Theaflavin-3,3′-Digallate Encapsulated β-Chitosan Nanoparticles for the Prevention of Chemotherapy-Induced Toxicity: Mechanisms, Therapeutic Potential, and Future Perspectives
DOI:
https://doi.org/10.65795/f8rm8k88Keywords:
cancer, human, health, green products, nanotechnologyAbstract
Chemotherapy remains a cornerstone of cancer management; however, its clinical effectiveness is often compromised by severe systemic toxicity that limits therapeutic dosing and adversely affects patent quality of life. In recent years, natural polyphenols have gained attention as adjunctive agents capable of mitigating chemotherapy induced adverse effects. Among these, theaflavin-3’,3’-digallate (TFDG), a major bioactive constituent of black tea, exhibits potent antioxidant, anti-inflammatory, and antitumour activities. Despite its therapeutic promise, the clinical translation of TFDG is hindered by poor aqueous solubility, low bioavailability, and rapid metabolic degradation. Nanotechnology based delivery systems, particularly biopolymeric carriers such as chitosan nanoparticles (CS-NPs), offer a viable strategy to overcome these limitations. Chitosan based nanoparticles provide enhanced stability, controlled release, improved cellular uptake, and favourable biocompatibility, making them suitable vehicles for polyphenol delivery. This review critically summarizes current knowledge on the chemical characteristics and biological functions of TFDG, recent advances in chitosan nanoparticle formulations, and their combined potential to act as a biological shield against chemotherapy-induced toxicity. The integration of TFDG with CS-NPs represents a promising nanotherapeutic approach to improve treatment tolerance with preserving anticancer efficacy.
Downloads
References
Atkins S, He F. Chemotherapy and beyond: infections in the era of old and new treatments for hematologic malignancies. Infectious Disease Clinics. 2019 Jun 1;33(2):289-309.
DOI: 10.1016/j.idc.2019.01.001 DOI: https://doi.org/10.1016/j.idc.2019.01.001
Radeva L, Yoncheva K. Doxorubicin Toxicity and Recent Approaches to Alleviating Its Adverse Effects with Focus on Oxidative Stress. Molecules. 2025 Aug 7;30(15):3311.
https://doi.org/10.3390/molecules30153311 DOI: https://doi.org/10.3390/molecules30153311
Alum EU, Uti DE, Offor CE. Redox Signaling Disruption and Antioxidants in Toxicology: From Precision Therapy to Potential Hazards. Cell Biochemistry and Biophysics. 2025 Jul 28:1-22.
https://doi.org/10.1007/s12013-025-01846-8 DOI: https://doi.org/10.1007/s12013-025-01846-8
Sivasakthivel S, Ramani P. Angiotensin-converting Enzyme 2 Expression in Oral Squamous Cell Carcinoma: Correlation with p53 and Vascular Endothelial Growth Factor Using Reverse Transcriptase Polymerase Chain Reaction-An Evaluative Study. Annals of Maxillofacial Surgery. 2025 Sep 23:10-4103.
DOI: 10.4103/ams.ams_26_25 DOI: https://doi.org/10.4103/ams.ams_26_25
Patil OP, Raja T, Dhanraj G, Prabhalakshmi KB. Green Synthesis and Characterization of Zinc Oxide Nanoparticles Derived from Ocimum Sanctum Leaves: Antibacterial, Antibiofilm, and Thermal Studies. Journal of Bio-and Tribo-Corrosion. 2026 Mar;12(1):34.
https://doi.org/10.1007/s40735-025-01095-5 DOI: https://doi.org/10.1007/s40735-025-01095-5
Ren J, Jiang T, Wei X, Bian T, Xu M, Zhao Y, Zheng Y, Li X. Unravelling the Mechanisms of Tea Against NAFLD: An Integration of Bibliometrics, Network Pharmacology, and the Gut‐Liver Axis. Diabetes/Metabolism Research and Reviews. 2026 Jan;42(1):e70118.
https://doi.org/10.1002/dmrr.70118 DOI: https://doi.org/10.1002/dmrr.70118
Wu X, Ozawa T, Li Y, Duan J, Zhu K, Huang J, Liu Z, Wang K. Effect of fermentation time and temperature on the of polyphenol compounds change of different Congou black tea. Journal of Food Processing and Preservation. 2021 Oct;45(10):e15844.
https://doi.org/10.1111/jfpp.15844 DOI: https://doi.org/10.1111/jfpp.15844
Li H, Bei S, Mo Y, Feng L. Theaflavins Inhibit Proliferation and Glycolysis of Colorectal Cancer Cells by Downregulating DDIT4. Drug Development Research. 2025 Sep;86(6):e70151. DOI: https://doi.org/10.1002/ddr.70151
https://doi.org/10.1002/ddr.70151Digital Object Identifier (DOI)
Wang M, Guo W, Ke Z, Mao H, Lv J, Qi L, Wang J. Inhibitory mechanisms of galloylated forms of theaflavins on α-glucosidase. International Journal of Biological Macromolecules. 2025 Mar 1;294:139324.
