with optimized molecular weight and lipophilic properties, naturally and easily cross the blood-brain barrier, but they quickly return to the blood by very strong efflux pumps. .(147)The use of nanotechnology to enhance drug delivery to the brain without damaging the blood-brain barrier may be useful in this context and holds promise for the treatment of brain diseases.(150,151 )For example, the Trojan horse trick has been used to combat drug resistance, where the drug is hidden inside a DNA capsule and enters the cell like a Trojan horse and prevents the cell from draining it drug.(152)Furthermore, the drug carrier can also specifically bind to receptors on endothelial cells and enter the brain parenchyma by receptor-mediated transport.(153)Two important advantages The importance and effectiveness of delivering drugs to target organs supported by nanotechnology is to improve drug effectiveness and reduce side effects on other organs.  Nowadays, different types of metallic, lipid and polymeric nanoparticles have been used to deliver drugs to the brain.(154,155)In neurodegenerative diseases, changes in the blood-brain barrier and the size of nanoparticles are the main factors. important factors affecting the release of nanoparticles into the brain parenchyma.  Assessing nanoparticle toxicity on neurons in clinical and in vivo settings is one of the most important challenges associated with the implementation of nanotechnology.(156,157)

Hình 9. (A) Là một protein xuyên màng, protein tiền chất amyloid (APP) trải qua một loạt sự phân cắt protein bởi các enzyme secretase. 

Figure 9. (A) As a transmembrane protein, amyloid precursor protein (APP) undergoes a series of proteolytic cleavages by secretase enzymes.  It is not amyloidogenic if APP is cleaved through α-secretase in the middle of Aβ, but cleavage through β- and γ-secretase enzymes is accompanied by the release of neurotoxic Aβ peptides that can accumulate into oligomer aggregates.  APP gene mutations prevent cleavage through α-secretase, which then allows preferential cleavage through β-secretase.  Mutations in the presenilin-1 and presenilin-2 genes (PSEN1 and PSEN2), considered components of the γ-secretase complex, increase γ-secretase-mediated cleavage at this site.  Notably, both situations lead to overproduction of Aβ peptide.  Over time, oxidative stress causes nerve cell death, followed by the development of neuritic plaques typical of Alzheimer’s disease.  Reprinted from ref (158)with permission from CMAJ.  (B) Immunofluorescence staining was performed on 18 μm sections of mouse brain.  (C) Double immunofluorescence staining was performed on 18 μm sections of mouse brain.  Xe (Veh), bexarotene (Bex) and NANO ASTAXANTHIN.  Reprinted from ref (141)with permission from Elsevier.

Hình 10. Sơ đồ minh họa các phương pháp xâm lấn và không xâm lấn được sử dụng để đưa thuốc vào não.(127)

