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 Table of Contents  
Year : 2022  |  Volume : 9  |  Issue : 3  |  Page : 419-430

Nanopolyphenols: Perspective on oxidative stress-induced diseases

MGMIHS OMICS Research Center, MGM Central Research Laboratory, MGM Medical College and Hospital, and Department of Medical Biotechnology, MGM School of Biomedical Sciences, MGM Institute of Health Sciences (Deemed to be University), Navi Mumbai, Maharashtra, India

Date of Submission04-Jul-2022
Date of Acceptance04-Aug-2022
Date of Web Publication29-Sep-2022

Correspondence Address:
Dr. Raman P Yadav
MGMIHS OMICS Research Center, MGM Central Research Laboratory, MGM Medical College and Hospital, and Department of Medical Biotechnology, MGM School of Biomedical Sciences, MGM Institute of Health Sciences (Deemed to be University), Navi Mumbai 410209, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mgmj.mgmj_100_22

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Recently nanopolyphenols are gaining widespread interest in the drug discovery domain. Nanonization of polyphenols has greatly affected the therapeutic index owing to improvement in pharmacokinetic and biopharmaceutical obstacles linked with the use of natural polyphenols. They have been looking at an emerging paradigm for an array of disease symptoms. In this article, we have explored the therapeutic potential of nanopolyphenols in oxidative stress-induced diseases such as neurodegeneration, cancer, obesity, and diabetes. This article will present the current state of the art of various nanopolyphenols targeting oxidative stress-induced diseases. The advanced fabrication strategies presented for polyphenols including nanocrystal, mesoporous silica nanoparticles, nanoparticles, nanoliposome, gold nanoparticle, and nanosuspension are discussed. The information presented in light of recent in vitro, in vivo, and clinical evidence for nanoformulation and delivery of polyphenols may show a new dimension to future research in the realm of herbal therapy for oxidative stress-induced diseases. Significant information on the molecular mechanisms underlying linkages of oxidative stress with neurodegenerative diseases, cancer, obesity, and diabetes is discussed. Valuable information on dietary polyphenols in these diseases and their clinical data is presented. Based on different experimental evidence, the review findings support phenomenal therapeutic strategies for nanopolyphenolic fabrication with extended benefits and a condensed time frame. The status of clinical trials conducted on nanopolyphenols is presented. Although clinical trials conducted on nanopolyphenols for mentioned diseases are few, we have tried to present as much available clinical data in this article.

Keywords: Antioxidant, cancer, diabetes, nanopolyphenols, neurodegeneration, obesity, oxidative, stress

How to cite this article:
Rathod P, Yadav RP. Nanopolyphenols: Perspective on oxidative stress-induced diseases. MGM J Med Sci 2022;9:419-30

How to cite this URL:
Rathod P, Yadav RP. Nanopolyphenols: Perspective on oxidative stress-induced diseases. MGM J Med Sci [serial online] 2022 [cited 2023 Feb 6];9:419-30. Available from: http://www.mgmjms.com/text.asp?2022/9/3/419/357479

  Introduction Top

Nanotechnology is one of the pioneering technologies set to streamline the process of drug discovery in terms of speed, size, reliability, and automation which involves research and development at the atomic, molecular, and macromolecular levels. In the drug discovery and development sector, nanotechnology is geared toward the betterment of diagnostics like bioimaging and biosensor, formulation of drugs, and targeted drug delivery systems.[1],[2] With the advent of nanotechnology, the number of nanomedicines is on a constant rise.[3] The unique chemical, physical, or biological features of these have offered new opportunities for research owing to the rise in the development of new delivery strategies, treatment modalities, approvals, and failures of drugs. Till now, a Large number of nanomedicines have been employed for cancer treatment and diagnostics and provide scope for other diseases too.[4] Recently, 3 nanomedicines- Patisiran/ONPATTRO, VYXEOS, and NBTXR3/Hensify got approval from FDA/EMA/CE mark. Patisiran/ONPATTRO, a lipid nanoparticle RNAi therapeutic approved by FDA (Food and Drug Administration) (2018) and EMA (European Medicines Agency) (2018) for Transthyretin (TTR)- mediated amyloidosis whereas VYXEOS is a liposomal formulation of cytarabine: daunorubicin which is approved from FDA,2017 and EMA (2018) for treatment of different leukemias. NBTXR3/Hensify is a hafnium oxide nanoparticle that got approval from CE Mark (European Conformity mark) (2019) for application to squamous cell carcinoma.[5] Since 2016, a clinical trial of 18 new nanoparticles has been registered. Out of these, 17 are used for cancer: 15 for treatment and 2 for imaging.[5]