https://doi.org/10.1016/j.ijbiomac.2024.139324 DOI: https://doi.org/10.1016/j.ijbiomac.2024.139324
Palati S, Yuwanati M, Babalola AE, Somoye VA, Akinjola A, Chaurasia A. Effectiveness of Curcumin Nanoparticles in the Management of Oral Mucositis: A Systematic Review.
https://doi.org/10.21203/rs.3.rs-8470615/v1 DOI: https://doi.org/10.21203/rs.3.rs-8470615/v1
Elsawy MM. Chitosan and its derivatives: a comprehensive review on structure, properties, andemerging applications. Pigment & Resin Technology. 2026 Jan 1:1-1.
https://doi.org/10.1108/PRT-06-2025-0059 DOI: https://doi.org/10.1108/PRT-06-2025-0059
Collado-González M, González Espinosa Y, Goycoolea FM. Interaction between chitosan and mucin: Fundamentals and applications. Biomimetics. 2019 Apr 25;4(2):32.
https://doi.org/10.3390/biomimetics4020032 DOI: https://doi.org/10.3390/biomimetics4020032
Ragunath AV, Pitchai A, Ramasamy P. Synthesis of chitosan nanoparticles from cuttlebone of Sepia pharaonis (Ehrenberg, 1831) and its antimicrobial effects against oral pathogens. Pharmacological Research-Natural Products. 2025 Nov 22:100438.
https://doi.org/10.1016/j.prenap.2025.100438 DOI: https://doi.org/10.1016/j.prenap.2025.100438
Alina S, Lungu II, Nicoleta A, Daniela D, Cristian G, Iulia O, Alina PC, Madalina DC, Marcu C, Gabriela C, Duceac LD. Chitosan Nanoparticle-Based Drug Delivery Systems: Advances, Challenges, and Future Perspectives. Polymers. 2025;17(11):1453.
doi:https://doi.org/10.3390/polym17111453 DOI: https://doi.org/10.3390/polym17111453
Yadav S, Singh A, Palei NN, Pathak P, Verma A, Yadav JP. Chitosan-based nanoformulations: preclinical investigations, theranostic advancements, and clinical trial prospects for targeting diverse pathologies. AAPS PharmSciTech. 2024 Nov 5;25(8):263.
https://doi.org/10.1208/s12249-024-02948-x DOI: https://doi.org/10.1208/s12249-024-02948-x
Teng Y, Jin Z, Ren W, Lu M, Hou M, Zhou Q, Wang W, Yang H, Zou J. Theaflavin‐3, 3′‐Digallate Protects Cartilage from Degradation by Modulating Inflammation and Antioxidant Pathways. Oxidative Medicine and Cellular Longevity. 2022;2022(1):3047425.
https://doi.org/10.1155/2022/3047425 DOI: https://doi.org/10.1155/2022/3047425
Mahdi MA, Dawood YJ, Jumaa AH, Abod KS, Manssor KJ. From ROS to Tumorigenesis: Understanding the Oxidative Pathways in Cervical Cancer Progression. Asian Pacific Journal of Cancer Biology. 2026 Jan 7;11(1):259-66. DOI: https://doi.org/10.31557/apjcb.2026.11.1.259-266
DOI 10.31557/apjcb.2026.11.1.259-266
Xue S, Chen H, Zhang J, Tian R, Xie C, Sun Q, Wang H, Shi T, Guo D, Wang Y, Wang Q. Qishen granule alleviates doxorubicin-induced cardiotoxicity by suppressing ferroptosis via nuclear erythroid factor 2-related factor 2 (Nrf2) pathway. Journal of Ethnopharmacology. 2024 Dec 5;335:118604.
https://doi.org/10.1016/j.jep.2024.118604 DOI: https://doi.org/10.1016/j.jep.2024.118604
Nargeh H, Aliabadi F, Ajami M, Pazoki-Toroudi H. Role of polyphenols on gut microbiota and the ubiquitin-proteasome system in neurodegenerative diseases. Journal of Agricultural and Food Chemistry. 2021 May 26;69(22):6119-44.
https://doi.org/10.1021/acs.jafc.1c00923 DOI: https://doi.org/10.1021/acs.jafc.1c00923
Ding Y, Chen B, Suo H, Tong H. The enzyme-oriented regulation of theaflavin-3, 3′-digallate synthesis and the accurate determination of its yield. International Journal of Food Science and Technology. 2020 Apr;55(4):1531-8.