Figure 10. Schematic illustration of invasive and non-invasive methods used to deliver drugs into the brain.(127)
4.2.  Neurological diseases and the role of NANO ASTAXANTHIN
4.2.1.  Oxidative stress and its roles in neurodegenerative diseases
Oxidative stress is an imbalance between free radicals and antioxidants in the body that leads to the generation of ROS.  Oxidative stress plays an important role in the development and progression of many degenerative diseases such as autoimmune diseases, cancer, heart disease and diabetes.  Notably, NANO ASTAXANTHIN plays a very special role in neurodegenerative inflammatory diseases such as Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, multiple sclerosis and other processes related to aging. pathology.(159,160)With the increase in lifespan, the incidence of neurodegenerative diseases is also increasing, with many different symptoms such as altered mitochondrial function, abnormal accumulation of proteins and proteasome, as well as impaired iron metabolism affecting different parts of the brain can lead to a defective cycle. and the onset of cell death.(161)ROS-generating factors can damage mitochondria, increase Ca 2+  levels, inhibit proteasome function and ultimately lead to neuronal destruction .  For physiological reasons, the central nervous system is thought to be very sensitive to oxidative stress.  The human brain makes up only a small percentage of the total body weight;  however, the brain consumes 20% of basal oxygen consumption.  The main ROS involved in neuronal damage are superoxide, hydrogen peroxide, and highly reactive hydroxyl radicals.(162)Nitric oxide as a highly diffusible biological messenger plays an important role in biology. of the central nervous system.  Once produced, nitric oxide reacts rapidly with superoxide to produce strong peroxynitrite (ONOO – ) and hydroxyl radicals;  ROS and nitrogen species react together to cause oxidative stress in the nervous system.  The CNS is a reservoir of unsaturated lipids that are vulnerable to peroxidation and oxidative changes.  The double bonds in unsaturated fatty acids are important sites for free radicals to attack, causing chain reactions, thereby damaging their neighboring unsaturated fatty acids.(163) The brain’s antioxidant defense system is insufficient;  Brain tissue has relatively lower antioxidant activity than other tissues;  for example, the brain has 10% of the antioxidant activity of the liver.(164)
4.2.2.  Inflammation and brain diseases
Encephalitis is called neuritis and can be caused by messages from damaged nerve cells in the nervous system, by invading germs such as viruses and bacteria, and by toxic chemicals. as deformed proteins (such as beta-amyloid peptide) in the brain.(165)Two main mechanisms of inflammation in the brain are
(1)Peripheral inflammation occurs in the body and can stimulate the brain’s immune system causing inflammation in brain tissue and
(2)Direct cellular damage to the brain can trigger inflammation.(166)Neuroinflammation is seen in many pathological conditions such as stroke, infections, and neurodegenerative disorders.(167)Processes This is characterized by microglia activation, increased blood-brain barrier permeability and peripheral immune cell permeability to brain tissue, sequestration of inflammatory cytokines and ultimately uncontrolled inflammation leading to to neurological damage and death.  These processes are influenced not only by microglia but also by astrocytes, neurons and endothelial cells of the cerebral vasculature, T cells and peripheral cells.(168)Microglia are part of of the immune system and act like macrophages in other tissues, accounting for ∼10–15% of the brain’s cell population.(168)In neurodegenerative diseases, microglial cells resemble the M1 of peripheral macrophages and creates a harmful environment for neurons by producing inflammatory cytokines (TNF-α, IL1β, IL-6, NO) and ROS.(169)4.2.3. Tác dụng của các yếu tố thúc đẩy viêm lên tế bào nội mô mạch máu não
Peripheral inflammation can affect the brain in many different ways.  Bacterial lipopolysaccharides are a prime example of a pathogen-associated molecular pattern in pathogen recognition and inflammatory signaling that stimulates the innate immune system.(170,171)Lipopolysaccharides target cells, expressing CD14 and TLR4, and by activating intracellular cascades, ultimately leads to activation of transcription factors including NFKβ and AP1.(172) These factors are transmitted to the cell nucleus and transcriptionally activates these factors. inflammatory factor.  iNOS, COX2, and NADPH oxidase activity increases, leading to enhanced production of NO, PGE2, ROS, inflammatory chemokines, and inflammatory cytokines in brain microvascular endothelial cells.(173,174)This activates microglia and stimulates astrocytes and initiates inflammatory cascades in brain tissue.  By increasing the expression of adhesion molecules and damaging the blood-brain barrier during inflammation, peripheral macrophages can also infiltrate brain tissue and promote inflammation in the brain.(175,176) Systemic injection of lipopolysaccharide also enhances the production and release of aldosterone, which overactivates mineralocorticoid receptors in cerebrovascular endothelial cells, thereby enhancing the production and release of proinflammatory cytokines.(177,178)Inflammatory mechanisms are triggered by various brain tissue cell damage, sometimes by genetic defects and in most cases by unknown factors, among which the Neurodegenerative or autoimmune diseases may play a role.  For example, amyloid-beta peptide, which accumulates in the brain in Alzheimer’s disease, can stimulate inflammatory processes in brain tissue.  Other causes of neuroinflammation include stroke, head trauma, and direct infection of brain tissue.(178)The concept is that there is a link between systemic inflammation and primary dementia first appeared when an increase in inflammatory processes was observed in Alzheimer’s patients after death.  Studies have shown an association between dementia and elevated levels of cytokines such as IL-1β, acute phase response protein, TNFα, and IL-6.(179)Furthermore, laboratory studies Experiments have shown that the serum and cerebrospinal fluid of Parkinson’s patients have higher levels of IL-1β, TNF-α, and IL-12 as well as CD4 + and CD8 + lymphocytes, suggesting that activation of peripheral lymphocytes.(180)Microglia activity generates a large amount of free radicals, including superoxide, hydrogen peroxide, hydroxyl radical and cytotoxic cytokines, causing damage to nerve cells. scripture.(181.182)
4.2.4.  NANO ASTAXANTHIN protects the brain
Inflammation, oxidative stress, and apoptosis pathways cause the destruction and death of neurons and ultimately lead to neurodegenerative disorders.(143)Several direct and indirect mechanisms have been proposed regarding the positive effects of antioxidants in improving cognitive function as they may influence cognitive function through reducing inflammation, regulating NF-κB, and reducing cytokine production.  NANO ASTAXANTHIN is a powerful antioxidant with restorative, antiseptic, anti-aging and anti-inflammatory properties and is being used in the treatment of many neurological diseases such as neuropathic pain, Alzheimer’s disease, Parkinson’s disease, autism, depression, etc.(183)Its unique chemical structure allows it to easily cross the blood-brain barrier and reach the brain, the most important target organ of NANO ASTAXANTHIN.  NANO ASTAXANTHIN’s ability to modulate the immune system, reduce inflammation, and treat neurodegenerative diseases has been confirmed.(184)Increased IL-6 production has been reported during disease progression Multiple sclerosis, (185) causes demyelination and neuroinflammation due to the destruction of the blood-brain barrier.  In one study, it was found that NANO ASTAXANTHIN easily crosses the blood-brain barrier, allowing the carotenoid to protect the central nervous system against chronic and acute neurological damage.(98)
Th1 cytokines are involved in the development of MS and NANO ASTAXANTHIN regulates the immune system response by shifting the Th1 cell response to Th2.(186)According to the data obtained, it was concluded that NANO ASTAXANTHIN, as an oral supplement, has an effective role in preventing, healing, and reducing inflammation and nerve damage caused by multiple sclerosis.  The ability of NANO ASTAXANTHIN to reduce ischemic damage in the mammalian brain through preventing apoptosis and inhibiting ROS has been reported;(187) it protects against blood pressure-induced damage high, vascular oxygenation and cerebral thrombosis.  Furthermore, NANO ASTAXANTHIN prevents nerve damage and reduces the risk of stroke by inhibiting ROS and activating the Nrf2-ARE pathway.  Therefore, it may be useful for patients susceptible to ischemia because of its protective effect against neurological disorders caused by free radical toxicity.(188)Accumulation of oligomers Amyloid-β peptide reduces the expression of type 2 ryanodine receptor and enhances mitochondrial ROS production, ultimately leading to neuronal cell death and Alzheimer’s disease.  NANO ASTAXANTHIN has the ability to protect neurons against the harmful effects of amyloid-β peptide oligomers by regulating type 2 ryanodine receptor gene expression and may therefore be useful in the treatment of Alzheimer’s disease.(103 )This red carotenoid significantly reduced the levels of amyloid-β peptide oligomer, TNF-α, nitrite and AChE, oxidative stress and the activity of GSK-3β and IRS-S307 in the hippocampus and prevented insulin resistance of the involved hippocampus. in Alzheimer’s disease.(189)A study has shed light on the potential of NANO ASTAXANTHIN as a protective agent against progressive Alzheimer’s disease.  Pure NANO ASTAXANTHIN and its combination with docosahexaenoic acid were administered to APP/PSEN1 double transgenic mice for up to 2 months.  The results showed that this combination had a stronger impact on regulating oxidative stress, inflammasome expression and activation, plus reducing Tau phosphorylation and suppressing neuroinflammation in mice. compared to pure NANO ASTAXANTHIN itself.(190)
High levels of glycosylated hemoglobin, acute phase reactive protein, IL-6, and TNF-α increase cognitive impairment in depressed diabetic patients.(191)On the other hand, some clinical studies suggest found that mood disorders may be a risk factor for Alzheimer’s disease.(192)Recent studies suggest that preventing inflammatory responses in the brain and reducing nerve damage may reduce depression in diabetic mice.(193)Therefore, reduction of inflammatory cytokines appears to be effective in the pathophysiology and treatment of depressive disorders.(194)In many studies, natural ingredients have been studied as a supplement to improve mood and reduce anxiety and stress by inhibiting inflammation.(195)Animal studies showed that depression levels were reduced when mice were treated with NANO ASTAXANTHIN orally (25 mg/kg) for 10 weeks.(196)In addition, in some studies, supplementation with 0.2 mg of shrimp oil containing NANO ASTAXANTHIN daily for 7 weeks improved learning ability, working memory and depression.(197)An increase in survival and proliferation of human adipose-derived stem cells was observed with NANO ASTAXANTHIN administration.  The use of NANO ASTAXANTHIN may increase the effectiveness of human adipose-derived stem cell transplantation in the treatment of MS, a disease that debilitates the brain and spinal cord (central nervous system).(198)