Considering the potential and benefits of nanotechnology in drug discovery, we have explored the therapeutic potential of nanopolyphenols (NPs) in chronic disease management. Recently, a study supported the increased use of NPs over the last two decades, especially in the pharmaceutical and nutraceutical sector. As per the data, a huge number of NPs have been patented and commercialized. In the last three years (2019–2021), 97 NPs patents are published.[6] Therefore, this article presents information on advanced nano strategies for the fabrication of NPs that can be explored for the amelioration of oxidative stress-linked diseases like neurodegeneration, cancer, obesity, and diabetes. Moreover, we have focused on dietary polyphenols, as food/ diet rich in polyphenols are reported as vital in conditions like obesity, diabetes, high blood pressure,[7] cancer, and neurodegenerative disorders.[8] It is considered an antioxidant strategy that may show implications for various oxidative stress-induced symptoms. Thus as an approach to rectify pharmacokinetic and pharmacodynamic challenges that limit therapeutic potential and to enhance the therapeutic index of polyphenols or plant bioactive, information on advanced nano-strategies is discussed in this article for designing NPs that may give a new dimension to future herbal drug research.

The manuscript was prepared using data from clinical studies, in-vitro, in silico, and in vivo studies and review articles published till May 2022 in various journals, books, and e-resources. The search was limited to an article written in the English language. The keyword search included but was not limited to polyphenols, nanopolyphenols, oxidative stress, obesity, diabetes, neurodegeneration, cancer, natural molecules, medicinal plants, herbal medicine, nanotechnology, nanocarrier, drug delivery system, and clinical studies. The search engines used for data collection were Pubmed, Google Scholar, Science Direct, ResearchGate, arXiv, SemanticScholar, Clinical trials portal, etc.

  Oxidative stress and induced diseases Top

Oxidative stress is the condition produced due to disturbance of the balance between generation and buildup of Reactive Oxygen Species (ROS) and antioxidants that further lead to disturbance of redox signaling and molecular damage.[9] ROS production is the normal physiological phenomenon going on inside the cell due to aerobic metabolism and inflammatory responses.[10] Moreover, environmental factors like UV radiation, pollutants, chemicals, etc severely increase the ROS concentration enforcing the development of oxidative stress. Interestingly, ROS manifests the phenomenon of hormesis with one phase for redox functions at low concentration contributing to physiological functions including regulated cellular differentiation, tissue regeneration, and prevention of aging whereas on the other side in higher concentration produces oxidative stress targeting biological molecules like DNA, protein, lipids, enzymes and other small molecules adversely.[11] Oxidative stress has been found to play role in the initiation and development of a myriad of pathological conditions and diseases covering atherosclerosis, cancer, neurodegenerative disorders, hypertension, and diabetes.[12],[13] How oxidative stress is involved in the induction/development of diseases is discussed in the next section.

Link between oxidative stress and neurodegenerative disease

Oxidative stress severely affects the central nervous system (CNS) and develops different neurodegenerative diseases due to high oxygen requirement, weak or dysfunctioning of antioxidant systems,[14] and occurrence of peroxidation-prone lipid cells in the brain.[15] Neurodegeneration represents multifactorial origin. Oxidative,[16] and nitrative stress is the central phenomenon during neuronal loss and neurodegeneration.[17] [Figure 1] shows the role of oxidative stress in the initiation and development of neurodegenerative diseases.[18],[19],[20],[21],[22],[23],[24],[25]
Figure 1: Schematic representation of the relation between oxidative stress and neurodegeneration. The key event in the pathogenesis of neurodegeneration is ROS-induced oxidative stress. Many oxidative and nitrative post-translationally modified protein aggregates have been considered a hallmark of several neurodegenerative diseases. Deposition of such aggregate induces a multitude of events like oxidative stress, proteasomal dysfunction, and mitochondrial dysfunction that continue up to neuronal cell death.[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25]

