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Pharmaceutical Biology ISSN: 1388-0209 (Print) 1744-5116 (Online) Journal homepage: www.tandfonline.com/journals/iphb20 Epigallocatechin-3-gallate at the nanoscale: a new strategy for cancer treatment Wenxue Sun, Yizhuang Yang, Cuiyun Wang, Mengmeng Liu, Jianhua Wang, Sen Qiao, Pei Jiang, Changgang Sun & Shulong Jiang To cite this article: Wenxue Sun, Yizhuang Yang, Cuiyun Wang, Mengmeng Liu, Jianhua Wang, Sen Qiao, Pei Jiang, Changgang Sun & Shulong Jiang (2024) Epigallocatechin-3-gallate at the nanoscale: a new strategy for cancer treatment, Pharmaceutical Biology, 62:1, 676-690, DOI: 10.1080/13880209.2024.2406779 To link to this article: https://doi.org/10.1080/13880209.2024.2406779 © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 30 Sep 2024. 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However, its low bioavailability and rapid degradation hinder its clinical application. Objective: this review explores the potential of nanoencapsulation to enhance the stability, bioavailability, and therapeutic efficacy of eGcG in cancer treatment. Methods: we searched the PubMed database from 2019 to the present, using ‘epigallocatechin gallate’, ‘eGcG’, and ‘nanoparticles’ as search terms to identify pertinent literature. this review examines recent nano-engineering technology advancements that encapsulate eGcG within various nanocarriers. the focus was on evaluating the types of nanoparticles used, their synthesis methods, and the technologies applied to optimize drug delivery, diagnostic capabilities, and therapeutic outcomes. Results: Nanoparticles improve the physicochemical stability and pharmacokinetics of eGcG, leading to enhanced therapeutic outcomes in cancer treatment. Nanoencapsulation allows for targeted drug delivery, controlled release, enhanced cellular uptake, and reduced premature degradation of eGcG. the studies highlighted include those where eGcG-loaded nanoparticles significantly inhibited tumor growth in various models, demonstrating enhanced penetration and efficacy through active targeting mechanisms. Conclusions: Nanoencapsulation of eGcG represents a promising approach in oncology, offering multiple therapeutic benefits over its unencapsulated form. Although the results so far are promising, further research is necessary to fully optimize the design of these nanosystems to ensure their safety, efficacy, and clinical viability. Introduction Cancer is one of the leading causes of death globally, accounting for one in every six deaths. In 2020, nearly 10 million people worldwide died from this disease (Singh et al. 2023). By 2050, the annual incidence of new cancer cases is projected to reach 35 million, representing a 77% increase from 2022 (Global can- cer burden growing, amidst mounting need for services 2024; Bray et al. 2024). In the global quest for more effective cancer treatments, natural compounds, notably green tea epigallocate- chin gallate (EGCG), have received significant attention due to their potential health benefits (Negri et al. 2018). EGCG, a catechin, belongs to a class of flavonoid compounds naturally found in plants and is noted for its diverse biological activities (Gan et al. 2018). The antioxidant, anti-inflammatory, and antitumor properties of EGCG have been validated in numerous studies (Yuan et al. 2020; Li et al. 2024), positioning it as a focal point in cancer research. EGCG impacts cancer cells through multiple mechanisms, including altering the cell cycle, inducing apoptosis, inhibiting invasion and metastasis, and mod- ulating the tumor microenvironment (TME). These complex interactions demonstrate the potential of EGCG as a multifaceted anticancer agent (Aggarwal et al. 2022). Despite its extensive bio- logical activities, the primary challenges associated with EGCG in clinical settings are its low bioavailability and poor stability, which lead to rapid metabolism and clearance from the body, reducing its therapeutic efficacy (Sahadevan et al. 2023). The advent of nanotechnology presents novel opportunities to enhance the clinical application of EGCG. Encapsulation of EGCG in nano-carriers has significantly improved its solubility, stability, and bioavailability and facilitated targeted tumor delivery (Wang, Huang, Jing, et al. 2021). Various natural and synthetic polymers, metals, and carbon-based materials have been explored for nano-carriers development. These carriers stabilize EGCG and allow targeted delivery