5. Nano astaxanthin delivery system into the eye

5.1.Ocular physiology, diseases and challenges

Medications used to treat eye diseases often affect the surface of the eye or its front part.  The treatment of certain diseases such as glaucoma, retinitis pigmentosa, leber’s congenital amaurosis, stargardt, X-linked juvenile macular degeneration (AMD), diabetic retinopathy are all related to relating to the back or back of the eye.  Certain anatomical structures, including the cornea, sclera, conjunctiva, and retinal pigment epithelium, limit the effectiveness of drug delivery to this part of the eye.(199,200)Due to protective mechanisms such as tearing and blinking reflex so a small percentage of the prescription drug may be absorbed.  Tears wipe away microorganisms and waste, even removing drugs from the surface of the eye.  In addition, part of the drug also binds to proteins in tears, so it is no longer effective. (201) The presence of tight junctions in the corneal epithelium limits drug delivery into the eye.  Because of the three layers of the cornea as well as its lipophilic and hydrophilic properties, drugs designed to overcome those barriers can reach their targets.(202,203)Ocular exposure time is about 5 minutes, just accounts for about 5% of prescription drugs.(204)Repeated use may compensate for the short exposure time of the drug to eye cells but may increase the risk of cytotoxicity.  In addition, intraocular injection of short-acting drugs to treat later eye diseases is also problematic because multiple injections will increase the risk of eye bleeding.(205)About 40% of the drugs studied used to treat eye diseases is a drug that is less soluble in water and is lipophilic.  As a result, they cannot be used in conventional water-based formulations.  Therefore, biocompatible and biodegradable nanoparticles selected for intraocular injection have an acceptable shelf life and adhesion to mucous membranes ( Figure 11 ) .(206 −208)In vivo study results show that bioadhesive nanoparticles increase drug shelf life and enhance drug absorption.  The use of biodegradable polymers is also a very suitable method for delivering drugs to the posterior region and treating chronic eye diseases.  By optimizing the surface of nanoparticles, the bioavailability and shelf life of drugs in the eye can be improved.

Hình 11. Các bệnh liên quan đến các phần khác nhau của mắt và các phương pháp đưa thuốc đến mắt khác nhau.

Hình 11. Các bệnh liên quan đến các phần khác nhau của mắt và các phương pháp đưa thuốc đến mắt khác nhau.

5.2.  Nano astaxanthin for eye diseases
NANO ASTAXANTHIN helps protect retinal cells against oxidative damage and UV rays, and reduces symptoms of eye strain(108,209) with confirmation that NANO ASTAXANTHIN inhibits ROS production and retinal cell death.(108,209) 210)Retinal ischemia increases NF-κB production and causes retinal inflammation.(211)In retinal diseases, glial cells play an essential role in inflammation by producing cytokines that cause inflammation such as IL1β and TNFα.(212)These cytokines activate COX2 and iNOS gene transcription, leading to the synthesis of NO and PGE2, which are inflammatory mediators.(213)NANO ASTAXANTHIN inhibits the activation and expression NF-κB expression of COX2 and iNOS.(214) Topical application of NANO ASTAXANTHIN limits damage caused by ultraviolet radiation, and apoptotic cell levels are also significantly lower in irradiated halos. radiation treated with NANO ASTAXANTHIN eye drops;  it is believed to be more effective in protecting the ocular surface from UV rays than systemic injections.(215)However, NANO ASTAXANTHIN reduces inflammation in the retina through reducing TNF and IL1β expression. (186)This antioxidant reduces apoptosis in retinal ganglion cells as well as retinal pigment epithelium by increasing the expression of p-Akt, p-mTOR, and Nrf2.  It also reduces the expression of caspase-3, thereby preventing glaucoma and AMD.(210,216)NANO ASTAXANTHIN has a protective effect on the retina and treats injuries caused by glaucoma(217)and by That inhibits retinal degeneration caused by glaucoma.(209)Today, drug macromolecules that inhibit angiogenesis include aflibercept, pegaptanib and ranibizumab with molecular weights of 97, respectively. , 50 and 48 kDa, are first-line treatments for AMD.  These drugs target vascular endothelial growth factor, which is involved in choroidal neovascularization in AMD.(218)To effectively deliver biological molecules to the posterior segment, it is often Intravitreal drug injection is currently available, but this method has disadvantages such as eye infection, patient discomfort, high intraocular pressure, and retinal artery occlusion.(219)Because macromolecular drug delivery is still in their infancy, alternative distribution strategies are highly sought after.  Notably, significant attention is currently focused on the delivery of eye drops.  NANO ASTAXANTHIN is a small molecule that can be used to treat eye diseases, especially AMD, which must target the posterior segment and overcome barriers.(220)In addition, NANO ASTAXANTHIN may be a potential agent to reduce ocular inflammatory mediators in mice through mRNA expression of TNF-α, IL-1β, and HMGB1 and protein expression of TNF-α, IL-1β, and HMGB1 ( Figure 12 ).(221)

Hình 12. (A – C) biểu hiện mRNA của TNF-α, IL-1β và HMGB1. (D – G) Biểu hiện protein của TNF-α, IL-1β và HMGB1. 

Figure 12. (A – C) mRNA expression of TNF-α, IL-1β, and HMGB1.  (D – G) Protein expression of TNF-α, IL-1β, and HMGB1.  (H) Fluorescence image shows expression of HMGB1 in the corneal epithelium.  Reprinted from ref (221)with permission from Elsevier.
5.3.  Distribution of NANO ASTAXANTHIN for eye health
Topical medications such as eye drops, eye ointments… to treat eye diseases have the advantage of being less invasive and convenient for the patient.  However, some lingering challenges remain.  Most eye drops are eliminated within seconds due to obstacles such as limited tear production and subsequent lacrimation, especially in the case of high molecular weight and hydrophilic drugs. like small molecule lipophilic drugs, have very limited permeability.  Drug molecules are transported through two pathways (corneal and noncorneal) to reach the anterior and posterior segments, respectively, and both present barriers to drug permeation.(222)So , several issues need to be resolved such as the size and molecular weight of the drug, permeability, hydrophilicity and hydrophobicity and above all the delivery system of the drug.  Topical application is the preferred method for diseases of the surface or anterior part of the eye affecting the cornea or sclera and lens.  To deliver drugs to the posterior parts of the eye, further research is needed to develop appropriate systems or devices to overcome barriers in the ocular tissue.  Among many studies, the use of drug formulations based on nanotechnology is one of the most successful.  Development of new nanoformulations for topical delivery and release of therapeutic molecules could disrupt ocular barriers and reduce systemic side effects.  NANO ASTAXANTHIN, as a lipid-soluble keto-carotenoid, is used in the treatment of eye diseases caused by oxidative stress including AMD and dry eyes due to aging, allergies, inflammation, etc.(108,183)Because cells The retinal epithelium is the site of action of this drug, so delivery of the drug to this location is of particular importance.  Since topical routes of application, specifically eye drops, are more practical and easier to use for patients, it is important to design an appropriate drug delivery system for topical application of NANO ASTAXANTHIN, the drug has poor solubility in aqueous solution.(223)Nano-sized liposomes are a good choice because they can well cover the hydrophobic NANO ASTAXANTHIN and change the surface charge of the drug, then deliver the substance to desired location in the posterior tissues of the eye.  Liposomes coated with NANO ASTAXANTHIN were applied in an in vitro dry eye model and its effects on reducing cell apoptosis and inhibiting ROS production and signs of aging were evident .  Furthermore, it was revealed that upon application of positively charged liposomes, the delivery of NANO ASTAXANTHIN to the desired location increases locally.  Cationic liposomes have a higher affinity for cells than neutral liposomes.  This higher affinity may make them suitable candidates as nanocarriers for drugs such as NANO ASTAXANTHIN.(224) Topical drug delivery may be enhanced by permeable delivery systems mucus to various ocular tissues beyond the mucus layer;  Mucus-penetrating nanoparticles were tested in vivo to see improvement in drug diffusion.  The results showed that it enhances diffusion not only towards the ocular surface but also towards the posterior segments.(225)Furthermore, some biomolecules such as peptides (as penetrating agents cells), proteins, monoclonal antibodies, genes, and oligonucleotides can be conjugated to nanoparticles to deliver drugs to the posterior part of the eye.(226) Nanoparticles and liposomes, nanomicelles, nanosuspensions, and dendrimers are Other nanotechnology-based carrier systems are being investigated for therapeutic ocular delivery.(227)However, nanoformulations appear to overcome ocular barriers better than NANO delivery systems Other ASTAXANTHIN.  However, there is still room to explore new drug delivery systems to increase the stability, solubility and bioavailability of NANO ASTAXANTHIN.

