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Abstract

Fungal infections, ranging from mild superficial conditions to severe systematic diseases, present a significant global health challenge, exacerbated by the rise of drug resistant strains. In response, there is growing interest in natural antifungal agents derived from traditional medicine, where plant based remedies have long been used to treat infections. This review traces the journey of these natural agents from their origins in folk remedies to their development into modern therapeutic drugs. We explore the efficacy of various natural compounds, their mechanicm of action, and their potential advantages over synthetic process, including standardization, clinical validation and regulatory hurdles. By examining both the historical significance and future potential of natural antifungal agents, this article undercomes their roles in shaping more sustainable and effective treatment for fungal infections in modern therapeutics.

Keywords

Antifungal, Tea tree oil, Turmeric, Terpinen-4-ol, Curcumin, Turmeric oil

Introduction

The search of effective antifungal agents has a long and diverse history, deeply rooted in traditional medicine. Across centuries, natural remedies sourced from plants, fungi, and microorganism have played a critical role in treating fungal infections, particularly in regions with limited access to modern pharmaceuticals. As fungal infections have become more prevalent and resistant to current treatments, there has been a renewed scientific interest in revisiting these folk remedies, some of which have been successfully developed into modern therapeutics. Fungal infections pose a significant global health challenge, affecting millions of individuals, particularly those with compromised immune systems. Despite advantages in antifungal therapy, many of the currently available treatments are hindered by limitations such as toxicity, drug resistance and narrow-spectrum activity. This has underscored the urgent need for novel antifungal agents with enhanced efficacy and safety profiles. Natural products have become a rich source of new drug leads due to their structural diversity and biological activities. Historically, compounds derived from natural sources such as polyenes, azoles and echinocandins have revolutionized antifungal therapy, exemplifying the successful translation of traditional knowledge into modern pharmacology. This study investigates the antifungal properties of two plant-based natural compounds, Tea tree oil and Turmeric, exploring their potential as effective antifungal agents.

TEA TREE OIL

Historical overview:

The name Tea tree is used for several plants, mostly from Australia and Newzealand. The use of the name probably originated from Captain James Cook’s description of one of these shrubs that he used to make an infusion to drink in place of tea.[2] Tea tree oil was first extracted from Melaleuca alterifolia in Australia, and this species remains the most important commercially. The commercial Tea tree oil industry originated in the 1920’s when Australian chemist Arthur Penfold investigated the business potential of a number of native extracted oils. In 1970’s and 1980’s commercial plantations began to produce large quantities of Tea tree oil from Melaleuca alternifolia.[3]

Botanical Identity:[4]

Melaleuca alternifolia, commonly known as Tea tree is a species of tree or tall shrub in the Myrtle family, Myrtaceae. Endemic to Australia, it occurs in Southeast Queensland and the north coast and adjacent ranges of new South wales where it grows along streams and on swampy flats, and is often the dominant species where it occurs. It can grow to about 7metre with a bushy crown and whitish, papery bark. The leaves are arranged alternately, sometimes scattered or whorled. The leaves are smooth, soft, linear in shape, 10-35mm long and 1mm wide. The flowers occur in white or cream-coloured masses of spikes 3-5cm long over a short period, mostly spring to early summer. The small, woody, cup-shaped fruit, 2-3mm diameter are scattered along the branches.

       
            fig 1.png
       

Chemical composition of Tea tree oil:[5]

Tea tree oil is an essential oil derived mainly from the Australian native plant Melaleuca Alternifolia via stream distillation of the leaves and terminal branches.

    • Terpinen-4-ol ( 41.49% )
    • ?-terpinene ( 20.55% )
    • ?-terpinene ( 9.59% )
    • ?-terpineol ( 4.42% )
    • ?-pinene ( 4.4% )
    • p-cymene ( 3.66% )
    • Terpinolene ( 3.18% )
    • 1,8-cineole ( 2.15% )
    • Limonene ( 1.78% )
    • Aromadendrene ( 1.38% )
    • Caryophyllene oxide ( 0.76% )
    • Myrcene ( 0.72% )

Extraction of Tea tree oil:[6]