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Link between oxidative stress and cancer

The role of oxidative stress in the development of cancer multistage is revealed. [Figure 2] shows the involvement of ROS-induced oxidative stress in various stages of cancer initiation, progression, and survival.[26],[27],[28],[29] ROS augmentation is the key to the initiation, progression, and development of cancer. The involvement of ROS at every step of disease development presents it as a therapeutic target.[30],[31] Therefore, a therapeutic strategy to ameliorate oxidative stress offers a significant potential target for cancer therapeutics.[32]
Figure 2: Schematic representation of the relation between oxidative stress and cancer. Oxidative stress plays role in the activation of gene expression for different cell cycle regulatory molecules, growth factors, inflammatory cytokines, anti-inflammatory molecules, and chemokines by activation of different transcription factors including β-catenin/Wnt, AP-1(Activator protein 1), p53, NF-κB (nuclear factor κ B), PPAR-γ (peroxisome proliferator-activated receptor-γ), etc affecting progression and survival of cancer.[26],[27],[28],[29]

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Link between oxidative stress and obesity

Obesity is characterized by excessive fat accumulation in the body and BMI >30 kg/m2 which impacts health adversely. Oxidative stress is one of the factors contributing to obesity development. There are several mechanisms responsible for the link between oxidative stress and obesity.[33],[34],[35],[36] [Figure 3] indicates the interplay between ROS-induced oxidative stress and obesity.
Figure 3: Schematic representation of the relation between oxidative stress and obesity. ROS-induced oxidative stress is found as the central player in the initiation and progression of obesity. Adiponectin is important for the amelioration of oxidative stress-induced damages. By inhibiting adiponectin production, ROS aggravates damage to the cell and nuclear processes thereby initiating the development of obesity.[34],[35],[36]

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Link between oxidative stress and diabetes

Type 2 diabetes (T2D) is a metabolic disorder of rising concern. Besides the multifactorial origin of disease, Oxidative stress is considered a crucial causative factor in the development of T2D, where ROS is involved in the initiation and development of insulin resistance.[37],[38],[39],[40],[41],[42] [Figure 4] shows the relationship between oxidative stress and diabetes.
Figure 4: Schematic representation of the relation between oxidative stress and diabetes. An upsurge of oxidative stress gives rise to T2D by affecting different pathological events like dyslipidemia, β-cell damage, mitochondrial DNA damage, and endoplasmic stress, which gives rise to the production of T2D.[37],[38],[39],[40],[41],[42]

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Polyphenols are naturally produced in the plant as secondary metabolites and are found in fruits, vegetables, cereals,[43] legumes, tea, and red wine.[44] The concentration of phenolic compounds in a plant can be a marker of antioxidant activities.[45] Due to the wide range of pharmacological activities offered by plant-derived bioactive, they can be explored for different chronic diseases like cardiovascular diseases, cancer, metabolic diseases including obesity, etc.[46],[47] Several polyphenols hold the potential to modulate different physiological and molecular pathways underlying energy metabolism, adiposity, and obesity. For eg curcumin, catechins, anthocyanins, and resveratrol[48],[49] Polyphenols lowers adipocyte viability, preadipocyte proliferation, and triglyceride deposition, trigger lipolysis, and fatty acid β-oxidation, suppress inflammation, etc. Such effects on adipogenesis and antioxidant mechanism may be the consequence of alteration of expression of signaling pathways adenosine-monophosphate-activated protein kinase, PPAR-γ (Peroxisome Proliferator-Activated Receptor-γ), CCAAT/enhancer-binding protein α, NF-κB (Nuclear Factor-κB), etc.[50] Additionally, Polyphenols induce the prosurvival pathway including microRNAs, sirtuins, metabolic intermediates, etc resulting in a cardioprotective effect.[7] [Figure 5] presents an illustrative diagram for dietary polyphenols as therapeutics for oxidative stress-generated diseases.
Figure 5: Illustrative diagram for dietary polyphenols as therapeutics for oxidative stress-generated diseases.[7],[48],[49],[50]