through modifications of surface functional groups (Yang et al. 2020). Ongoing research investigates the syner- gistic effects of combining EGCG with other therapeutic agents to increase its anticancer properties (Shan et al. 2019). © 2024 the author(s). Published by informa uK limited, trading as taylor & Francis group. CONTACT Shulong Jiang jnsljiang@163.com; changgang Sun scgdoctor@126.com; Pei Jiang jiangpeicsu@sina.com translational Pharmaceutical laboratory, Jining No.1 People’s hospital, Shandong First medical university, Jining, 272000, china #equal contribution https://doi.org/10.1080/13880209.2024.2406779 this is an open access article distributed under the terms of the creative commons attribution-Noncommercial license (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. the terms on which this article has been published allow the posting ofand a low dose of DOX within complex algal sugar-based nanoparticles. These pH-sensitive nanoparticles can regulate the effective release of drugs and target prostate cancer cells through recognition mech- anisms of CD44 and P-selectin ligands. In vitro cellular experi- ments demonstrated that this drug carrier inhibited cancer cell growth by inducing G2/M cell cycle arrest. Further in vivo experiments showed that these nanoparticles carrying the combi- nation drugs significantly inhibited tumor growth and promoted apoptosis by increasing the expression of the M30 protein with- out causing significant organ damage. Another study (Huang et al. 2021) developed a nanoparticle system based on chromaffin (FD) and d-α-tocopheryl polyeth- ylene glycol succinate (TH), which actively co-delivers EGCG Ta bl e 4. c ar bo hy dr at e- ba se d na no pa rt ic le s. N an o ca rr ie rs ; m at er ia ls/ na m es Sy nt he tic m et ho d Pa rt ic le s iz e (n m ) ce ll lin es /a ni m al m od el s an tic an ce r eff ec t re fe re nc es eg cg /c u- lo ad ed F u/ ha / Pe g- ge la tin N Ps ad ju st ed c om po sit io n ra tio , Su rf ac ta nt a dd iti on 19 7. 73 ± 1 8. 53 pr os ta te c an ce r ce lls or th ot op ic p ro st at e tu m or m od el th e eg cg /D X- lo ad ed F D /t h/ Pg n an op ar tic le s en ha nc e ta rg et ed d el iv er y to g as tr ic t um or s, im pr ov in g effi ca cy w hi le m in im iz in g sid e eff ec ts . ch u et a l. 20 19 eg cg / Dt X- lo ad ed t Pg S- g- ha /F D / Pe g- g- ge n an op ar tic le s Se lf- as se m bl y w ith h ya lu ro ni c ac id co nj ug at io n 18 9. 96 ± 7 .9 8 Pc 3 ce lls S ev er e co m bi ne d im m un od efi ci en t m ic e( Sc iD ) th e eg cg /D tX -lo ad ed n an op ar tic le s de m on st ra te d en ha nc ed s yn er gi st ic a nt ic an ce r eff ec ts c om pa re d to tr ea tm en ts u sin g th e dr ug s in c om bi na tio n or a lo ne . ch en , l ai , et a l. 20 20 eg cg /D X- lo ad ed F D /t h/ Pg N Ps So lv en t ev ap or at io n, g el at io n te ch ni qu e 20 0- 23 0 lu c m KN 45 c el ls Sc iD m ic e eg cg /D X- lo ad ed F D /t h/ Pg n an op ar tic le s ou tp er fo rm t he co m bi na tio n so lu tio n by o ffe rin g ta rg et ed , m or e eff ec tiv e de liv er y to g as tr ic t um or s w ith r ed uc ed s id e eff ec ts hu an g et a l. 20 21 eg cg &r 84 8@ N g po ly m er iz at io n D m em + 1 0% FB S 17 4. 7 ± 10 .2 3 16 40 + 1 0% FB S 16 6. 6 ± 4. 67 B1 6F 10 m el an om a ce lls fe m al e c5 7B l/ 6J m ic e eg cg &r 84 8@ N g eff ec tiv el y de liv er s r8 48 a nd e gc g to t he tu m or m ic ro en vi ro nm en t, en ha nc in g de nd rit ic c el l m at ur at io n, s up pr es sin g PD -l 1 ex pr es sio n, a nd im pr ov in g th er ap eu tic p en et ra tio n w ith c on tr ol le d, p h- re sp on siv e re le as e. So ng e t al . 2 02 1 PHARMAceuticAl BioloGY 687 and DOX to gastric cancer cells through recognition of P-selectin and CD44 ligands. The nanoparticle system regulates drug release through pH-sensitive adjustments. Compared with a combined solution of EGCG/DX, the nanoparticles prepared for the com- bined drug delivery system significantly improved the synergistic anticancer effects of EGCG and DX. Targeting improved the dis- tribution of nanoparticles in gastric cancer cells and reduced their distribution in the major organs in orthotopic gastric tumors. In terms of immunosuppressive TME-responsive nano- technology, Song et al. (2021) developed a permeating nanogel (NGs) that effectively improved the delivery and penetration of co-loaded R848 (a toll-like receptor agonist) and EGCG in tumors through a soluble cyclodextrin nano-level controlled release