Tea tree oil is extracted by steam distillation of the leaves and terminal branches of Melaleuca Alternifolia. Once condensed, the clear to pale yellow oil is obtained and separated from the aqueous distillate. The yield of oil is typically 1-2% of wet plant material weight. Supercritical fluid extraction overcomes the drawbacks associated with steam distillation process like loss of components due to thermal degradation, hydrolysis or volatilization. On the other hand, supercritical fluid extraction is non-toxic and cheap involving little no organic solvents, safe extraction of thermolabile compounds.

       
            fig 2.png
       

Reason for the Anti-Fungal effects of Tea tree oil:

The major component of Tea tree oil, Terpinen-4-ol, which is extracted from leaves of Melaleuca alternifolia, has been found to have several medicinal effects as an anti-inflammatory, anti-bacterial, onychomycosis, candidiasis, clearance of bronchial congestion; effective in asthma, coughs, sinusitis, whooping cough, tuberculosis, antifungal and an anticancer activity in human melanoma cell lines (M14) as well as in lung cancer cells.

Invitro evaluation of Tea tree oil:[7]

Broth microdilution assay:

Broth microdilution assay were performed according to National Committee for Clinical Laboratory Standards (NCCLS) methods (NCCLS 1997, 1998) with minor modifications. Briefly, doubling dilutions of components, with final concentrations ranging from 8-0.002% (v/v) were prepared in 96-well microtitre trays (Becton Dickinson Labware, Franklin Lakes, NJ, USA). Tween 80 (Sigma) was included at a final concentration of 0.001% (v/v) to enhance the solubility of each component or Tea tree oil. The activity of Terpinen-4-ol, terpinolene, 1,8-cineole, ?-terpinene, ?-terpinene, p-cymene, ?-terpineol and ?-myrcene against Candida albicans ATCC 10231 was also determined with a final concentration of 0.1% Tween 80 to ascertain whether an increased concentration of surfactant significantly influenced results. The results obtained for Terpinolene were considerably lower with 0.1% Tween 80, with an MIC of 1.0% and MFC of 2.0%, compared with values of  >8% obtained with 0.001% tween.

Table: In vitro activity of Tea tree oil (% v/v) against fungi, determined by broth microdilution method.

       
            fig 3.jpg
       

Present scenario of usage of Tea tree oil:[6]

Burners and vaporizers:

In vapour therapy, Tea tree oil helps with colds, sinusitis, bronchitis and any other respiratory ailment and is also of use to help the mind cope after shock.

Blended massage oil in the bath:

As a blended massage oil or diluted in the bath, Tea tree oil helps with all respiratory ailments, as well as arthritis, colds, dermatitis, skin infections, scalp disorders, sinusitis, viral infexctions, nettle rash, babies colds and coughs, bronchitis, as well as for sweaty feet.

In wash or applied neat:

When it is added to the water for washing it has great value to treat abscesses, bed sores, acne, boils, lice, dandruff, wounds, as well as animal or human bites and can also be applied neat on problem areas with a cotton bud. For lice- apply neat onto the scalp- leave for 40 minutes and wash the hair. This must be repeated every second day for 12 days. Fungal outbreaks such as athlete’s foot and nail infections (paronychia) as well as vaginal thrush and cradle cap can be treated with frequent direct application of a 2.5% dilution of Tea tree oil.

Mouthwash:

The Tea tree oil can be used as a mouthwash for gum infections, mouth ulcers, throat infections and tonsillitis, while garlic eaters believe that it reduces the smell of garlic on the breath.

Cream or lotion:

When Tea tree oil is blended into a cream or lotion and applied to the skin, it will help to clear up any fungal, bacterial as well as viral infections – and can therefore be used for a variety of problems- ranging from boils, abscesses, acne, bite wounds from animals and humans (although a medical practitioner must also be consulted), dandruff and other scalp disorders and is also effective to help sort out bed sores, diaper rash or any other rashes. There is the death of E.coli, Proteus mirabilis, Staphylococcus aureus and Pseudomonas aeruginosa after exposure to a mixture of Tea tree oil and Jojoba oil. The Tea tree oil has the ability to control the growth of five bacteria Bacillus subtilis, Escherichia coli, Micrococcus roseus, Sarcina luteus and Serratia marcescens.