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Limitations of polyphenols as a therapeutic agent

The structure of polyphenols has played an important role in its therapeutic potential that also affects the rate and extent of absorption into the system.[43] Upon consumption of polyphenols in food, from ingestion up to delivery to the target tissue, polyphenols face different modification stress during their absorption, deposition, metabolism, and excretion (ADME) which hence disturbs their bioactivity.[51] During the development of any drug, bioavailability is an important factor. It is the percentage of active drugs that finally come to systemic circulation or site of the action.[52] Invivo dietary antioxidants can only work as an antioxidant when they are present in an ample amount within bodily fluids and tissues.[53] The most challenging issue in the development of polyphenols as a therapeutic agent is the low bioavailability of polyphenols. Other factors like poor solubility, short half-life, low body absorption, in vivo stability, and tissue-specific delivery[54],[55],[56] limit their therapeutic potential. For example, the stability of EGCG in the intestine and blood is poor. It absorbs at a low rate and shows low bioavailability.[57] Similarly, the low bioavailability found with quercetin may be associated with its poor absorption, higher metabolism, or faster elimination.[58] Certainly, research work focused to improve the stability of polyphenols and specific delivery of these molecules will be of great value.


Within a few years, many advances have been made in designing polyphenol on nano scaffolds to achieve enhanced bioavailability. The advantages are often accompanied by increased biocompatibility, nonimmunologic behavior, increased biodegradability, augmented strength of mucoadhesion,[59] and improves stability,[60] which leads to constant drug release thereby increasing the intracellular concentration of polyphenols. [Figure 6] represents different nanocarriers employed for the generation of nanopolyphenols able to efficiently attenuate ROS-induced oxidative stress and subsequent development of associated diseases. Different nanoformulations utilized for delivery of dietary polyphenols like solid lipid nanoparticles, polymeric nanoparticles, polymeric complex nanoparticles, liposomes, nanocrystals, gold nanoparticles, nanosuspensions, electrospun nanofibers, electro-sprayed nano-particles, and nano-spray dried particles and nano-caseins.[61],[62]
Figure 6: Schematic presentation of different nanocarrier employed for generation of nanopolyphenols, able to efficiently attenuate ROS induced oxidative stress and subsequent development of associated diseases

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Recently, for targeted drug delivery of natural products, Mesoporous silica nanoparticles (MSNs) of different morphology are gaining significant interest due to simple synthesis, significant chemical stability, biocompatibility, more drug loading capacity, and regulated drug release, tunable pore sizes. The safety aspect of MSNs has been supported by data obtained from various in vivo pre-clinical evaluations. These have been reported as an excellent nanocarrier for the stimuli-responsive release of drugs both internally and externally.[63] In a study to generate an integrated dual-responsive nanoplatform, mesoporous melanin-like polydopamine co-formulated with curcumin and silver nanoparticles was produced to study antibacterial and antitumor properties. The generated [email protected]/PDA/Ag efficiently responded to pH and ROS stimuli to release the silver and curcumin. The nanoformulation showed enhanced bactericidal activity and chemotherapeutic ability against drug-resistant cancer cells. The study nicely presented the combinatorial design of natural molecules and silver nanoparticles to control infection and tumors in mice.[64] The cerium oxide nanoparticles synthesized from the proteome of Justicia adhatoda leaf show a significant increase in antioxidant activity and stability.[65] Clinical trials indicate that liposome formulations are found as more effective on pharmacological and pharmacokinetic parameters for the treatment of acute myeloid leukemia, ovarian cancer, breast cancer, hepatitis A, etc., and are one of the most potent, safe, and healthy nanoparticles generated so far.[66] Interestingly, Nanomedicine based on natural molecules like curcumin, camptothecin, paclitaxel, and resveratrol is already in the market and clinic with positive results.[67] Therefore, nanotechnology presents proficient strategies to surmount the pharmacokinetic and biopharmaceutical obstacles during the use of polyphenols [Figure 6].[68]

