Nanotechnology and Natural Products: Plant Bioactive Compounds for Drug Delivery (Volume II)

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 18919

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Guest Editor
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal
Interests: phenolic compounds; immunometabolism; food nanotechnologies; nanoencapsulation; drug delivery systems; biodisponibility; colorectal cancerolic compounds; persimmon; food science; functional foods; biochemistry; haematology; in vitro/in vivo inflammation and cancer models
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Special Issue Information

Dear Colleagues,

Currently, environmental and climate concerns have actively contributed to a growing interest in plant foods, be they exotic or not so well known, or underutilized or even discarded fruits/vegetables, which are all important sources of bioactive compounds with proven health benefits. The use of these bioactive compounds for drug delivery is only now beginning to gain interest at an increasing rate.

However, further studies are necessary in order to clarify mechanisms of action at the cellular, molecular and genetic levels, pharmacokinetics, and toxicokinetics. Pharmaceutical formulations, delivery systems and controlled-release systems have to be duly studied in order to guarantee the efficiency of these plant bioactive compounds.

This Special Issue aims to address this need and how we can be innovative when dealing with natural compounds in the management of health, and how “old” nutrition habits can be encompassed in modern lifestyles through supplementation, as a therapeutic adjuvant, or as an aid to personalized medicine through biopharmaceuticals and nutraceuticals.

New and promising strategies in the area of drug delivery systems that permit bioactive compounds from plants to be more bioavailable and/or even more potent in their health effects, that could improve the state of health in the face of certain diseases with safety, and efficacy, are especially welcome. Formulations with natural products, tested in vitro and in vivo models of chronic inflammatory diseases, cancer, non-communicable diseases (NCDs) in general, and preclinical studies demonstrating the beneficial effect, in which drug-delivery, dose and pharmacokinetics is involved, are encouraged to submit their work.

Authors are invited to submit original research articles and reviews in this important and exciting research field in an effort to envision future drug delivery strategies of natural products.

Dr. Rosa Direito
Guest Editor

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Keywords

  • diet
  • plant foods
  • bioactive compounds
  • phenolic compounds
  • nutrition
  • delivery systems
  • nanoencapsulation
  • supplementation
  • inflammation
  • cancer
  • bioavailability
  • antioxidants
  • safety
  • efficacy
  • biopharmaceuticals
  • pharmacokinetics
  • toxicokinetics

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Published Papers (10 papers)