system. This nanogel promoted dendritic cell maturation, stimulated the production of cytotoxic T lymphocytes (CTLs), and reduced PD-L1 expression in tumors. Combining NGs with an OX40 agonist further synergistically enhanced CTL activation and infiltration into deep tumors, suppressing the inhibitory effect of regulatory T cells (Tregs). Experimental results showed a 20.66-fold increase in the ratio of active CTLs to Tregs in tumors, achieving a tumor inhibition effect of 91.56%, indicating the successful conversion of ‘cold’ tumors to ‘hot’ tumors, signifi- cantly improving the effects of antitumor immunotherapy. Chu et al. (2019) developed a dual-targeting nanoparticle system for co-delivering EGCG and curcumin (CU). These nanoparticles, composed of hyaluronic acid, alginate, and polyethylene glycol-gelatin, effectively encapsulated EGCG and CU. The dual targeting mechanisms of hyaluronic acid and alginate, specifically targeting CD44 on prostate cancer cells and P-selectin on tumor vasculature, increased drug uptake and anticancer efficiency. The study demonstrated that these nanoparticles stably released EGCG and CU under-regulated pH conditions, avoiding prema- ture drug release, and significantly inhibited tumor growth in mouse models without causing organ damage. Discussion EGCG, the most abundant catechin in green tea, has received immense interest in the scientific community for its rich biolog- ical properties, such as antioxidant, anti-inflammatory, and anti- tumor activities. The therapeutic potential of EGCG is particularly significant in oncology due to its ability to regulate various cel- lular pathways, control the cell cycle, induce apoptosis, and affect TME. However, the low bioavailability of EGCG and its rapid degradation in the human body limits its clinical application, and traditional administration methods cannot effectively main- tain therapeutic concentrations in the blood, restricting its anti- cancer efficacy. Nanotechnology offers innovative solutions to these chal- lenges. By designing lipid, polymer, and metal-based nanocarri- ers, the solubility, stability, and targeted delivery of EGCG can be enhanced, increasing its bioavailability and therapeutic efficacy. Studies have shown that polymer-based nanoparticles can effec- tively encapsulate EGCG, prevent premature degradation, and promote targeted delivery to tumor sites. Zhang et al. (2020) reported that EGCG-loaded poly-PLGA nanoparticles signifi- cantly inhibited tumor growth in a mouse melanoma model, demonstrating the potential of this approach to improve systemic administration and targeted release to enhance EGCG’s antitu- mor activity. The field is moving toward complex targeting mechanisms, where nanoparticles modified with ligands can rec- ognize and bind to specific markers overexpressed on cancer cells. This precise targeting minimizes the impact on healthy cells. It maximizes the therapeutic potential of EGCG, such as the development of folic acid-conjugated nanoparticles to target cancer cells overexpressing folate receptors, thus improving tar- geted cancer cell absorption of EGCG and its antitumor efficacy (Das et al. 2019). Reviews also detail the use of nanoparticles to combine EGCG with chemotherapy, PTT, and PDT in combined therapies, which have shown the potential to enhance therapeutic effects by mak- ing cancer cells more sensitive to conventional therapies and reducing resistance (Ren et al. 2020; Gao et al. 2022). Theranostic approaches, which integrate therapy and diagnostics, provide an efficient and precise new strategy for cancer treatment. These particles can respond to specific stimuli (such as pH changes or light) to control drug release or enhance therapeutic effects and are capable of imaging functions, such as MRI or SWIR imaging, helping totrack drug delivery and release (Jiang et al. 2019; Ren et al. 2020; Li et al. 2021). Recent research increasingly integrates these traditional thera- pies with gene therapy and immunotherapy for in vitro and in vivo cancer experiments. For example, nanoparticles designed by Wu et al. (2022), combined with si-RNA, enhance the ability of T cells to kill tumors, serving both as PD-L1 inhibitors and car- riers of immunobiological molecules (Han et al. 2024). Song et al. (2021) and Luo et al. (2024) developed TME hypoxia-responsive NGs that can enhance EGCG delivery and penetration in tumors, effectively improving tumor immunosup- pressive status and increasing CTL infiltration