Nanopolyphenols for neurodegenerative diseases

One of the major limitations of drug delivery in the central nervous system is the blood-brain barrier (BBB) which is a selectively permeable system. Extensive nanotechnology-based studies are being conducted to explore drug delivery to the brain in the form of nanoparticles, nanoliposomes, nano micelles, carbon nanotubes, etc which may prove promising in this direction.[69] Further, combination therapy of dietary antioxidants and nanotechnology is a vast area that remains less explored and may yield novel neuroprotective therapeutic agents.[60] Different nanoformulations including resveratrol, quercetin, etc have been explored that showed mitigating effects on neurodegenerative disorders.[70] Recently, quercetin nanoparticles (QNPs) showed increased bioavailability in a rat model of Alzheimer’s disease. QNPs significantly lowered hippocampal neuronal damage induced due to aluminum chloride (AlCl3) at cellular, subcellular and molecular levels and supported the prophylactic and therapeutic effect of QNPs.[71] Similarly, nanosystems are constructed using microbubbles in combination with focused ultrasound to deliver drugs across the blood-brain barrier in Alzheimer’s disease (AD). Upon exposure to ultrasonic pulses, [email protected] (quercetin-modified sulfur nanoparticles ([email protected]) in microbubbles) gets destroyed immediately thereby increasing the permeability of blood vessels and causing BBB to open slightly and leading to the accumulation of [email protected] in the brain parenchyma. This nanosystem efficiently overcomes the effects of endoplasmic reticulum stress and lowers oxidative stress, neuronal apoptosis, inflammation, and shielded nerve cells thus treating AD efficiently. This study reported a combination of [email protected] with ultrasound as a potential method for treating both neurodegenerative diseases and endoplasmic reticulum stress.[72]

It was observed that the treatment efficacy of neurodegenerative diseases especially Parkinson’s disease, can be enhanced with the use of nanophytomedicine with a specific size of 1–100 nm. Nanosizing of phytobioactive molecules increases their stability and efficiency along with an increase in penetrating ability like ginsenosides (19.9 nm) showed an increase in bioavailability in the rat brain.[73] Recently, colloidal nanoparticles of anti-amyloidogenic small molecules are shown to inhibit the formation of protein aggregate, fragmentation of protein aggregates, and clearance of toxic protein aggregates. Antiamyloidogenic molecules are molecules inhibiting the formation of protein aggregates. Their example includes polyphenols, alkaloids, osmolytes, etc. Since, the presence of protein aggregates is characteristic of some diseases such as Alzheimer’s disease and Parkinson’s disease, the strategy of inhibiting the formation of protein aggregates may prove valuable as a therapeutic strategy for the control of such diseases. In this study, anti-amyloidogenic molecules were transformed into colloidal nanoparticle form which showed 100000 times better performance than its native form. Improved bioavailability, increased brain delivery, and modular binding properties with protein were reported as the reason for enhanced performance. The authors suggested some facts for future designing of colloidal nanoparticles as adjustment of size and surface chemistry of colloidal nanoparticles for selective interaction with protein, design of NP to regulate the intracellular activity for clearance of toxic protein aggregates, and design of NP with controlled multivalency and further selection for the disintegration of protein fibrils. The strategy found as promising for targeting protein aggregate-linked diseases.[74]