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Research

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21 pages, 6831 KiB  
Article
Intranasal Nanotransferosomal Gel for Quercetin Brain Targeting: II. Antidepressant Effect in an Experimental Animal Model
by Mohammed H. Elkomy, Fatma I. Abo El-Ela, Randa Mohammed Zaki, Omar A. Alsaidan, Mohammed Elmowafy, Ameeduzzafar Zafar, Khaled Shalaby, Mohamed A. Abdelgawad, Hany A. Omar, Rania Salama and Hussein M. Eid
Pharmaceutics 2023, 15(8), 2095; https://doi.org/10.3390/pharmaceutics15082095 - 7 Aug 2023
Cited by 3 | Viewed by 1283
Abstract
Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Quercetin (QER) demonstrated antidepressant effects in rats exhibiting anxiety and depressive-like behaviors. In an attempt to improve QER’s antidepressant activity, a QER-loaded transferosome (QER-TFS) thermosensitive gel for [...] Read more.
Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Quercetin (QER) demonstrated antidepressant effects in rats exhibiting anxiety and depressive-like behaviors. In an attempt to improve QER’s antidepressant activity, a QER-loaded transferosome (QER-TFS) thermosensitive gel for intranasal administration was formulated and optimized. The therapeutic effectiveness of the optimized formulation was assessed in a depressed rat model by conducting a behavioral analysis. Behavioral study criteria such as immobility, swimming, climbing, sucrose intake, number of crossed lines, rearing, active interaction, and latency to feed were all considerably enhanced by intranasal treatment with the QER-TFS in situ gel in contrast to other formulations. A nasal histopathological study indicated that the QER-TFS thermosensitive gel was safe for the nasal mucosa. An immunohistochemical analysis showed that the animals treated with the QER-TFS thermosensitive gel had the lowest levels of c-fos protein expression, and brain histopathological changes in the depressed rats were alleviated. According to pharmacodynamic, immunohistochemical, and histopathological experiments, the intranasal administration of the QER-TFS thermosensitive gel substantially alleviated depressive symptoms in rats. However, extensive preclinical investigations in higher animal models are needed to anticipate its effectiveness in humans. Full article
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20 pages, 6687 KiB  
Article
Intranasal Nanotransferosomal Gel for Quercetin Brain Targeting: I. Optimization, Characterization, Brain Localization, and Cytotoxic Studies
by Mohammed H. Elkomy, Randa Mohammed Zaki, Omar A. Alsaidan, Mohammed Elmowafy, Ameeduzzafar Zafar, Khaled Shalaby, Mohamed A. Abdelgawad, Fatma I. Abo El-Ela, Mostafa E. Rateb, Ibrahim A. Naguib and Hussein M. Eid
Pharmaceutics 2023, 15(7), 1805; https://doi.org/10.3390/pharmaceutics15071805 - 23 Jun 2023
Cited by 5 | Viewed by 1415
Abstract
Numerous neurological disorders have a pathophysiology that involves an increase in free radical production in the brain. Quercetin (QER) is a nutraceutical compound that shields the brain against oxidative stress-induced neurodegeneration. Nonetheless, its low oral bioavailability diminishes brain delivery. Therefore, the current study [...] Read more.
Numerous neurological disorders have a pathophysiology that involves an increase in free radical production in the brain. Quercetin (QER) is a nutraceutical compound that shields the brain against oxidative stress-induced neurodegeneration. Nonetheless, its low oral bioavailability diminishes brain delivery. Therefore, the current study aimed to formulate QER-loaded transferosomal nanovesicles (QER-TFS) in situ gel for QER brain delivery via the intranasal route. This study explored the impacts of lipid amount, edge activator (EA) amount, and EA type on vesicle diameter, entrapment, and cumulative amount permeated through nasal mucosa (24 h). The optimum formulation was then integrated into a thermosensitive gel after its physical and morphological characteristics were assessed. Assessments of the optimized QER-TFS showed nanometric vesicles (171.4 ± 3.4 nm) with spherical shapes and adequate entrapment efficiency (78.2 ± 2.8%). The results of short-term stability and high zeta potential value (−32.6 ± 1.4 mV) of QER-TFS confirmed their high stability. Compared with the QER solution, the optimized QER-TFS in situ gel formulation exhibited sustained release behavior and augmented nasal mucosa permeability. CT scanning of rat brains demonstrated the buildup of gold nanoparticles (GNPs) in the brains of all treatment groups, with a greater level of GNPs noted in the rats given the transferosomal gel. Additionally, in vitro studies on PCS-200-014 cells revealed minimal cytotoxicity of QER-TFS in situ gel. Based on these results, the developed transferosomal nanovesicles may be a suitable nanocarrier for QER brain targeting through the intranasal route. Full article
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20 pages, 21346 KiB  
Article
CD44-Targeted Lipid Polymer Hybrid Nanoparticles Enhance Anti-Breast Cancer Effect of Cordyceps militaris Extracts
by Jiraphong Suksiriworapong, Nutthachai Pongprasert, Somnuk Bunsupa, Vincenzo Taresco, Valentina Cuzzucoli Crucitti, Thitapa Janurai, Pornpoj Phruttiwanichakun, Krisada Sakchaisri and Amaraporn Wongrakpanich
Pharmaceutics 2023, 15(6), 1771; https://doi.org/10.3390/pharmaceutics15061771 - 20 Jun 2023
Cited by 7 | Viewed by 1970
Abstract
This study aimed to improve the anticancer effect of Cordyceps militaris herbal extract (CME) on breast cancer cells with hyaluronic acid (HYA) surface-decorated lipid polymer hybrid nanoparticles (LPNPs) and evaluate the applicability of a synthesized poly(glycerol adipate) (PGA) polymer for LPNP preparation. Firstly, [...] Read more.
This study aimed to improve the anticancer effect of Cordyceps militaris herbal extract (CME) on breast cancer cells with hyaluronic acid (HYA) surface-decorated lipid polymer hybrid nanoparticles (LPNPs) and evaluate the applicability of a synthesized poly(glycerol adipate) (PGA) polymer for LPNP preparation. Firstly, cholesterol- and vitamin E-grafted PGA polymers (PGA-CH and PGA-VE, respectively) were fabricated, with and without maleimide-ended polyethylene glycol. Subsequently, CME, which contained an active cordycepin equaling 9.89% of its weight, was encapsulated in the LPNPs. The results revealed that the synthesized polymers could be used to prepare CME-loaded LPNPs. The LPNP formulations containing Mal-PEG were decorated with cysteine-grafted HYA via thiol-maleimide reactions. The HYA-decorated PGA-based LPNPs substantially enhanced the anticancer effect of CME against MDA-MB-231 and MCF-7 breast cancer cells by enhancing cellular uptake through CD44 receptor-mediated endocytosis. This study demonstrated the successful targeted delivery of CME to the CD44 receptors of tumor cells by HYA-conjugated PGA-based LPNPs and the new application of synthesized PGA-CH- and PGA-VE-based polymers in LPNP preparation. The developed LPNPs showed promising potential for the targeted delivery of herbal extracts for cancer treatment and clear potential for translation in in vivo experiments. Full article
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15 pages, 3434 KiB  
Article
Nanostructured Lipid Carriers Aimed to the Ocular Delivery of Mangiferin: In Vitro Evidence
by Debora Santonocito, Ignazio Barbagallo, Alfio Distefano, Giuseppe Sferrazzo, Maria Vivero-Lopez, Maria Grazia Sarpietro and Carmelo Puglia
Pharmaceutics 2023, 15(3), 951; https://doi.org/10.3390/pharmaceutics15030951 - 15 Mar 2023
Cited by 1 | Viewed by 1678
Abstract
Although mangiferin (MGN) is a natural antioxidant that could be a good candidate for the treatment of ocular diseases, its use in ophthalmology is strongly compromised due to its high lipophilicity. Its encapsulation in nanostructured lipid carriers (NLC) seems to be an interesting [...] Read more.