6. Delivers NANO ASTAXANTHIN through the skin to protect the skin

6.1.Skin morphology, barriers and penetration pathways

The skin is the organism’s initial barrier against the environment and the first barrier to its entry is the stratum corneum, the main barrier to drug penetration.(228)There are two main routes through which active substances penetrate through the skin: through the appendages and through the epidermis.  The transepidermal pathway is responsible for permeation through the skin and consists of two pathways, the intracellular (paracellular) pathway and the transcellular (polar) pathway ( Figure 13 ).(229)Middle pathway cells are the main route of penetration of active antioxidants into the skin and possibly even into deeper areas of the skin.(230)Nanotechnology greatly helps in the delivery of drugs through the skin into labour.  It can control drug release to enhance performance, provide higher drug loading capacity, help achieve physical and chemical stability of drugs during storage, and prolong digestion. drug delivery, thereby improving drug concentration.(231)The size of the drug molecule is the primary challenge for its penetration due to the 10–40 μm thick stratum corneum in which the drug has a relatively low molecular weight (∼less than 500 g/mol) can reach the dermis.(228)In addition, the cells in this layer are haphazardly arranged;  therefore, the drug has to travel a long way to penetrate this layer.(232)To date, various physical and chemical methods to enhance the drug delivery parameters through the skin have been invented;  many of them are costly stimulants.(233)New nanotechnology-based approaches for topical drug delivery with controlled drug release have been recognized as an effective strategy, especially for drugs with poor water solubility and short half-life.(234−236)Besides the role of nanoparticles and nanocarriers in the treatment of skin disorders, they are also used widely used in the cosmetic industry;  Moisturizers containing liposomes were first developed 40 years ago.(237)The skin is the area most exposed to the external environment, so it requires more care and maintenance.  Daily skin care, implementing cosmetics containing pharmaceuticals, enhances skin elasticity, texture and smoothness, thereby enhancing skin health.(238)Transdermal drug delivery using patches Penetration through the skin or topical application is difficult due to the presence of the stratum corneum;  This cuticle limits the delivery of bioactive molecules of relatively low molecular weight.  To overcome these limitations in overcoming biological barriers, microneedle patches are a promising tool to penetrate the stratum corneum.(239)Microneedles, which consist of micro/small sized needles , which can deliver cargo into the dermis in a non-invasive route.(228)However, to date, no studies have been conducted to deliver NANO ASTAXANTHIN via microneedles.  Therefore, there is an opportunity to conduct research on microneedle-mediated delivery of NANO ASTAXANTHIN.

Hình 13. Sơ đồ minh họa các lớp da và các đường thẩm thấu chính vào da để phân phối các hạt nano

Figure 13. Schematic illustration of the skin layers and the main routes of penetration into the skin for nanoparticle delivery.  The first is the route through open areas of the skin such as sweat glands and hair follicles so that the drug penetrates the skin better.  Drug molecules diffuse across the phospholipid membrane and cytoplasm of dead keratinocytes.  In this way, biologically active substances continuously pass through the small spaces between the cells of the skin.
6.2.  Distributing NANO ASTAXANTHIN for skin health
There is a balance between the generation of reactive oxygen and nitrogen species and the activity of antioxidant systems in living cells.  The structure and function of normal cells change when any factor leads to disruption of this balance.(240)The downside of excessive oxidative stress to the skin is the appearance of wrinkles. facial wrinkles, deep wrinkles, dullness and roughness, dry skin and loss of elasticity.(241)UV rays can penetrate the skin and create oxidative stress, followed by damage to DNA, proteins and lipids as well as errors in DNA repair leading to mutations, collagen degradation, wrinkles, erythema and skin cancer.(242) NANO ASTAXANTHIN enhances skin health through several mechanisms including its properties antioxidant, anti-inflammatory effect,(243)improved immunity,(244)and DNA repair effect.(245)Many studies have evaluated the effectiveness of NANO ASTAXANTHIN on the skin and demonstrated that it improves skin elasticity, texture and moisture, while reducing wrinkles and visible signs of aging.(246,247)Due to NANO ASTAXANTHIN’s anti-inflammatory and antioxidant properties, it is believed to have ability to reduce skin cancer rates;(248)The cosmetic benefits of NANO ASTAXANTHIN have also been studied by some researchers.  In topical application, a cream containing NANO ASTAXANTHIN was used on the skin of 11 women.  After three weeks, skin moisture and elasticity in the majority of participants increased, and three women with small wrinkles showed improvement in their skin.  In another study, a group of 49 women aged 45–50 years were given 4 mg of NANO ASTAXANTHIN for 6 weeks and more than 50% of participants’ skin characteristics, including elasticity and moisture, improved.(249)NANO ASTAXANTHIN initiates the cell’s antioxidant defense system and regulates the Nrf2 pathway, leading to an antioxidant response.(250)The Keap1-Nrf2-ARE signaling pathway is important antioxidant defense system against oxidative stress.  Nrf2 is an important transcription factor negatively regulated by Keap1 and its main role is to regulate cellular protective responses to oxidative stress.  Under basal conditions, most Nrf2 molecules in the cytoplasm bind to the Keap1 protein and are destroyed.  Oxidative stress reduces Nrf2 degradation by altering the specific cysteine code in Keap1, leading to Nrf2 translocation to the nucleus.  It binds to the ARE in the promoter region of genes encoding antioxidant enzymes and induces the production of endogenous antioxidant enzymes.(81)These enzymes include superoxide dismutase, catalase, peroxiredoxin, etc., which have important role in fighting ROS.(251)