In this domain, nanocrystals are highlighted as an efficient way for an oral mode of drug consumption. In a study, quercetin nanocrystals were found more efficient in treating Parkinson-like rat models compared to quercetin alone and showed more distinguished results in behavioral and biochemical experiments. The data supports nano-quercetin as a significant neuroprotection candidate for Parkinson’s disease.[75] Cheng et al, 2013 developed a highly stable nanocurcumin formulation (mean particle size,<80 nm) with significant reproducibility and storage ease. Upon administration of nanocurcumin in the Alzheimer’s disease model Tg2576 mice showed good cue memory and working memory than placebo. Their findings reported the significant potential of prepared Nanocurcumin formulation for Alzheimer’s disease and supported the future development of nanoparticle-based drugs.[76] A preliminary work reported designing of more effective naringin nanoparticle encapsulated in modified PEG 3000 silica based on pegylation effect. The designed NP was able to entrap a higher volume of insoluble drugs and showed enhanced protection against amyloid β-linked oxidative stress-mediated Alzheimer’s disease in primary rat neuronal and glial hippocampal cultures. The mentioned strategy holds remarkable potential as brain delivery therapeutics.[77] The use of different strategies for nanopolyphenol shows a promising realm for neurodegenerative therapeutics as these can cross the major obstacle in neurotargeting of drugs. After the success of this technical strategy in neurodegeneration delivery in in-vitro and animal trials, more human trials are required further to confirm compatibility and potency in the human system.

Nanopolyphenols for cancer

Nanonization by different mechanisms is reported to enhance the valuable activities of natural polyphenols against cancer. Nanoformulations of several molecules like resveratrol, curcumin, quercetin, epigallocatechin-3-gallate, etc found as effective in the control of cancer,[61] and represent a significant approach for targeting tumors.[55] Coumarins naturally show anticancer activities, the effect of nanoencapsulation of chemically synthesized 4-methyl-7-hydroxy coumarin (SC) with poly lactide-co-glycolide acid (PLGA) nanoparticles (nanocoumarin) on the anticancer property was studied. It was observed that the synthesized Nanocoumarin possesses anticancer activities. Based on scanning electronic and atomic force microscopies data, the drug uptake of Nanocoumarin into the melanoma cell line A375 was also found more represent increased drug efficacy. Based on polydispersity index and zeta potential, NC was found a good anticancer agent with negligible cytotoxic effects. The designed NC was found able to cross the blood-brain barrier due to the presence of NC in the brain along with a presence in other tissues.[78] Similarly, Catechin nanoemulsions produced from Oolong tea leaf waste were checked for anticancerous activity. The prepared nanoemulsion significantly inhibited prostate cancer cells DU-145 induced tumor in mice. Nanoemulsion prepared by adding lecithin, Tween 20, and water showed more stability and significant encapsulation efficiency of 83.4%. It was found efficient in lowering the size of mice tumors. The results obtained from the study supported further clinical trials of catechin nanoemulsions.[79]

In the field of breast cancer, a study reported a significant breakthrough in prevention and treatment. The study reported the synthesis of biocompatible and biodegradable EGCG encapsulated chitosan-coated nanoliposomes (CSLIPO-EGCG) with augmented chemopreventive activity, lessened immunogenicity, and adverse effects. The studied nanoliposome showed increased stability of EGCG, controlled drug release, and stimulates apoptosis of cancer cells along with inhibition of cell proliferation. The intracellular content of EGCG obtained was more indicating strong potency of CSLIPO-EGCG for breast cancer treatment than native EGCG.[80] Besides, for oral delivery of molecules with low bioaccessibility, coloaded lipid-based carriers are reported as potential vehicles. Nanostructured lipid carriers (NLCs) upon fabrication for co-loading of curcumin and genistein, were found to enhance the solubility of molecules in simulated intestinal medium (SIM), stability in both SIM and simulated gastric medium. Coloading increased cell growth inhibition of prostate cancer cells.[81]

Among various plant-derived molecules, Resveratrol is a molecule with vast pharmacological potential, Nanonization of resveratrol may add up to its therapeutic activity. The anticancer potential of gelatin encapsulated resveratrol nanoparticles (RSV-GNPs) was studied in NCI-H460 lung cancer cells. The results found showed more antiproliferation activity and increased ROS generation, DNA damage, and apoptosis in cancer cells treated with RSV-GNPs. It showed enhanced bioavailability, increment of cellular uptake sustained release of the drug, and an increase in half-life period than free RSV with no toxicity.[82] The resveratrol-loaded polyethylene glycol-polylactic acid polymer nanoparticles (RSV- PEG-PLA NP) in a model for studying the metabolic and anti-tumor effect in vitro, showed an increase in apoptosis, reduction in both CT26 colon cancer cell number, and colony-forming capacity whereas in vivo administration of RSV-NP to CT26 tumor-bearing mice, showed tumor regression along with increased survival.[83] Thus, Nanotechnology offers multiple opportunities in the field of cancer therapeutics. The promising results obtained with the use of NPs in cancer treatment have shown a ray of new hope and have opened new research dimensions which may help to untag the incurable term used for cancer.