https://doi.org/10.1111/ijfs.14429 DOI: https://doi.org/10.1111/ijfs.14429
Li M, Li W, Dong Y, Zhan C, Tao T, Kang M, Zhang C, Liu Z. Advances in metabolism pathways of theaflavins: digestion, absorption, distribution and degradation. Critical Reviews in Food Science and Nutrition. 2025 Aug 5;65(21):4195-203. https://doi.org/10.1080/10408398.2024.2384647 DOI: https://doi.org/10.1080/10408398.2024.2384647
Liu Z, de Bruijn WJ, Bruins ME, Vincken JP. Microbial metabolism of theaflavin-3, 3′-digallate and its gut microbiota composition modulatory effects. Journal of agricultural and food chemistry. 2020 Dec 21;69(1):232-45.
https://doi.org/10.1021/acs.jafc.0c06622 DOI: https://doi.org/10.1021/acs.jafc.0c06622
He Y, Li Y, Wei Z, Zhang X, Gao J, Wang X, Li X, Wu W, Li W, Yi X, Zeng Y. Pharmacokinetics, tissue distribution, and excretion of FGF‐21 following subcutaneous administration in rats. Drug Testing and Analysis. 2018 Jul;10(7):1061-9.
https://doi.org/10.1002/dta.2365 DOI: https://doi.org/10.1002/dta.2365
Ramakrishnan N, Palati S, Sekaran S, Ganapathy D. Synergistic Effects of Zinc-Doped Chitosan and Whitlockite Nanoparticles in Bone Regeneration: A Comprehensive In Vitro Evaluation. Trends in Biomaterials and Artificial Organs. 2025 Aug 26;39(2):199-205.
https://doi.org/10.5281/zenodo.16959513
Martin TM, Kumar MS. Chemoprotective Horizons: Bioactive Molecules as Therapeutic Shields Against Cytotoxicity. Asian Pacific Journal of Cancer Biology. 2025 Nov 26;10(4):1061-74. DOI: https://doi.org/10.31557/apjcb.2025.10.4.1061-1074
DOI 10.31557/apjcb.2025.10.4.1061-1074
Kurczewska J. Chitosan-based nanoparticles with optimized parameters for targeted delivery of a specific anticancer drug—a comprehensive review. Pharmaceutics. 2023 Feb;15(2):503.
https://doi.org/10.3390/pharmaceutics15020503 DOI: https://doi.org/10.3390/pharmaceutics15020503
Martin TM. Seaweeds and Their Secondary Metabolites: A Promising Drug Candidate With Novel Mechanisms Against Cancers and Tumor Angiogenesis. Cureus. 2024 Aug 12;16(8).
DOI: 10.7759/cureus.66662 DOI: https://doi.org/10.7759/cureus.66662
Payra M, Mohanraj KG, Martin TM, Payra Jr M. Modulation of Inflammation in McCoy Cells by Zinc Nanoparticles Conjugated With β-Chitosan. Cureus. 2024 Sep 4;16(9).
DOI: 10.7759/cureus.68653 DOI: https://doi.org/10.7759/cureus.68653
Ding Y, Zou L, Lu C, Tong H, Chen B. In situ enzymatic synthesis and purification of theaflavin-3, 3′-digallate monomer and incorporation into nanoliposome. International Journal of Food Science and Technology. 2018 Nov;53(11):2552-9.
https://doi.org/10.1111/ijfs.13849 DOI: https://doi.org/10.1111/ijfs.13849
Chang H, Yhee JY, Jeon S, Shim MK, Yoon HY, Lee S, Kim K. In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity. Journal of Nanobiotechnology. 2023 Mar 9;21(1):82.
https://doi.org/10.1186/s12951-023-01824-3 DOI: https://doi.org/10.1186/s12951-023-01824-3
Hejjaji EM, Smith AM, Morris GA. Evaluation of the mucoadhesive properties of chitosan nanoparticles prepared using different chitosan to tripolyphosphate (CS: TPP) ratios. International journal of biological macromolecules. 2018 Dec 1;120:1610-7.
https://doi.org/10.1016/j.ijbiomac.2018.09.185 DOI: https://doi.org/10.1016/j.ijbiomac.2018.09.185
Niu Y, Hu W. Preparation, characterization and application in environmental protection of low-molecular-weight chitosan: a review. Sustainable Environment Research. 2024 Nov 25;34(1):29.
https://doi.org/10.1186/s42834-024-00236-8 DOI: https://doi.org/10.1186/s42834-024-00236-8
Altaani BM, Al-Nimry SS, Haddad RH, Abu-Dahab R. Preparation and characterization of an oral norethindrone sustained release/controlled release nanoparticles formulation based on chitosan. Aaps Pharmscitech. 2019 Jan 7;20(2):54.