at tumor sites, generating strong antitumor immune responses. In vitro and in vivo studies show that optimizing the delivery and efficacy of EGCG through nanotechnology is a significant advancement in oncology. Although nanocarriers offer substan- tial advantages, their potential toxic effects remain a cause for concern. For example, Aborig et al. (2019) investigated the dis- tribution of EGCG-coated gold nanoparticles in murine models and developed a physiologically based pharmacokinetic (PBPK) model. The study revealed that gold nanoparticles predominantly accumulate in the liver and spleen of mice, with extravascular leakage and phagocytic uptake representing the primary distribu- tion mechanisms. There is still limited preclinical toxicity data on EGCG nanoparticles. Comprehensive assessments of their toxicity following chronic exposure and pharmacokinetic studies of nanoparticles as drug delivery systems are lacking. Most research has concentrated on the pharmacokinetics of encapsu- lated drugs rather than the carriers themselves, emphasizing the necessity for further studies on the pharmacokinetic and toxi- cokinetic mechanisms of nanoparticles as carriers and the valida- tion of their in vivo performance. The current synthetic drug delivery systems, including inor- ganic and polymeric nanoparticles, are inherently exogenous sub- stances that may pose significant toxicity and immunogenicity risks (Najahi-Missaoui et al. 2020). Identifying safe, biocompati- ble, and efficacious drug delivery carriers remains a major challenge. Exosomes, nano-sized drug delivery platforms, offer a unique set of advantages. Their small size (30–150 nm) enables them to traverse biological barriers such as the blood-brain barrier, while their cellular origin ensures excellent biocompatibility, reducing the risk of immune responses (Liang et al. 2021). Additionally, exosomes possess intrinsic targeting capabilities, which can be enhanced by modifying their surface proteins and lipids to increase specificity for particular tissues or cells. As drug carri- ers, exosomes can encapsulate small molecules, proteins, and nucleic acids, effectively protecting these therapeutic agents from degradation in the bloodstream and delivering them directly to 688 w. SuN et Al. target cells through mechanisms like membrane fusion or endo- cytosis (Tian et al. 2018). Given these properties, exosomes hold significant potential for the delivery of EGCG. However, no stud- ies currently explore the use of exosomes for EGCG delivery in cancer therapy, indicating the need for further research to eval- uate the capabilities of this promising nanomaterial. Authors’ contributions Jiang SL, Sun CG, and Jiang P conceptualized and designed the review. Sun WX, Yang YZ, Wang CY, and Liu MM conducted literature searches, data extraction, methodology development, visualization, and drafting the initial manuscript. Sun WX and Yang YZ handled the manuscript review and edit- ing. Yang YZ and Wang JH conducted the statistical analysis and produced the tables and figures. Jiang SL and Qiao S contributed to manuscript revi- sions. All authors have read and approved the final version of the manuscript. Disclosure statement The authors report that there are no competing interests to declare. Funding This work was supported by the Medical and Health Technology Development Program of Shandong Province (No. 202113050502), the Key R&D Program of Jining (No. 2022YXNS118), and the Doctoral Fund of Jining No.1 People’s Hospital (No. 2021-BS-008). References Aborig M, Malik PRV, Nambiar S, Chelle P, Darko J, Mutsaers A, Edginton AN, Fleck A, Osei E, Wettig S. 2019. 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ARTICLE HISTORY received 18 June 2024 revised 21 august 2024 accepted 15 September 2024 KEYWORDS egcg; nanomedicine; catechins; medicinal chemistry mailto:jnsljiang@163.com mailto:scgdoctor@126.com mailto:jiangpeicsu@sina.com https://doi.org/10.1080/13880209.2024.2406779 http://creativecommons.org/licenses/by-nc/4.0/ http://crossmark.crossref.org/dialog/?doi=10.1080/13880209.2024.2406779&domain=pdf&date_stamp=2024-9-30 http://www.tandfonline.com PHARMAceuticAl BioloGY 677 Given the significance and rapid advancements in EGCG-related nanoparticles and their therapeutic potential, a comprehensive and current review is warranted. We discuss the effects and potential mechanisms of EGCG on cancer, address issues related to its bio- availability and stability, summarize recent advances