Nanopolyphenols for obesity

In recent years, NPs have been explored for the antiobesity effect. In a study, Nanoemulsion oleoresin capsicum (NOC) upon administration to obese rats significantly lowered body weight and adipose tissue mass. Alteration in multiple gene expression, AMPK activation, and suppression of glycerol-3-phosphate dehydrogenase in white adipose tissue might be the reason behind the antiobesity effect of NOC.[84]

A clinical trial with nano curcumin (NC) on overweight/obese NAFLD patients reported significant findings. NC showed improved glucose indices and decreased HbA1c, TG, TC, LDL, and inflammatory markers.[85] Since overweight and increased oxidative stress are correlated, The antioxidant potential of cerium oxide nanoparticles (nanoceria) was evaluated as a therapeutic strategy for the management of obesity. In 3T3-L1 pre-adipocytes, nanoceria by suppressing transcription of adipogenic genes and hampering triglyceride accumulation drove modulation of adipogenic pathway while in Wistar rats, nanoceria efficiently lowers body weight, levels of insulin, glucose triglyceride, and leptin in plasma. The results supported the anti-adipogenic properties of cerium oxide nanoparticles and reported the promising potential of nanoceria in obesity treatment.[86] To perform targeted delivery of resveratrol nanoparticles to adipose stromal stem cells (ASC), a target peptide was incorporated on the nanoparticle surface; ASC targeted nanoparticles (ATnano). The synthesized ATnano showed enhanced intracellular concentration in primary stromal vascular fraction. It showed increased deposition of resveratrol in white adipose tissue (WAT). The results highlighted the strategy as a significant breakthrough in obesity treatment.[87] Additionally, the antiobesity strategies based on nanotechnology include the betterment of intestinal health, lowering of energy intake, targeting cell abnormalities, maintaining redox balance and elimination of free lipoprotein from blood,[88] antiangiogenesis, the transformation of WAT to brown adipose tissues, and photothermal lipolysis of WATs,[89] which reflects the importance of nano strategies in disease management.

Nanopolyphenols for diabetes

Nanopolyphenols are gaining importance in diabetes research. In this direction, quercetin nanorods (QCNr) showed efficient antioxidant and antidiabetic activities in alloxan-induced diabetic mice. This system efficiently improves lipid peroxidation and protein carbonylation, augmentation of antioxidant enzymes like SOD (Superoxide dismutase), and catalase along with improvement in liver and kidney activities.[90] Despite various techniques, the High-Pressure Homogenization method employed for the preparation of drug-loaded nanosuspensions is more efficient and productive than other methods. Based on this method, preparation of berberine nanosuspension (Ber-NS) composed of Ber and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and administration to streptozotocin-induced diabetic C57BL/6 mice, effectively ameliorates T2D by lowering blood glucose and improvement of lipid metabolism. A significant decrease in body weight and good hypoglycemic and total cholesterol levels was reported.[91] Further, Pluronic nano micelles loaded with curcumin (CURnp) were evaluated for antidiabetic potential using pancreatic tissues. CURnp triggers Pdx-1 and NKx6.1 gene expression and maintains redox balance thereby improving streptozotocin-induced β-cell damage by activating insulin gene expression. An increase of 40% insulin-positive cells proved the antidiabetic potential of CUR-loaded pluronic nanomicelles.[92]