TURMERIC

Historical overview:[8]

Turmeric is an integral part of Indian’s culture. It is used as an ingredient in many dishes. It is used in the composition of many traditional remedies. Turmeric possess Anti-inflammatory, Anti-mutagenic, Anti-microbial, Anti-oxidant and Anti-cancer properties.

Botanical identity:[8]

The Botanical name of Turmeric is Curcuma longa and it is a flowering plant of the Ginger family Zingiberaceae. It is a Rhizomatous, herbaceous and perennial plant. It reaches upto the height of 1metre tall. The leaves are arranged in alternate manner in two rows. The leaf of the plant consists of Leaf sheath, petiole and Leaf blade. A false stem is formed from leaf sheaths.
        
            fig 3.png
       

Chemical Composition:[8]

There are around 110 species of Curcuma longa are present. From these, nearly 20 species have been studied phytochemically. Curcuma longa is the most chemically investigated species of Curcuma. Till date, atleast 235 compounds, primarily phenolic compounds and terpenoids have been identified, including diaryl heptanoids ( commonly known as curcuminoids ), diaryl pentanoids, monoterpenes, sesquiterpenes, diterpenes, triterpenes, alkaloid and sterols.

Components of Rhizome oil obtained by Conventional hydrodistillation of Curcuma longa:[9]

  • ar-turmerone (31.7%)
  • ?-turmerone (12.9%)
  • ?-turmerone (12.0%)
  • (z)- ?-ocimene (5.5%)

Components of Leaf oil obtained by Conventional hydrodistillation of Curcuma longa:[9]

  • ?-phellandrene (9.1%)
  • Terpinolene (8.8%)
  • 1,8-cineole  (7.3%)
  • Undecanol (7.1%)
  • p-cymene (5.5%)

Chemical composition of Ethanolic extract of Curcuma longa:[10]

Coumaric acid

Calebin-A

Bis demethoxy curcumin (curcuminoids) [in both keto and enol forms]

Demethoxy curcumin [in both keto and enol forms]

Curcumin [in both keto and enol forms]

Usage of Turmeric during Ancient times:[8]

Since Ancient times, inhaling of fumes from burning of turmeric is used to reduce congestion. Turmric juice was used to heal wounds. Turmeric paste was applied to all sorts of skin conditions like Small pox, Chicken pox, Blemishes and Shingles. Turmeric has a long history of medicinak use in South Asia and is cited in Sanskrit medical treatises and widely used in Ayurvedic and Unani systems. Susrutas’ Ayurvedic compendium, dating to 250 B.C., recommends an ointment containing Turmeric to relieve the effects of poisoned food. Chinese are using Turmeric as medicine especially for spleen, stomach and liver medicines. Turmeric is extensively used in Ayurveda, Unani, Siddha medicine as home remedy for various diseases.

       
            fig 4.png
       

Reason for Antifungal activity of Turmeric:

Curcumin and Turmeric oil exert Antifungal effect against two phytophagous Fungi namely Fusarium solani and Helminthosporium oryzae. Turmeric oil exhibited the most effective antifungal activity of Fusarium solani and Helminthosporium oryzae. Curcumic is a high potential photosensitizer compound for Fungicidal photodynamic therapy especially against Candida species.

Synergestic activity of curcumin with existing Fungicides:[11]

Azole derivatives: Voriconazole, Itraconazole, Ketoconazole, Miconazole, Fluconazole.

Polyene derivatives: Amphotericin, Nystatin.

Evaluation of Curcumin Antifungal activity:[12]

The Evaluation of Curcumin antifungal activity against 23 fungi strains of clinical interest are given below.

Table: MICs of Curcumin that completely inhibited the growth of human-pathogenic fungi.

       
            fig 5.png
       

Here, Curcumin was tested in the range of 0.5-256 mg/L and Fluconazole (0.06-64 mg/L) was included as a positive control. The MIC values correspond to the lowest concentrations that did not allow for the detection of any visual fungal growth. Candida species isolates were exposed to curcumin at its MIC value for 1 hour and were then incubated with BEC for another 1 hour. The assay with Candida parapsilosis was carried out with 256 mg/L Curcumin since its MIC value was not determined. The number of yeast cells that adhered to BEC was quantified by light microscopy (×400 magnification) from 50 randomly choosen BEC.