Although mangiferin (MGN) is a natural antioxidant that could be a good candidate for the treatment of ocular diseases, its use in ophthalmology is strongly compromised due to its high lipophilicity. Its encapsulation in nanostructured lipid carriers (NLC) seems to be an interesting strategy for improving its ocular bioavailability. As reported in our previous work, MGN–NLC showed high ocular compatibility and fulfilled the nanotechnological requirements needed for ocular delivery. The aim of the present work was to investigate, in vitro and ex vivo, the capability of MGN–NLC to act as a potential drug delivery system for MGN ocular administration. The data obtained in vitro on arising retinal pigment epithelium cells (ARPE-19) did not show cytotoxic effects for blank NLC and MGN–NLC; likewise, MGN–NLC showed the maintenance of the antioxidant role of MGN by mitigating ROS (Reactive Oxygen Species) formation and GSH (glutathione) depletion induced by H2O2. In addition, the capacity of MGN-released to permeate through and accumulate into the ocular tissues was confirmed ex vivo using bovine corneas. Finally, the NLC suspension has been formulated as a freeze-dried powder using mannitol at a concentration of 3% (w/v) in order to optimize its storage for long periods of time. All this evidence suggests a potential application of MGN–NLC in the treatment of oxidative stress-related ocular diseases. Full article
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19 pages, 2826 KiB  
Article
Potential Use of Quercus dalechampii Ten. and Q. frainetto Ten. Barks Extracts as Antimicrobial, Enzyme Inhibitory, Antioxidant and Cytotoxic Agents
by Corneliu Tanase, Mihai Babotă, Adrian Nișca, Alexandru Nicolescu, Ruxandra Ștefănescu, Andrei Mocan, Lenard Farczadi, Anca Delia Mare, Cristina Nicoleta Ciurea and Adrian Man
Pharmaceutics 2023, 15(2), 343; https://doi.org/10.3390/pharmaceutics15020343 - 19 Jan 2023
Cited by 4 | Viewed by 1483
Abstract
The bark resulted as a by-product after different Quercus sp. processing is a valuable alternative source of phenolic compounds (mainly tannins). Hence, the focus of the present work was to obtain eight extracts from the rhytidome of the less-studied Q. dalechampii and Q. [...] Read more.
The bark resulted as a by-product after different Quercus sp. processing is a valuable alternative source of phenolic compounds (mainly tannins). Hence, the focus of the present work was to obtain eight extracts from the rhytidome of the less-studied Q. dalechampii and Q. frainetto and characterize them in terms of chemical and bioactive profiles. Ultrasound and microwave-assisted extraction methods were used for the preparation of the extracts. Total phenolic and tannin contents were assessed through classic spectrophotometric methods, while several individual phenolic compounds were identified and quantified using UPLC-PDA. Antioxidant, enzyme-inhibitory, antibacterial, and cytotoxic activities were tested using in vitro assays; additionally being evaluated was the ability of the extracts to inhibit the adherence of MRSA to suture wires. The UPLC analysis confirmed the presence of gallic acid, catechin, taxifolin, vanillic acid, epicatechin, and caffeic acid. The results showed that tested extracts were able to exert cytotoxic effects, at 6% and 3% concentrations, on confluent cells. The tested solutions inhibit α-glucosidase activity and the antibacterial potential suggested a mild to moderate effect against the Gram-positive strains. Overall, the obtained results revealed rich phenolic and tannin contents for the extracts obtained from both species through microwave-assisted extraction, probably responsible for their mild antibacterial and cytotoxic effects. Full article
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21 pages, 3389 KiB  
Article
Protein Biocargo and Anti-Inflammatory Effect of Tomato Fruit-Derived Nanovesicles Separated by Density Gradient Ultracentrifugation and Loaded with Curcumin
by Ramila Mammadova, Serena Maggio, Immacolata Fiume, Ramesh Bokka, Maneea Moubarak, Gabriella Gellén, Gitta Schlosser, Giorgia Adamo, Antonella Bongiovanni, Francesco Trepiccione, Michele Guescini and Gabriella Pocsfalvi
Pharmaceutics 2023, 15(2), 333; https://doi.org/10.3390/pharmaceutics15020333 - 19 Jan 2023
Cited by 6 | Viewed by 2304
Abstract
Plant-derived nanovesicles (PDNVs) have become attractive alternatives to mammalian cell-derived extracellular vesicles (EVs) both as therapeutic approaches and drug-delivery vehicles. In this study, we isolated tomato fruit-derived NVs and separated them by the iodixanol density gradient ultracentrifugation (DGUC) into twelve fractions. Three visible [...] Read more.