NANO ASTAXANTHIN also affects the function of the immune system;  for example, in a study of human lymphocytes, NANO ASTAXANTHIN enhanced immunoglobulin production in response to T-cell stimulation. In other studies, it has been shown that NANO ASTAXANTHIN enhances immune response and improves cytotoxic activity of T and NK cells in vivo.  (244,252)In a study performed on healthy female college students, immune system markers included IFN-g and IL-6 production, NK cytotoxic activity, and expression of LFA-1 was significantly enhanced;  Cellular and humoral immune responses were improved by dietary intake of NANO ASTAXANTHIN.(253)It is worth mentioning that participants with an average age of 21 years received NANO ASTAXANTHIN daily during 8-week period and their immune response was evaluated in a clinical study.  In the middle of the experiment, it was observed that DNA damage biomarkers were reduced by NANO ASTAXANTHIN as the immune response of young women improved.(253)Ultraviolet radiation induces the production of produces reactive oxygen species (ROS) and free radicals such as hydroxyl and singlet oxygen, and these are reactive molecules that cause DNA strand breaks and oxidation of its bases.(245)Do Antioxidant properties of NANO ASTAXANTHIN, it prevents the accumulation of free radicals, thereby preventing DNA damage.(104)In addition, the effects of NANO ASTAXANTHIN in tissue engineering and wound healing in both the in vitro and in vivo phases showed very promising results.  In this way, the combination of NANO ASTAXANTHIN with certain types of polysaccharides, such as chitosan and collagen, leads to increased wound healing rates in a short period of time compared to other types of studies using only polysaccharides and /or other types of habits. polymer nanostructures.  Comparing the results of the used collagen combined with NANO ASTAXANTHIN with the control group (saline only) and the drug control group (collagen combined with gentamicin) shows that NANO ASTAXANTHIN can accelerate wound healing in mice up to 50% compared to the two control groups. ( Figure 14 ).(254)In addition, it has been reported that NANO ASTAXANTHIN can influence DNA repair kinetics.(250)In one study, the protective ability of NANO ASTAXANTHIN against DNA alteration caused by ultraviolet rays were evaluated;  Synthetic NANO ASTAXANTHIN hinders DNA damage in human melanocytes and intestinal CaCo-2 cells.(255)Alterations in extracellular matrix components such as fibrous proteins including collagen, elastin and glycosaminoglycans lead to dry skin, wrinkle formation, and loss of skin elasticity.(256)Ultraviolet-induced ROS production stimulates metalloproteinase synthesis leading to destruction of the extracellular matrix and loss of collagen.  NANO ASTAXANTHIN with its antioxidant properties prevents the growth and accumulation of free radicals, and it has been observed to suppress metalloproteinase expression in various cells.(257)Effects The utility of NANO ASTAXANTHIN in promoting matrix-metalloproteinase-1 and skin fibroblast elastase to UV-treated cultured human skin fibroblasts was evaluated in which NANO ASTAXANTHIN reduces the effects of UV radiation on the skin.(99)Inflammatory mediators are known to increase during UV radiation and NANO ASTAXANTHIN inhibited the production of inflammatory mediators. inflammation by blocking the activation of NF-κB.  The effects of NANO ASTAXANTHIN on the expression of NF-κB p65, IL-6, TNF-α and IFN-γ have been studied elsewhere.  A total of 32 buffaloes were supplemented with NANO ASTAXANTHIN for a period of 30 days.  Inflammatory mediator expression from peripheral blood mononuclear cells was compared with control groups.  It turned out that mRNA expression of IL-6, TNF-α, and IFN-γ was reduced compared to control groups.(258)As noted, NANO ASTAXANTHIN reduced inducible nitric oxide and cyclooxygenase levels.  This property has an important influence on the development of anti-inflammatory drugs.(259)

Hình 14. (A) Các hình ảnh được cho là của quá trình điều chế NANO ASTAXANTHIN và màng collagen kết hợp thuốc được chiết xuất từ ​​D. singhalensis như sau

Figure 14. (A) Images attributed to the preparation of NANO ASTAXANTHIN and the drug-incorporated collagen membrane extracted from ​​D. singhalensis as follows: (A1) Collagen solution, (B1 and C1) membrane containing NANO ASTAXANTHIN and gentamycin in collagen membrane solution, (Membrane B2 and C2) before processing form a square shape (5 × 4 cm) change.  (B) Antioxidant activity (DPPH) of NANO ASTAXANTHIN extracted from ​​D. singhalensis compared to ascorbic acid at different concentrations.  (C) Images showing wound contraction on different days of postoperative wound healing (1–21 days).  Group 1 is the control group;  Group 2 is collagen combined with NANO ASTAXANTHIN;  and group 3 is collagen combined with gentamicin.  Reprinted from ref (254)with permission from Elsevier.

7. NANO ASTAXANTHIN AND DIABETES TREATMENT

Diabetes mellitus, also known as human diabetes, refers to a group of metabolic disorders and is defined by having high blood sugar levels over a long period of time.  The number of people with diabetes is about 463 million and it is expected that this number will increase to 578 million in the next 10 years.(260)Oxidative stress caused mainly by ROS-induced hyperglycemia is known to have a detrimental effect on the progression of diabetes.  NANO ASTAXANTHIN with its outstanding antioxidant activity can compensate for oxidative damage through different mechanisms─ eliminating free radicals, hindering lipid peroxidation and quenching singlet oxygen.  In contrast to other members of the carotenoid family, the polar structure of NANO ASTAXANTHIN helps the drug molecule self-incorporate into the cell membrane without disorganizing it, thereby leading to a decrease in the hydroperoxide concentration of the lipid layer. (261)Furthermore, it has been revealed that NANO ASTAXANTHIN has the ability to enhance mitochondrial activity through reducing ROS generated in mitochondria leading to increased ATP and respiratory activities.(262)Figure 15 indicates mechanisms that may help NANO ASTAXANTHIN prevent oxidation-related damage.