The results indicate that the MICs of Curcumin that completely abolished the growth of fungi strains are shown in the table. P.brasiliensis isolates were the most susceptible to Curcumin. Curcumin was 32-fold more potent than Fluconazole in the inhibition of P.brasiliensis MG05 growth. Curcumin effect on P.brasiliensis 17 was roughly the same as that of Fluconazole. Curcumin (32mg/L) was able to inhibit the growth of Candida neoformans and the clinical isolates of candida dubliniensis (cd22 and cd28). The growth of remaining fungi isolates was only affected by curcumin at concentrations >256mg/L.

       
            fig 6.jpg
       

Figure: Effect of Curcumin on the adhesion of Candida species to BEC. Percentage of cell adhesion inhibition (a). The results obtained with curcumin were significantly different from those obtained with fluconazole (P<0>[13]

Present scenario of usage of Turmeric:[8]

The United States Food and Drug Administration has approved Curcuminoids as “Generally Recognized as Safe” (GRAS). Also clinical trials have shown its good tolerability and safety profiles for Human beings even at doses between 4000 and 8000 mg/day and of doses upto 12000 mg/day of 95% concentration of curcumin, bisdemethoxy curcumin and demethoxy curcumin. It has been shown that Turmeric has a wide range of biological activities such as anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-mutagenic, anti-coagulant, anti-fertility, anti-diabetic, anti-bacterial, anti-fungal, anti-protozoal, anti-viral, anti-fibrotic, anti-venin, anti-ulcer, hypotensive and hypocholesteremic activities. Curcumin present in Turmeric inhibits human sperm motility and also has the potential for the development of a novel intravaginal contraceptive.

Attempts to manage Bioavailability and pharmacokinetics of Curcumin formulation:[14,15]

The main limitation of the use of Curcumin-based formulations is its poor solubility and fast metabolism. Therefore inorder to increase its solubility, stability and pharmacological activities, study on chemically modified Curcumin derivatives as well as improved formulations and delivery systems should be studied to achieve its therapeutic effects. Nano-carriers like Curcumin-loaded PLGA ( poly lactide-co-glycolide ) and Curcumin nanoparticle formulation lead to better bioavailability as well as increased cellular uptake compared to Curcumin were reported. Another study revealed that the heat-extracted Curcumin elevated the solubility of curcumin 12-fold without significant disintegration due to heat treatment.

Nanoparticles:

Nanoparticles encapsulating Curcumin have been prepared by the Emulsion thechnique. This leads to a 9-fold increase in Curcumin oral bioavailability as compared to curcumin administered with piperine.

Micelles:

Injectable Curcumin-loaded poly(Ethylene-oxide)-b-(?-caprolactone) micelles for controlled delivery of Curcumin confirmed that Curcumin in this form retained its cytotoxicity in Mouse melanoma.

Phospholipid-based delivery systems:

Complexation of Curcumin with phosphatidyl choline resulted in enhanced bioavailability, improved pharmacokinetics and increased hepatoprotective activity as compared to plain mixtures of Curcumin and phosphatidyl choline.

Liposomes: 

Liposomal Curcumin has a higher stability than free curcumin in phosphate buffer saline, human blood and plasma. Novel liposomal delivery systems enhance stability, bioavailability and cellular uptake of Curcumin.

CONCLUSION:

In this review, we aim to highlight the burgeoning recognition that plants are a rich source of anti-fungal natural products, with a focus on elucidating their mechanisms of action and exploring the exciting opportunities they present for anti-fungal drug discovery.

Tea tree oil- Terpinen-4-ol, the primary constituent of Tea tree oil, has been shown to be a highly effective antifungal agent, inhibiting the growth of various fungal strains. Notably, its potency surpasses that of several synthetic drugs, making it a promising natural alternative for antifungal therapy.

Turmeric- As we previously discussed, Curcumin, a key component of Turmeric, has been shown to be 32 times more effective than Fluconazole in inhibiting the growth of the fungus P.brasiliensis. Curcumin’s antifungal prowess extends beyond P.brasiliensis, as it effectively inhibits the growth of various fungal strains, outperforming numerous synthetic drugs with its potent efficacy in treating a range of fungal infections. Since ancient times, various natural products like Tea tree oil and Turmeric have been used to treat fungal infections due to their antifungal properties. Even today, numerous plants with therapeutic activities remain untapped. It is crucial to identify plants with potent antifungal properties and harness their potential for drug development, ultimately leading to the creation of effective antifungal treatments.