in EGCG deliv- ery via nanotechnology, highlight its impact on cancer treatment, and present various perspectives. Materials and methods We conducted a comprehensive search of the PubMed database from 2019 to the present, using the keywords ‘epigallocatechin gallate’, ‘EGCG’, and ‘nanoparticles’ to identify relevant literature. The initial search yielded 232 articles. To ensure the inclusion of pertinent and high-quality studies, duplicates were removed using EndNote, resulting in a refined list of unique articles. We then applied specific inclusion and exclusion criteria, focusing on studies that detailed advancements in nanotechnology techniques for encapsulating EGCG in various nanocarriers. Specifically, we included studies that addressed the types of nanoparticles used, their synthesis methods, and technologies applied to optimize drug delivery, diagnostic capabilities, or therapeutic outcomes. Articles that were not directly related to EGCG or lacked exper- imental data were excluded during the title and abstract screen- ing process. After a full-text review, 47 studies were selected for inclusion in this review. This review explores the latest advance- ments in nanotechnology techniques for encapsulating EGCG, with a focus on evaluating the types of nanoparticles used, their synthesis methods, and the technologies applied to optimize drug delivery, diagnostic capabilities, and therapeutic outcomes. Results The role of EGCG in cancer research and its potential therapeutic mechanisms EGCG inhibits tumor initiation, growth, metabolism, and metasta- sis through various mechanisms at the cellular and molecular lev- els. EGCG has shown significant effects in inducing apoptosis in cancer cells. A study (Zhao et al. 2021) has shown that EGCG can activate caspases and affect the P53/Bcl-2 signaling pathway, pro- moting cell apoptosis. EGCG exhibits antitumor functions by inhibiting proliferative signaling pathways in tumor cells, such as the epidermal growth factor receptor (EGFR) and the phosphatase and tensin homolog (PTEN) (Qin et al. 2020; Rehan et al. 2023). The effect of EGCG in preventing tumor development is also sig- nificant. It (Shimizu et al. 2008) can block the early formation and development of tumors through multiple mechanisms. EGCG has also been shown to prevent obesity-related liver tumors, achieved by inhibiting the insulin-like growth factor (IGF) axis, highlighting EGCG’s importance in regulating cellular proliferation signals. When discussing the anti-tumor mechanisms of EGCG, its ability to influence cell escape from anti-growth signals is partic- ularly significant. EGCG can impact the regulation of cell cycle factors, such as P21, and cyclin-dependent kinase (CDK) inhibi- tors, such as CDK4. This interaction allows EGCG to inhibit cancer cell growth by inducing cell cycle arrest, particularly in the G1 phase. This disruption prevents cancer cells from pro- gressing through their division cycle, effectively curbing their proliferation. By altering the expression of these factors, EGCG can arrest cells in the G1 phase, stopping the progression of the cancer cell cycle (Ma et al. 2014). This direct regulation of the cell cycle illustrates the role of EGCG in modulating the processes of cell division and proliferation. In addition, the impact of EGCG on tumor metabolism is a crucial aspect of its anticancer action. It affects tumor cell energy metabolism by inhibiting key enzymes in glycolysis, such as hexokinase and pyruvate kinase (Wei et al. 2019). This regulatory effect on tumor metabolism is not limited to glycolysis but also impacts lipid metabolism and redox balance. EGCG demonstrates potent anticancer potential in terms of inflammation and immune evasion. It can regulate immune responses by affecting inflammatory factors and immunomodulatory molecules in TME, such as tumor necrosis factor (TNF) and programmed death proteins (PD-1/PD-L1) (Ravindran Menon et al. 2021). In summary, EGCG has significant antitumor effects. Its mechanisms of action are complex and diverse. Although these findings are based on laboratory studies and animal models, they provide a vital foun- dation for future clinical research and applications. Challenges of EGCG bioavailability, pharmacokinetic properties, and stability EGCG faces significant clinical limitations due to its bioavailabil- ity, pharmacokinetic properties, and stability. Its bioavailability is extremely low, typically not exceeding 1% (Figure 1). This low