Hình 15. Sơ đồ trình bày các con đường phân tử ngụ ý về khả năng bảo vệ của astaxanthin (NANO ASTAXANTHIN):

Figure 15. Schematic representation of the molecular pathways implied by the protective potential of astaxanthin (NANO ASTAXANTHIN): Due to its ability to penetrate membranes, NANO ASTAXANTHIN has both intracellular and extracellular ROS scavenging activities .  Furthermore, in phospholipid membranes, the polyene chain NANO ASTAXANTHIN participates in the reduction of lipid peroxidation.  Through regulating various pathways, NANO ASTAXANTHIN reduces inflammation, oxidative stress and apoptosis.  The red arrow represents the inhibitory action and the green arrow represents the reinforcing action.  Reprinted from ref (260)under an open access license.
Due to damage to the renal tubules and glomeruli, diabetic nephropathy is a microvascular complication of diabetes (type I and type II), the main symptoms recognized are reduced glomerular filtration rate, cell damage. epithelial cells of renal tubules, etc. .(263)Oxidative stress is the main factor causing diabetic nephropathy and NANO ASTAXANTHIN with its outstanding antioxidant properties is of particular interest for application in this case.  Depending on the stage of diabetes, NANO ASTAXANTHIN is effective in treating and reducing complications.  The antidiabetic effect of Astaxanthin has been observed by
  • decreased serum glucose and fructosamine concentrations in patients receiving NANO ASTAXANTHIN (8 mg daily for 8 weeks)(264)
  • Improves glucose metabolism and lowers blood pressure(264)
  • fasting hypoglycemia in rats(265)
  • reduces MDA (malondialdehyde) in serum and increases SOD activity with a glucose-lowering effect (266)
  • protects pancreatic beta cells against glucose toxicity by increasing insulin secretion (265)
  • suppress ER stress mediation of beta cell apoptosis(267)
  • increased insulin sensitivity and glucose uptake as well as reduced insulin resistance in high-fructose-fed (HFFD) mice administered NANO ASTAXANTHIN for 45 days (6 mg/kg/day) were impressive on insulin signaling pathway(268)
  • increased muscle glucose tolerance and metabolism and reduced insulin resistance in this tissue as well as enhanced mitochondrial biogenesis in muscle cells of HFD (high fat diet) treated mice (269)
  • Improves glucose metabolism by acting on NANO ASTAXANTHIN on liver metabolic enzymes and enhancing glycogen storage in the liver(270)
    reduced diabetes-induced inflammation and liver dysfunction in STZ (Streptozotocin)-induced diabetic rats by reducing ROS and AGEs (glycation end products) levels and reducing hepatic lipid peroxidation for 18 days consume 50 mg/kg NANO ASTAXANTHIN per day(271)

Some complications of diabetes include:

  • (1) Retinal disease .  A slowly progressive complication of diabetes with increased inflammation, reduced antioxidant enzyme function, multiple metabolic changes in retinal cells, microvascular damage, oxidative stress in the retina retina and its capillary cells and activation of the autophagy pathway in retinal cells.(272−274)In a study, the preventive role of NANO ASTAXANTHIN against retinopathy in mice was examined and a reduction in oxidative stress and inflammatory mediators as well as an increase in antioxidant enzymes was observed.(275)An in vitro experiment on human retinal pigment epithelial cells showed that NANO ASTAXANTHIN can reduce the effects of high sugar intake on cells by reducing AGEs, ROS and lipid peroxidation.(276)Khedher et al.  showed the inhibitory effect of NANO ASTAXANTHIN on the activity of aldolase reductase, which is a key enzyme in the pathogenesis of retinal diseases.(277)
  • (2) Neuropathy .  Side effects of this complication are neurological abnormalities, programmed brain cell death, hippocampal-based cognitive dysfunction, and neurobehavioral problems.(278)All of these problems is due to the activity of oxidative stress, the presence of inflammatory mediators and the activation of apoptosis-related molecules.  Studies show that the protective and ameliorative effects of NANO ASTAXANTHIN in neuropathy include increasing the activity of antioxidant enzymes, reducing levels of inflammatory molecules, and protecting cells from damage. apoptosis,(279)improved neurological behavior in STZ mice,(98)and cognitive impairment by inhibiting oxidative stress and inflammation in diabetic mice.(280)
  • (3) Cardiovascular effects .  They are diabetes-related disorders caused by thrombosis, arteriosclerosis, vascular damage, and platelet aggregation, all of which result from high glucose and oxidative stress.(281,282)NANO ASTAXANTHIN reduces these effects by reducing oxidative stress and inflammation as it shows anti-inflammatory and anticoagulant effects,(283)modulates redox reactions, controls and regulates vasoconstriction, blood pressure and blood fluidity,(284)and reduced LDL levels.(285)
  • (4) Kidney disease .  The renoprotective effect of NANO ASTAXANTHIN was observed through increased urinary albumin and reduced oxidative stress markers in db/db mice after 12 weeks of NANO ASTAXANTHIN administration,(286) inhibiting COX- 2, MCP-1, TGFB and ROS in high glucose-stimulated cells in the glomerular mesangium,(287)normalized creatinine and uric acid levels, reduced urea and glomerular hypertrophy in diabetic rats and improve renal dysfunction,(288)increase the expression of antioxidant enzymes and maintain the antioxidant status of kidney and plasma, reduce renal complications of diabetes(289) and prevent Prevents renal fibrosis by reducing the accumulation of ECM components and protects against oxidative damage by activating the transcription factor Nrf 2-ARE.(290)

However, the poor solubility and stability of the drug negatively affect its antioxidant capacity and bioavailability.  A recent study targeting diabetic nephropathy through a drug delivery system consisting of liposomes encapsulating NANO ASTAXANTHIN with the aim of designing a smart delivery system targeting glomerular mesangial cells based on Glucose transporter 1 is believed to play an important role in glucose transport to glomerular mesangial cells.(291)NANO ASTAXANTHIN-encapsulated glucose-modified liposomes can successfully penetrate glucose transporter 1 of Glomerular mesangial cell membrane and drug delivery system effectively eliminated ROS generated by oxidative stress.(292)Furthermore, NANO ASTAXANTHIN release study was performed at different pHs;  The acidic medium represents the lysosomal medium, while phosphate-buffered saline +10% fetal bovine serum represents the blood medium.  Liposomes exhibit faster release in acidic environments and better protect drug molecules.  Figure 16 shows the physicochemical and biological properties of NANO ASTAXANTHIN encapsulated liposomes in vitro along with a diagram showing how glucose ligand drug delivery can reach mesangial cells.

Hình 16. (A) Sơ đồ nhắm mục tiêu vào các tế bào trung mô cầu thận thông qua liposome biến đổi phối tử glucose bao bọc NANO ASTAXANTHIN.