ACKNOWLEDGEMENT:

The Authors wish to thank Sakthi Arul Thiru Amma and Thirumathi Amma ACMEC Trust, for providing facilities to do the work in successful manner. We are grateful to thank our Dean Research and Director Academic Prof. Dr. T. Vetrichelvan for the kind support and encouraging for the completion of work.

REFERENCES

  1. Haung M.Y., Kao,M.C., and Tsai. Y.L Natural compounds with anti-fungal activity 2020.
  2. Melaleuca alternifolia, The University of Arizona, Retrieved June 23, 2023.
  3. C F Carson, K A Hammer, T V Riley, Melaleuca alternifolia (Tea Tree) Oil: a Review of Antimicrobial and Other Medicinal Properties 2006
  4. Holliday, Ivan, Melaleucas: a field and garden guide ( 2nd edition ) 2004.
  5. Alberto Elmi, Domenico Ventrella, Francesca Barone, Giacomo Carnevali, Gianfranco Filippini, Annamaria Pisi, Stefania Benvenuti, Maurizio Scozzoli and Maria Laura Bacci, In Vitro Effects of Tea Tree Oil (Melaleuca Alternifolia Essential Oil) and its Principal Component Terpinen-4-ol on Swine Spermatozoa 2019.
  6. Sunita Lahkar, Malay Kumar Das, Sudarshana Bora An Overview on Tea Tree (Melaleuca Alternifolia) Oil 2013.
  7. K.A. Hammer, C.F. Carson1 and T.V. Riley Antifungal activity of the components of Melaleuca alternifolia (tea tree) oil 2003.
  8. Amanjot Kaur, Historical background of usage of turmeric: A review 2018.
  9. Awasthi PK, Dixit SC, Chemical Composition of Curcuma longa leaves and Rhizome oil from the plains      of Northern India 2009.
  10. Huan Wu, Zhihao Liu, Yaqiong, Boyan Gao, Yanfang Li, Xiaohua He, Jianghao Sun, Uyory Choe, Pei Chen, Ryan A. Blaustein and Liangli Yu, Chemical composition of Turmeric (C.longa L.) Ethanol extract and its Antimicrobial activities and Free Radical scavenging capacities 2024.
  11. Soheil Zorofchian Moghadamtousi, Habsah Abdul Kadir, Pouya Hassandarvish, Hassan Tajik, Sazaly Abubakar, Keivan Zandi, A review on antibacterial, antiviral, and antifungal activity of curcumin 2014.
  12. C. V. B. Martins, D. L. da Silva, A. T. M. Neres, T. F. F. Magalhaes, G. A. Watanabe,L. V. Modolo, A. A. Sabino, A . de Fatima and M. A. de Resende, Curcumin as a promising antifungal of clinical interest 2008.
  13. Al-Tawfiq JA, Wools KK. Disseminated sporotrichosis and Sporothrix schenckii fungemia as the initial presentation of human immunodeficiency virus infection 1998.
  14. Grzegorz Grynkiewicz and Piotr slifirski, Curcumin and Curcuminoids in quest for Medicinal status 2012.
  15. Y.Wang, Z. Lu, H.Wu, and F. Lv, “Study on the antibiotic activity of microcapsule curcumin against foodborne pathogens 2009.