https://doi.org/10.1208/s12249-018-1261-3 DOI: https://doi.org/10.1208/s12249-018-1261-3
Park JH, Saravanakumar G, Kim K, Kwon IC. Targeted delivery of low molecular drugs using chitosan and its derivatives. Advanced drug delivery reviews. 2010 Jan 31;62(1):28-41.
https://doi.org/10.1016/j.addr.2009.10.003 DOI: https://doi.org/10.1016/j.addr.2009.10.003
Bakhru SH, Altiok E, Highley C, Delubac D, Suhan J, Hitchens TK, Ho C, Zappe S. Enhanced cellular uptake and long-term retention of chitosan-modified iron-oxide nanoparticles for MRI-based cell tracking. International journal of nanomedicine. 2012 Aug 22:4613-23. https://doi.org/10.2147/IJN.S28294 DOI: https://doi.org/10.2147/IJN.S28294
Huang WT, Larsson M, Lee YC, Liu DM, Chiou GY. Dual drug-loaded biofunctionalized amphiphilic chitosan nanoparticles: Enhanced synergy between cisplatin and demethoxycurcumin against multidrug-resistant stem-like lung cancer cells. European Journal of Pharmaceutics and Biopharmaceutics. 2016 Dec 1;109:165-73.
https://doi.org/10.1016/j.ejpb.2016.10.014 DOI: https://doi.org/10.1016/j.ejpb.2016.10.014
Yi LI, Qing GA, Linzhu LI, Di TI, Jialin XI, Zhuoya LU, Yiting LU, Peng WU. Preparation of theaflavin-3, 3'-digallate-chitosan nanoemulsion and its characteristics. China Food Additives. 2022 Sep 1;33(9).
19804/j.issn1006-2513.2022.09.021 DOI: https://doi.org/10.1088/1475-7516/2022/09/021
Rizeq BR, Younes NN, Rasool K, Nasrallah GK. Synthesis, bioapplications, and toxicity evaluation of chitosan-based nanoparticles. International journal of molecular sciences. 2019 Nov 16;20(22):5776.
https://doi.org/10.3390/ijms20225776 DOI: https://doi.org/10.3390/ijms20225776
Du S, Chang J, Zhou Z. A comprehensive review of theaflavins: Physiological activities, synthesis techniques, and future challenges. Food Science & Nutrition. 2025 Aug;13(8):e70762.
https://doi.org/10.1002/fsn3.70762 DOI: https://doi.org/10.1002/fsn3.70762
Chougule PR. Shaping the Future of Chronic Diseases: A Phyto-Mediated Natural Approach. InMedicinal Plants and Their Nanoparticles: A Double Blade Sword Against Human Diseases 2025 Oct 17 (pp. 355-390). Cham: Springer Nature Switzerland.
https://doi.org/10.1007/978-3-032-03604-9_15 DOI: https://doi.org/10.1007/978-3-032-03604-9_15
Salaritabar A, Darvishi B, Hadjiakhoondi F, Manayi A, Sureda A, Nabavi SF, Fitzpatrick LR, Nabavi SM, Bishayee A. Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review. World journal of gastroenterology. 2017 Jul 28;23(28):5097.
doi: 10.3748/wjg.v23.i28.5097 DOI: https://doi.org/10.3748/wjg.v23.i28.5097
Khalid JP, Martin TM, Prathap L, Nisargandha MA, Boopathy N, Kumar MS, PK J, Nisargandha MA. Exploring tumor-promoting qualities of cancer-associated fibroblasts and innovative drug discovery strategies with emphasis on thymoquinone. Cureus. 2024 Feb 10;16(2).
DOI: 10.7759/cureus.53949 DOI: https://doi.org/10.7759/cureus.53949
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Taniya Mary Martin, Meenakshi Sundaram Kishore Kumar (Author)

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Copyright and Licensing
All articles published in Trends in Biomaterials and Artificial Organs are published Open Access. To ensure the widest possible dissemination of research while protecting the integrity of the original work, we utilize the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) 4.0 International License.
User Rights
Under this license, the public is free to share (copy and redistribute the material in any medium or format) under the following terms:
- Attribution: Users must give appropriate credit, provide a link to the license, and indicate if changes were made.
- Non-Commercial: Users may not use the material for commercial purposes. This includes, but is not limited to, the sale of the article or its use in promotional materials for-profit.
- No Derivatives: If a user remixes, transforms, or builds upon the material, they may not distribute the modified material.
Author Rights
Authors retain copyright of their work while granting the journal a non-exclusive license to publish. Because of the NoDerivs (ND) and Non-Commercial (NC) designations:
- Third parties (such as other researchers) must seek permission from the authors/journal to include figures, tables, or portions of the text in new works or commercial publications.
- Authors may deposit the "Version of Record" in institutional repositories immediately upon publication, provided the CC BY-NC-ND 4.0 license is clearly linked.
How to Cite
Accepted 27-06-2026
Published 09-07-2026