Plant-derived nanovesicles (PDNVs) have become attractive alternatives to mammalian cell-derived extracellular vesicles (EVs) both as therapeutic approaches and drug-delivery vehicles. In this study, we isolated tomato fruit-derived NVs and separated them by the iodixanol density gradient ultracentrifugation (DGUC) into twelve fractions. Three visible bands were observed at densities 1.064 ± 0.007 g/mL, 1.103 ± 0.006 g/mL and 1.122 ± 0.012 g/mL. Crude tomato PDNVs and DGUC fractions were characterized by particle size-distribution, concentration, lipid and protein contents as well as protein composition using mass spectrometry-based proteomics. Cytotoxicity and anti-inflammatory activity of the DGUC fractions associated to these bands were assessed in the lipopolysaccharide (LPS)-stimulated human monocytic THP-1 cell culture. The middle and the low-density visible DGUC fractions of tomato PDNVs showed a significant reduction in LPS-induced inflammatory IL-1β cytokine mRNA production. Functional analysis of proteins identified in these fractions reveals the presence of 14-3-3 proteins, endoplasmic reticulum luminal binding proteins and GTP binding proteins associated to gene ontology (GO) term GO:0050794 and the regulation of several cellular processes including inflammation. The most abundant middle-density DGUC fraction was loaded with curcumin using direct loading, sonication and extrusion methods and anti-inflammatory activity was compared. The highest entrapment efficiency and drug loading capacity was obtained by direct loading. Curcumin loaded by sonication increased the basal anti-inflammatory activity of tomato PDNVs. Full article
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19 pages, 3428 KiB  
Article
Phenylboronic Acid-Grafted Chitosan Nanocapsules for Effective Delivery and Controllable Release of Natural Antioxidants: Olive Oil and Hydroxytyrosol
by Omnia M. Hendawy, Mohammad M. Al-Sanea, Rehab M. Elbargisy, Hidayat Ur Rahman, Ahmed A. B. Mohamed, Islam Kamal, Reda F. M. Elshaarawy, Amgad I. M. Khedr and Wesam Abd El-Fattah
Pharmaceutics 2023, 15(1), 81; https://doi.org/10.3390/pharmaceutics15010081 - 27 Dec 2022
Cited by 6 | Viewed by 1963
Abstract
Olives and virgin olive oil (VOO) are a staple of Mediterranean diets and are rich in several beneficial phenolic compounds, including hydroxytyrosol (HT). Therefore, VOO was extracted from Koroneiki olive fruits, and its volatile as well as phenolic components were identified. Meanwhile, in [...] Read more.
Olives and virgin olive oil (VOO) are a staple of Mediterranean diets and are rich in several beneficial phenolic compounds, including hydroxytyrosol (HT). Therefore, VOO was extracted from Koroneiki olive fruits, and its volatile as well as phenolic components were identified. Meanwhile, in order to upgrade the pharmaceutical capabilities of VOO and HT, a new conjugate phenylboronic acid-chitosan nanoparticles (PBA-CSNPs, NF-1) was fabricated and applied as nanocapsules for implanting high loading and efficient delivery of VOO and HT nanoformulations (NF-2 and NF-3). Due to the H-bonding interactions and boronate ester formation between the hydroxyl groups of the phenolic content of VOO or HT and the PBA groups in the nanocapsules (NF-1), VOO and HT were successfully loaded into the PBA-CSNPs nanocapsules with high loading contents and encapsulation efficacies. The NF-2 and NF-3 nanoformulations demonstrated physicochemical stability, as revealed by their respective zeta potential values, and pH-triggered drug release characteristics. The in vitro studies demonstrated that the nascent nanocapsules were almost completely nontoxic to both healthy and cancer cells, whereas VOO-loaded (NF-2) and HT-loaded nanocapsules (NF-3) showed efficient anti-breast cancer efficiencies. In addition, the antimicrobial and antioxidant potentials of VOO and HT were significantly improved after nanoencapsulation. Full article
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Review