Reference

  1. Haung M.Y., Kao,M.C., and Tsai. Y.L Natural compounds with anti-fungal activity 2020.
  2. Melaleuca alternifolia, The University of Arizona, Retrieved June 23, 2023.
  3. C F Carson, K A Hammer, T V Riley, Melaleuca alternifolia (Tea Tree) Oil: a Review of Antimicrobial and Other Medicinal Properties 2006
  4. Holliday, Ivan, Melaleucas: a field and garden guide ( 2nd edition ) 2004.
  5. Alberto Elmi, Domenico Ventrella, Francesca Barone, Giacomo Carnevali, Gianfranco Filippini, Annamaria Pisi, Stefania Benvenuti, Maurizio Scozzoli and Maria Laura Bacci, In Vitro Effects of Tea Tree Oil (Melaleuca Alternifolia Essential Oil) and its Principal Component Terpinen-4-ol on Swine Spermatozoa 2019.
  6. Sunita Lahkar, Malay Kumar Das, Sudarshana Bora An Overview on Tea Tree (Melaleuca Alternifolia) Oil 2013.
  7. K.A. Hammer, C.F. Carson1 and T.V. Riley Antifungal activity of the components of Melaleuca alternifolia (tea tree) oil 2003.
  8. Amanjot Kaur, Historical background of usage of turmeric: A review 2018.
  9. Awasthi PK, Dixit SC, Chemical Composition of Curcuma longa leaves and Rhizome oil from the plains      of Northern India 2009.
  10. Huan Wu, Zhihao Liu, Yaqiong, Boyan Gao, Yanfang Li, Xiaohua He, Jianghao Sun, Uyory Choe, Pei Chen, Ryan A. Blaustein and Liangli Yu, Chemical composition of Turmeric (C.longa L.) Ethanol extract and its Antimicrobial activities and Free Radical scavenging capacities 2024.
  11. Soheil Zorofchian Moghadamtousi, Habsah Abdul Kadir, Pouya Hassandarvish, Hassan Tajik, Sazaly Abubakar, Keivan Zandi, A review on antibacterial, antiviral, and antifungal activity of curcumin 2014.
  12. C. V. B. Martins, D. L. da Silva, A. T. M. Neres, T. F. F. Magalhaes, G. A. Watanabe,L. V. Modolo, A. A. Sabino, A . de Fatima and M. A. de Resende, Curcumin as a promising antifungal of clinical interest 2008.
  13. Al-Tawfiq JA, Wools KK. Disseminated sporotrichosis and Sporothrix schenckii fungemia as the initial presentation of human immunodeficiency virus infection 1998.
  14. Grzegorz Grynkiewicz and Piotr slifirski, Curcumin and Curcuminoids in quest for Medicinal status 2012.
  15. Y.Wang, Z. Lu, H.Wu, and F. Lv, “Study on the antibiotic activity of microcapsule curcumin against foodborne pathogens 2009.

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Dr. G. Abirami
Corresponding author

Department of Pharmaceutical Chemistry, Adhiparasakthi College of Pharmacy Melmaruvathur (affiliated to) The Tamil Nadu Dr. M.G.R. Medical University, Chennai- 32

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Dr. D. Nagavalli
Co-author

Department of Pharmaceutical Chemistry, Adhiparasakthi College of Pharmacy Melmaruvathur (affiliated to) The Tamil Nadu Dr. M.G.R. Medical University, Chennai- 32

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Cheran V.
Co-author

Department of Pharmaceutical Chemistry, Adhiparasakthi College of Pharmacy Melmaruvathur (affiliated to) The Tamil Nadu Dr. M.G.R. Medical University, Chennai- 32

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Keerthana K
Co-author

Department of Pharmaceutical Chemistry, Adhiparasakthi College of Pharmacy Melmaruvathur (affiliated to) The Tamil Nadu Dr. M.G.R. Medical University, Chennai- 32

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Madhan S
Co-author

Department of Pharmaceutical Chemistry, Adhiparasakthi College of Pharmacy Melmaruvathur (affiliated to) The Tamil Nadu Dr. M.G.R. Medical University, Chennai- 32

Photo
Mahalakshmi M.
Co-author

Department of Pharmaceutical Chemistry, Adhiparasakthi College of Pharmacy Melmaruvathur (affiliated to) The Tamil Nadu Dr. M.G.R. Medical University, Chennai- 32

Photo
Thikish G.
Co-author

Department of Pharmaceutical Chemistry, Adhiparasakthi College of Pharmacy Melmaruvathur (affiliated to) The Tamil Nadu Dr. M.G.R. Medical University, Chennai- 32

Chaitanya Bopate*, Minal Paneri, Aakanksha Panajwar, Dr. Nilesh Chachda, Carbon Dots: A Review on Nowel Type of Carbon-Based Nanomaterial Used Treat Cancer, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 12, 1020-1027. https://doi.org/10.5281/zenodo.14331355

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