Figure 16. (A) Schematic diagram of targeting glomerular mesangial cells via glucose ligand-modified liposomes encapsulating NANO ASTAXANTHIN.  (B) Antioxidant activity of NANO ASTAXANTHIN (i), excess ratio of NANO ASTAXANTHIN in the removal of H 2 O 2 (ii), cell viability of GLU-LIP, NANO samples ASTAXANTHIN and NANO ASTAXANTHIN-GLU-LIP when exposed to human kidney mesenchymal cells (HRMC) at different concentrations for 24 h (iii), cellular uptake of DiO-labeled samples through HRMC (iv), ROS levels for different samples exposed to HRMC (v).  The p values, including * p < 0.05, ** p < 0.01, and *** p < 0.001, demonstrated significant differences between the sample and HG.  Abbreviations: 1,2-distearoyl- sn -glycero-3-phosphatidyletanolamine (DSPE), liposome (LIP), glocuse ligand (GLU), yolk lecithin (EPC), diabetic cell model (HG), negative control (NC), and glucose transporter 1 (GLUT1).  Reprinted from ref (292)with permission from Elsevier.

8. Provides therapeutic NANO ASTAXANTHIN for other disorders such as Cancer

Cancer basically means the growth of a malignant cell.  Human malignancies are the result of a distinct set of genetic events.  These changes occur in genes that affect cell cycle control, cell survival, cell migration, and angiogenesis.  Cell entry and progression during the cell cycle are accompanied by changes in the amount and activity of a family of proteins called cyclins.  The number of different cyclins increases at certain phases of the cell cycle and due to this increase, activation of cyclins E/CDK2, D/CDK6 and D/CDK4 takes place, causing phosphorylation RB metabolism, leading to cell proliferation.  Cell proliferation occurs spontaneously when genes that control the cell cycle are impaired by mutation or amplification.  For example, activation of cyclin D1, which occurs by mutation, increases the rate of cell proliferation by facilitating RB phosphorylation.(293)Studies show that NANO ASTAXANTHIN stops the cycle cells in the G0/G1 phase and suppresses the expression of cyclin D1, by increasing the expression of p53, p27 and p21WAF-1/CLP1 at the same time.  One way for cells to escape cancer is to choose death, i.e. apoptosis.  Degradation of the nuclear membrane and cytoplasm of cells and organelles leads to fragmentation of cells, which are then rapidly engulfed by phagocytes and abducted from the environment.  Several genes play important roles in apoptosis, including Bim, Bcl-2, Bcl-XL, Bak, Bax, Bad, p53, and Mcl-1.  Mcl-1, Bcl-2, and Bcl-XL proteins work together to counteract apoptosis, while Bim, Bad, Bak, and Bax proteins play a role in apoptosis.(294−296)Studies Research has shown that NANO ASTAXANTHIN reduces the expression of anti-apoptotic substances and increases the expression of pro-apoptotic proteins, promoting the release of cytochrome c and Smac/Diablo into the cytoplasm.  Bcl-2 induces cytochrome c release from mitochondria, leading to activation of caspase-9 and subsequently caspase-3.  NANO ASTAXANTHIN induces mitochondrial apoptosis in cells via caspases, leading to cancer cell death.(297,298)NANO ASTAXANTHIN exerts its anti-proliferative effect by increasing Bax and caspase 3 expression, while decreasing expression of malondialdehyde and bcl2 in the LS-180 cell line.(299,300)NANO ASTAXANTHIN can treat prostate cancer by inhibiting alpha-reductase enzyme function.(301)Many studies have shown its anti-inflammatory role. of NANO ASTAXANTHIN for prostate, liver, colon, lung, breast and other cancers.(302−304)Currently, a large number of drug delivery systems include Nanoparticles and various materials have been used as drug promoters or enhancers to improve the therapeutic efficacy as well as the durability and stability as well as the safety of anticancer drugs.  NANO ASTAXANTHIN is a biomolecule that can reduce metal salts to form nanoparticles suitable for processing in biological systems;  The production of gold nanoparticles (Au NPs) with NANO ASTAXANTHIN as a natural reducing agent was evaluated.  The cytotoxic effect of the prepared nanostructures against human breast cancer cells (MDA-MB-231) was evaluated through a tetrazolium-based assay;  NANO ASTAXANTHIN-Au NPs exhibited strong cytotoxic effects against cancer cells and apoptotic morphology was detected in the treated cells.  On the other hand, NANO ASTAXANTHIN-reduced Au NPs have the potential to act as a promising agent in the field of optical-based diagnostics and therapeutics because they display an interesting UV-vis absorption peak in the near-infrared region surgery, which is essential in optical-based diagnostics and therapy.  Near-infrared lasers can effectively penetrate tissue, and nanoparticles can convert this light into thermal energy, which is applied in photothermal therapy.(305)Interesting to note is that NANO ASTAXANTHIN alone has photocatalytic properties, thanks to which it can convert light into heat without the need for additional photothermal agents.  This property has been exploited to eliminate ocular tumors through photothermal therapy.  An increase in the local temperature of tumors was observed when near infrared rays were applied.  The results obtained clearly show that NANO ASTAXANTHIN is a very promising candidate for the treatment of any type of cancer through photothermal therapy as depicted in Figure 17 .