bioavailability can be attributed to the instability of EGCG in the gastrointestinal tract and its expulsion by ATP-dependent efflux pumps (such as multi-drug resistance-related protein [MRP] and P-glycoprotein) located in intestinal cells (Pervin et al. 2019). To improve the bioavailability of EGCG, Andreu-Fernández et al. (2020) have explored various methods, including co-ingestion with other nutrients, and using nanocarrier systems to protect EGCG from degradation. The pharmacokinetic properties of EGCG involve its absorption, distribution, metabolism, and excretion in the body. Zeng et al. (2022) has been found that food intake can affect the maximum concentration (Cmax) and the time to reach the maximum concentra- tion (Tmax) of EGCG administered orally in plasma. These parame- ters are significantly reduced when EGCG is ingested with food. The half-life of EGCG in the body ranges from 1.9 to 4.6 h, indicating that its levels in the blood gradually decrease to undetectable levels within 24 h (Chen et al. 1997). The chemical structure of EGCG contains multiple phenolic hydroxyl groups, which confer strong antioxidant activity and contribute to its instability in vivo and in vitro. It is susceptible to oxidation influenced by external factors such as light, temperature, and pH (Hong et al. 2002). Faced with the challenges of the bioavailability, stability, and pharmacokinetic properties of EGCG, researchers are dedicated to innovating drug delivery strategies and formulation techniques to enhance its bioavailability. The application of nanotechnology demonstrates excellent potential, particularly in improving the water solubility, stability, and bioavailability of EGCG. Figure 2 shows the methodologies and procedures used for encapsulating EGCG in various nanocarriers. The loading efficiency of EGCG was analyzed using modern analytical techniques, including flu- orescence and UV-visible spectroscopy (Peng et al. 2024). The following sections explore the classification of these nanocarriers, the enhancement of EGCG’s bioavailability, and its specific achievements in cancer prevention, providing new perspectives and strategies for applying EGCG in cancer treatment. EGCG-loaded nanoparticles Nanotechnology plays a crucial role in enhancing the therapeutic effects of new natural compounds in cancer treatment. In recent 678 w. SuN et Al. years, nanotechnology-based delivery systems have been pro- posed to improve the efficacy of EGCG. These systems use improved solubility, extended circulation times,and environmen- tally responsive release mechanisms to release EGCG within the body. This section explores these nano-carriers, focusing on their achievements in enhancing EGCG bioavailability and improving cancer treatment outcomes. Detailed information is listed in sub- sequent sections and summarized in Figure 3. Lipid-based nanoparticles in cancer therapy In cancer therapy, lipid-based nano-platforms have shown signif- icant advantages. These platforms can be specially designed to enhance the targeted delivery and biocompatibility of drugs. For example, incorporating EGCG into lipid nanoparticles (LNPs) such as liposomes, solid lipid nanoparticles (SLNs), nanostruc- tured lipid carriers (NLCs), and lipid nanoemulsions can signifi- cantly improve their stability and bioavailability. These carriers can be custom-designed to control particle size and facilitate multifunctional applications, including more precise delivery of EGCG to cancer cells while reducing side effects on healthy tis- sues. These nanoparticles have been widely used to enhance the stability of EGCG in physiological environments, achieve sus- tained EGCG release, and improve its bioavailability (Table 1). Addressing two critical issues in cancer therapy: effective delivery of anticancer drugs and prevention of common compli- cations such as secondary infections, Das et al. (2019) developed a novel nano-drug delivery system by co-encapsulating EGCG with the chemotherapy drug doxorubicin (DOX) in liposomes. This system could target cancer cells precisely while reducing potential toxicity to surrounding healthy cells. This technology not only improved the effectiveness of cancer treatment but also helped reduce the risk of chemotherapy-induced secondary infec- tions, achieving a dual-effect treatment strategy in the same year. Granja et al. (2019) improved the oral bioavailability of EGCG by loading it into folate-functionalized NLCs. This system showed Figure 