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26 pages, 3999 KiB  
Review
Plant-Derived Bioactive Compounds: Exploring Neuroprotective, Metabolic, and Hepatoprotective Effects for Health Promotion and Disease Prevention
by Rosa Direito, Sandra Maria Barbalho, Bruno Sepodes and Maria Eduardo Figueira
Pharmaceutics 2024, 16(5), 577; https://doi.org/10.3390/pharmaceutics16050577 - 24 Apr 2024
Viewed by 868
Abstract
There is a growing trend among consumers to seek out natural foods and products with natural ingredients. This shift in consumer preferences had a direct impact on both food and pharmaceutical industries, leading to a focus of scientific research and commercial efforts to [...] Read more.
There is a growing trend among consumers to seek out natural foods and products with natural ingredients. This shift in consumer preferences had a direct impact on both food and pharmaceutical industries, leading to a focus of scientific research and commercial efforts to meet these new demands. The aim of this work is to review recent available scientific data on foods of interest, such as the artichoke, gooseberry, and polygonoideae plants, as well as olive oil and red raspberries. Interestingly, the urgency of solutions to the climate change emergency has brought new attention to by-products of grapevine bunch stem and cane, which have been found to contain bioactive compounds with potential health benefits. There is a pressing need for a faster process of translating scientific knowledge from the laboratory to real-world applications, especially in the face of the increasing societal burden associated with non-communicable diseases (NCDs), environmental crises, the post-pandemic world, and ongoing violent conflicts around the world. Full article
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37 pages, 1354 KiB  
Review
Nanotechnology-Based Topical Delivery of Natural Products for the Management of Atopic Dermatitis
by Mário Pedro Marques, Carla Varela, Laura Mendonça and Célia Cabral
Pharmaceutics 2023, 15(6), 1724; https://doi.org/10.3390/pharmaceutics15061724 - 14 Jun 2023
Cited by 4 | Viewed by 2323
Abstract
Atopic dermatitis (AD) is a chronic eczematous inflammatory disease that may arise from environmental, genetic, and immunological factors. Despite the efficacy of current treatment options such as corticosteroids, such approaches are mainly focused on symptom relief and may present certain undesirable side effects. [...] Read more.
Atopic dermatitis (AD) is a chronic eczematous inflammatory disease that may arise from environmental, genetic, and immunological factors. Despite the efficacy of current treatment options such as corticosteroids, such approaches are mainly focused on symptom relief and may present certain undesirable side effects. In recent years, isolated natural compounds, oils, mixtures, and/or extracts have gained scientific attention because of their high efficiency and moderate to low toxicity. Despite their promising therapeutic effects, the applicability of such natural healthcare solutions is somewhat limited by their instability, poor solubility, and low bioavailability. Therefore, novel nanoformulation-based systems have been designed to overcome these limitations, thus enhancing the therapeutic potential, by promoting the capacity of these natural drugs to properly exert their action in AD-like skin lesions. To the best of our knowledge, this is the first literature review that has focused on summarizing recent nanoformulation-based solutions loaded with natural ingredients, specifically for the management of AD. We suggest that future studies should focus on robust clinical trials that may confirm the safety and effectiveness of such natural-based nanosystems, thus paving the way for more reliable AD treatments. Full article
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19 pages, 2980 KiB  
Review
Tocotrienol in the Treatment of Topical Wounds: Recent Updates
by Anroop B. Nair, Bapi Gorain, Manisha Pandey, Shery Jacob, Pottathil Shinu, Bandar Aldhubiab, Rashed M. Almuqbil, Heba S. Elsewedy and Mohamed A. Morsy
Pharmaceutics 2022, 14(11), 2479; https://doi.org/10.3390/pharmaceutics14112479 - 16 Nov 2022
Cited by 1 | Viewed by 2485
Abstract
Healing wounds is an important attempt to keep the internal higher organs safe. Complications in topical wound healing may lead to the formation of scars, which can affect the patient’s quality of life. Although several approaches are ongoing in parallel in the exploration [...] Read more.
Healing wounds is an important attempt to keep the internal higher organs safe. Complications in topical wound healing may lead to the formation of scars, which can affect the patient’s quality of life. Although several approaches are ongoing in parallel in the exploration of natural compounds via advanced delivery, in this article, an attempt has been made to highlight tocotrienol. Tocotrienol is a natural form of vitamin E and has shown its potential in certain pharmacological activities better than tocopherol. Its antioxidant, anti-inflammatory, cell signal-mediating effects, angiogenic properties, management of scar, and promotion of wound environment with essential factors have shown potential in the management of topical wound healing. Therefore, this review has aimed to focus on recent advances in topical wound healing through the application of tocotrienols. Challenges in delivering tocotrienols to the topical wound due to its large molecular weight and higher logP have also been explored using nanotechnological-based carriers, which has made tocotrienol a potential tool to facilitate the closure of wounds. Exploration of tocotrienol has also been made in human volunteers for biopsy wounds; however, the results are yet to be reported. Overall, based on the current findings in the literature, it could be inferred that tocotrienol would be a viable alternative to the existing wound dressing components for the management of topical wounds. Full article
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