Hình 17. (A) Bố trí thử nghiệm liệu pháp quang nhiệt do NANO ASTAXANTHIN gây

Figure 17. (A) Experimental setup for photothermal therapy induced by NANO ASTAXANTHIN;  (B) tumor volume (i), rabbit body weight (ii) and H&E staining images at ×40 (iii) and ×100 (iv) of the sample;  (C) in vitro assessment of temperature changes when 532 nm NIR is irradiated;  (D) treatment of ocular tumors for up to 14 days: control (i), tumors treated with laser alone for 4 minutes at 532 nm and 0.11 W cm –2 (ii), injection of NANO ASTAXANTHIN solution (300 μg mL –1 ) without exposure to laser irradiation (iii), tumors were treated with both NANO ASTAXANTHIN injection followed by laser irradiation (532 nm and 0.11 W cm –2 in 4 minutes) (iv).  Reprinted from(306)with permission of the Public Library of Science.
Detecting cancer early can greatly increase the likelihood of successful treatment.  Such imaging tests could have a significant impact on cancer diagnosis.  Photoacoustic imaging is a hybrid imaging technique based on the photoacoustic effect with high resolution and sensitivity, which can be used to diagnose different stages of cancer.  Compared with other common tumor imaging methods, it is more economical and has better contrast in tumor diagnosis.(307)NANO ASTAXANTHIN, with an absorption peak at 490 nm, can be used as a potential photoabsorbing agent to enhance photoacoustic response in targeting cancerous tumors.(308,309)Nguyen et al.  demonstrated that NANO ASTAXANTHIN can be used as an exogenous photocompatible biocontrast agent to identify the size and location of bladder tumors.(310)In addition, Bharathiraja et al.  synthetic polypyrrole nanoparticles using NANO ASTAXANTHIN-conjugated bovine serum albumin as optical contrast agent for phototherapy and cancer detection.  In another study, NANO ASTAXANTHIN-alpha tocopherol nanoemulsion was synthesized by spontaneous emulsification and ultrasound and its effects were tested on three different types of cancer cells;  it has significant anticancer potential against various cancer cells and has antibacterial and wound-healing properties.(305)
Additionally, some researchers have examined the use of solid lipid nanoparticles as oral delivery systems for vitamins and their analogues because they are biocompatible with lipid matrices (including triglycerides, fat or glycerol ester) and is easily broken down in the body ;  NANO ASTAXANTHIN, as a natural carotenoid, is effective against several disorders and is more potent than β-carotene and vitamin E.(5)However, its use in oral formulations is limited due to photosensitivity, Decomposes in the presence of oxygen and has poor solubility in water.  Therefore, NANO ASTAXANTHIN was incorporated into solid lipid nanoparticles to improve its bioavailability.(311)A drug delivery system based on Tween 20 ester and glycerol was developed to deliver NANO ASTAXANTHIN with The average diameter of these solid lipid nanoparticles is 163–167 nm, while the packing ratio is ∼89%.  The results showed that solid lipid nanoparticles induced long-term release of NANO ASTAXANTHIN in simulated GI juice.(312)In another study, colloidal particles loaded with NANO ASTAXANTHIN were developed to address limiting factors of NANO ASTAXANTHIN for oral drug delivery applications via chitosan oligosaccharide-coated poly(lactic- co -glycolic acid) in which drug molecules are loaded.  Notably, two types of poly(lactic- co -glycolic acid) with different lactide and glycolide ratios were tested (50:50 and 25:75, respectively), and their physicochemical and drug distribution properties were tested. and biological properties were evaluated in vitro .  The chitosan oligosaccharide coating makes the drug delivery system pH-responsive and the release rate increases as the pH of the medium turns acidic.  In contrast to pure NANO ASTAXANTHIN samples and poly(lactic- co -glycolic acid) samples without NANO ASTAXANTHIN coating, chitosan oligosaccharide coating resulted in good dispersion in water at room temperature and enhanced bioavailability , which is beneficial for drug delivery applications.(313)Table 3 shows some examples of NANO ASTAXANTHIN loaded nanocomposites for various biomedical applications.

Bảng 3. Các chất mang nano được nạp NANO ASTAXANTHIN khác nhau được nhắm mục tiêu cho các cơ quan khác nhau

Abbreviations: NANO ASTAXANTHINDC NP, astaxanthin-DNA/chitosan Nanoparticles;  SLN, solid lipid nanoparticle;  ASTAXANTHIN- Fe 3 O 4 -Tf- PEG NANO NPs, astaxanthin/Fe 3 O 4 /transferrin/PEG Nano particles;  NLC and CD, nanosized lipid carrier and cyclodextrin;  NE, nanoemulsion;  NLC, nanostructured lipid carrier;  NANO ASTAXANTHIN-TP-KC NE, Nano astaxanthin/alphatocopherol/κ-carrageenan emulsion

9. NANO ASTAXANTHIN FROM BED TO BED

In addition to medicine, NANO ASTAXANTHIN also has many applications in many industrial fields.  This primary microalgae ( Haematococcus ) carotenoid is used by the cosmetics, food, nutrition and seafood industries, among others.  Commercially, there is high demand and a very competitive market among manufacturing companies for the production of this pigment and its derivatives.  The NANO ASTAXANTHIN market for animal feed and nutraceuticals was 300 million USD and 30 million USD in 2009, respectively.(320)In 2018, this market exceeded 600 million USD,(321)and it has exceeded 650 million USD million USD by 2020 (Global market insights: https://www.gminsights.com/industry-analysis/astaxanthin-market ).  Based on Global Market Insights, the NANO ASTAXANTHIN market size is estimated to grow at a CAGR of over 5.5% (compound annual growth rate) from 2021 to 2027. NANO Synthetic and natural ASTAXANTHIN are the two sources of this market.  Generally, the consumption of synthetic NANO ASTAXANTHIN is in poultry, pet food and aquaculture applications and nearly 95% of the NANO ASTAXANTHIN market is produced by chemical synthesis.(322) Although consumption of synthetic NANO ASTAXANTHIN dominates, consumer demand for effective natural Haematococcus astaxanthin is still increasing, especially in the nutritional industry.  Natural NANO ASTAXANTHIN is predicted to reach USD 770 million (with a production of 190 tons) by 2024, with a CAGR growth rate of 7.7%.(320)The NANO ASTAXANTHIN market has shown steady growth since 2014 and the global market size is predicted to reach USD 3.4 billion by 2027, at a CAGR of 16.2%.(323)It can be easily obtained in many dry powder forms , various powders, oils and biomass, thus showing an increase in the global pigment sales volume and will have the most significant global market development by 2026.(324)There is great interest to carotenoids from natural sources and the widespread applications of NANO ASTAXANTHIN in foods, pharmaceuticals, nutraceuticals, dietary supplements, feeds and personal care products are predicted to increase.

10. FUTURE PERSPECTIVES AND COMMENTS

One of the problems of people today is facing chronic and dangerous diseases.  In general, free radicals and oxidants are continuously produced in living organisms through various metabolic reactions.  Because of the role of free radicals and oxidants in the development and progression of these diseases, their counteractive molecules, antioxidant compounds are becoming valuable dietary supplements. human diet.  Over the past two decades, oxidative stress and antioxidants have become one of the most important and popular areas of study for researchers.(325)Dietary Supplementation with Antioxidants Synthetic antioxidants are considered a treatment for ROS disorders, but research shows that regular use of synthetic antioxidants increases mortality.(326)Therefore, the hypothesis is based on a therapeutic effect. The value of antioxidant conditions in vitro does not agree with its effects in vivo. (327)The side effects of chemical drugs and their incompatibility with human nature have given special importance to the precise identification and study of chemical compounds in medicinal plants, yeast , algae and some bacteria including natural antioxidants. Natural antioxidants appear to be a good alternative to synthetic antioxidants because they can effectively fight inflammation and oxidative stress;(328)developed countries have considered developing Healthy food is an important priority. By identifying and using these compounds, while improving diet and reducing disease, they contribute to improving consumer safety and health as confirmed by research. clinical on the health effects of bioactive compounds.(329)NANO ASTAXANTHIN is a healthy nutrient with no toxicity and due to its strong antioxidant properties, it is involved in the protection of cells fight oxidative damage and regulate gene expression, creating cell-cell communication and cell health. On the other hand, its use as a natural antioxidant is limited due to low bioavailability, sensitivity to environmental, process and gastrointestinal conditions as well as lack of suitable drug delivery systems. fit. Therefore, considerable research has been conducted on the use of nanocarriers containing NANO ASTAXANTHIN for therapeutic applications. In addition, the combination of NANO ASTAXANTHIN with other nanomaterials can provide synergistic effects, such as antioxidant activity, which can be used to treat various diseases.(330−334 )