1. Bioavailability of egcg. Figure 2. the preparation and functionalization process of egcg-loaded nanovehicles. PHARMAceuticAl BioloGY 679 good biocompatibility with epithelial Caco-2 cells and signifi- cantly increased EGCG transport across the intestinal barrier, achieving a 1.8-fold increase in apparent permeability (P_app). Farabegoli et al. (2022) turned their research toward targeted therapy strategies for EGCG, assessing folate-functionalized LNPs and EGCG-loaded LNPs in breast cancer cell lines MCF-7, MDA-MB-231, and MCF-7TAM, as well as normal MCF10A breast epithelial cells. The results indicated that low concentra- tions of EGCG-LNPs induced significant cytotoxicity in cancer cell lines without affecting normal cells, demonstrating that these nanocarriers are suitable for in vitro studies and can optimize EGCG delivery in vivo. Radhakrishnan et al. (2019) extended this line of research by encapsulating EGCG in SLNs and innovatively coupling them with a high-affinity gastrin-releasing peptide receptor (GRPR) peptide, bombesin (BBN). This strategy not only improved the stability and bioavailability of EGCG but also achieved precise targeting of breast cancer cells. In a mouse model, BBN-coupled nanoparticles were more effective at inhibiting tumor growth and prolonging mouse survival than free EGCG. Unlike previous studies, Chen, Hsieh, et al. (2020) used a nanoemulsifier as the EGCG delivery method, demonstrating that EGCG nanoemulsi- fiers could significantly activate the AMP-activated protein kinase (AMPK) signaling pathway in lung cancer cell treatment, enhanc- ing its antitumor activity. El-Kayal et al. (2019) have revealed a novel approach: local application of nano-encapsulated EGCG for the prevention and treatment of skin cancer. They used different types of gel-based nanocarriers, including penetration enhancer vesicles (PEVs), ethosomes, and transethosomes, to encapsulate EGCG. These carriers improved the stability and local bioavailability of EGCG and promoted its deposition in the skin, optimizing EGCG’s potential for photoprotection and therapeutic effects. These car- riers showed inhibitory effects on epidermal cancer cell lines. They reduced tumor volume in mouse models, while histopatho- logical analysis and biochemical quantification of skin oxidative stress biomarkers confirmed their potential therapeutic effects on skin cancer. This expands the knowledge boundaries of the Figure 3. Nanoparticle-mediated targeted egcg delivery to cancer. 680 w. SuN et Al. therapeutic applications of EGCG and provides empirical evi- dence for its local application. Polymer-based nanoparticles in cancer therapy Polymeric nanomaterials, due to their adjustable size, shape, sur- face chemistry, and biocompatibility, have been widely used as nanocarriers for drugs and biomolecules in cancer therapy. Common polymeric materials used in this context include biode- gradable polymers such as poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyethylene glycol (PEG) and their copo- lymers, as well as polysaccharide-based biopolymers. These nanomaterials can be further functionalized to achieve specific targeted delivery and have been extensively researched and applied in chemotherapy, immunotherapy, and gene therapy (Table 2). Encapsulation of EGCG in polymer nanomaterials signifi- cantly enhances its stability, biological activity, and drug delivery efficiency, thus augmenting its anticancer effects. EGCG encap- sulated in PLGA nanoparticles significantly inhibited tumor growth in A549 cells and patient-derived xenograft models, out- performing treatments with EGCG alone (Zhang et al. 2020). This nanoparticle formulation of EGCG effectively inhibited the activation of the NF-κB signaling pathway and led to the down-regulation of key genes associated with tumor proliferation and metastasis. Yongvongsoontorn et al. (2019) found similar results with EGCG-modified PEG conjugated polymer nanocom- posites, which not only improved the stability and targeting of EGCG but also synergistically enhanced the efficacy of the anti- cancer drug sunitinib while reducing systemic toxicity. These nanocomposites demonstrated significant potential in treating kidney cancer. Following the achievements of polymer nanomaterials encap- sulating EGCG, the advent of functionalized nanotechnology cat- alyzes therapeutic innovation. With specific surface modifications, such as the addition of targeting ligands, these highly customized nanocarriers can