Interestingly, a combination therapy involving coenzyme Q10 and curcumin both encapsulated separately in poly(D, L-lactic-co-glycolic acid)-based nanoparticles upon administration to streptozotocin-induced diabetic rats showed a decrease in the levels of plasma triglycerides and total cholesterol with a concomitant increase of the level of HDL-cholesterol. The data support the potential of nanoparticulate formulations of coenzyme Q10 and curcumin in diabetes management.[93] In a study, ferulic acid encapsulated chitosan nanoparticles (FANPs) were synthesized by the ionotropic gelation process. Upon administration to streptozotocin (STZ) induced diabetic Wistar albino rats, improved hyperglycemic activities with regulated lipid profile. The result marked the potential of encapsulated FANPs in diabetes management and highlighted the strategy useful to avoid the derived hurdles observed during the use of synthetic drugs.[94]

Yucel et al, 2018 developed new RSV-loaded nanoliposomal formulations and incubated them with pancreatic β TC cell-induced with glucose and streptozotocin. The synthesized liposomal formulation showed prolonged antioxidant activity. A significant lowering of glucose levels along with a synchronous increase in insulin levels was observed. The data reported resveratrol nanoliposomes as a novel approach to target diabetes mellitus.[95] Additionally, Resveratrol nanoemulsion (nano-Resv) lowers the level of serum glucose and improves the level of serum insulin in STZ-induced diabetic rats.[96] In a study, individual effects of curcumin nanoparticles (Curc-NP), zinc oxide nanoparticles (ZnO-NP), and curcumin-zinc oxide composite nanoparticles (Curc-ZnO-NP) were evaluated on streptozotocin-induced diabetic rats. Lowering of blood glucose, increased insulin levels, and maintenance of GLUT-2 and glucokinase gene were observed. Besides, Curc-ZnO-NP out of three nanoparticles was found to show the most potent anti-diabetic activities based on histopathological findings.[97] In a double-blind randomized clinical trial, the effect of nano-curcumin(NC) was studied on HbA1C, fasting blood glucose (FBG), and lipid profile in 70 diabetic patients. NC was found to show an HbA1c lowering effect on type-2 diabetes along with a significant lowering of fasting blood glucose, triglyceride, and BMI.[98] In addition to nanopolyphenols, Nanotechnology has helped in diabetes research in diagnostics, monitoring, and treatment.[99]

Undoubtedly, Nanonization has tremendously augmented the therapeutic properties of polyphenols and subsequent improvement in the therapeutic index. Still, there is a shortage of clinical trials on NPs in the field of oxidative stress-generated diseases. In the present scenario, as per data search, capsaicin nanoparticles and nano curcumin was only found to get evaluated under clinical trial. Capsaicin nanoparticles were evaluated on patients with painful diabetic neuropathy whereas 5 clinical trials have been performed with nano curcumin on different disease conditions- Multiple sclerosis (completed), Ankylosing spondylitis (completed), recurrent aphthous ulcer and recurrent aphthous stomatitis (completed), Prostate cancer (active), Metabolic syndrome (completed).[100] Upsurge in the number and frequency of clinical trials are sincerely required to further validate the data. Perhaps, the challenge faced while the clinical translation of nanomedicine is appropriate designing in a way that it remains stable during systemic circulation and shows the controlled release of drugs at the right site. Immunotoxicological studies are required before clinical translation of nanomedicine as nanocarrier is found to modulate immune responses and is left in the body.[67] The use of proper standards and correct controls, and reporting of details during research may resolve difficulties encountered while the development of nanotechnology-based therapeutics.[4]

  Conclusion Top

Nanotechnological advances made in the area of drug discovery and development in terms of nanomaterial-based targeted drug delivery have revolutionized the research. Based on a wide array of experimental evidence including in-vitro, animal trials, and clinical trials favors NPs in treatment strategies for many disease symptoms of oxidative stress origin. Different nano-strategies explored so far have proven the augmentation of pharmacological activities due to improvement not only in the specificity and selectivity of drug delivery to target tissue but in the bioavailability, stability, and intracellular concentration of polyphenols to drive the optimal activity. Despite the observed benefits, more well-controlled clinical studies are of the essence which is sincerely needed to further validate the data.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]


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