precisely deliver EGCG directly to cancer cells, significantly reducing damage to healthy cells. Wang, Huang, et al. (2019) developed a novel oral drug delivery system using a complex co-precipitation method with gelatin and chitosan to prepare nanoparticles, further modified with wheat germ agglu- tinin (WGA). Co-loading with 5-fluorouracil (5-FU) and EGCG, these nanoparticles demonstrated the characteristics of sustained drug release, enhanced cellular uptake, and extended circulation time. Compared to unmodified nanoparticles, WGA-modified nanoparticles exhibited superior antitumor activity and promoted apoptosis. Kazi et al. (2020) developed folate-modified EGCG-loaded PLGA nanoparticles that significantly enhanced the potential for breast cancer treatment through folate receptor targeting. These nanoparticles possess high drug load capacity and stability, increasing toxicity to breast cancer cells. Introducing folate-optimized tumor cell affinity enhanced antitumor effects, extending the plasma half-life, reduced dosing frequency, and reduced side effect risks. Das et al. (2021) developed similar folate-polyethylene glycol nanoparticles (FA-PEG-NPs), with encapsulated EGCG signifi- cantly boosting its effectiveness in treating triple-negative breast cancer (TNBC). TNBC cell lines and animal models could acti- vate CCN5 to inhibit in vitro cell activity by promoting apopto- sis, reduce their self-renewal and spread potentialby reversing TNBC stem cell traits, and inhibit tumor growth in vivo. Guo et al. (2021) used the π-π stacking and hydrogen bonding inter- actions of EGCG in aqueous solutions to form the core of the nanoparticles, using polyethylene glycol bromide (PEG-Br) as the Ta bl e 1. l ip id -b as ed n an op ar tic le s. N an o ca rr ie rs ;m at er ia ls/ na m es Sy nt he tic m et ho d Pa rt ic le s iz e (n m ) ce ll lin es /a ni m al m od el s an tic an ce r eff ec t re fe re nc es li po so m al f or m ul at io n (D ox or ub ic in , Q ue rc et in , eg cg ) li po so m e Pr ep ar at io n 34 2 K5 62 c el ls th e lip os om al f or m ul at io n de m on st ra te s en ha nc ed a nt ic an ce r an d an tim ic ro bi al a ct iv ity , w ith im pr ov ed s ta bi lit y an d co nt ro lle d re le as e, t o re du ce t he r isk o f se co nd ar y in fe ct io n in ca nc er p at ie nt s. D as e t al . 2 01 9 eg cg P eV s th in F ilm h yd ra tio n 40 0 a4 31 c el ls; m al e Ba lb /c n ud e m ice eg cg P eV s en ha nc e th e de liv er y of e gc g fo r sk in c an ce r tr ea tm en t, de m on st ra tin g in hi bi tio n of c an ce r ce ll gr ow th a nd re du ct io n of t um or s iz e. el -K ay al e t al . 2 01 9 Fo lic a ci d- fu nc tio na liz ed eg cg -lo ad ed N lc (e gc g- N lc ) h ig h sh ea r ho m og en iz at io n an d ul tr as on ic at io n te ch ni qu e 30 0 ca co -2 c el ls eg cg -N lc e m pl oy s a na no st ru ct ur ed li pi d ca rr ie r fu nc tio na lis ed w ith f ol ic a ci d to e nh an ce t he o ra l b io av ai la bi lit y of e gc g. th is w as d em on st ra te d by a n im pr ov em en t in t he t ra ns it of th e co m po un d th ro ug h th e in te st in al b ar rie r an d an in cr ea se in t he a pp ar en t pe rm ea bi lit y. gr an ja e t al . 2 01 9 Bo m be sin -c on ju ga te d so lid lip id n an op ar tic le s (e gc g- Sl N ) D ou bl e em ul sifi ca tio n- ev ap or at io n 16 3. 4 ± 3. 2 m Da -m B- 23 1 an d B1 6F 10 c el ls; fe m al e c5 7/ Bl 6 m ic e eg cg -S lN e nc ap su la tin g eg cg w ith in s ol id li pi d na no pa rt ic le s an d co nj ug at ed w ith g rP r- sp ec ifi c pe pt id es s ho w s en ha nc ed po te nc y ag ai ns t br ea st c an ce r ce lls in v iv o, in di ca tin g pr om isi ng t he ra pe ut ic e ffi ca cy . ra dh ak ris hn an e t al . 2 01 9 N an o- eg cg ul tr as on ic at io n N ot e xp lic itl y st at ed h1 29 9, a 54 9, B ea S2 B ce lls N an o- eg cg e nh an ce s th e de liv er y an d an tit um or e ffe ct s of e gc g in lu ng c an ce r tr ea tm en t by in hi bi tin g ce ll pr ol ife ra tio n an d in va sio n, p ot en tia lly t hr ou gh t he a m PK s ig na lin g pa th w ay ac tiv at io n. ch en , h sie h, et a l. 20 20 lN Ps -F a (fo lic a ci d fu nc tio na liz ed ) lo ad ed w ith e gc g h ig h sh ea r ho m og en iz at io n an d ul tr as on ic at io n 31 3 m cF -7 , m Da -m B- 23 1, m cF -7 ta m , an d m cF 10 a ce lls lN Ps -F a lo ad ed w ith e gc g eff ec tiv el y ta rg et c an ce r ce lls t hr ou gh fo la te r ec ep to r m ed ia tio n, e nh an ci ng e gc g bi oa va ila bi lit y, off er in g co nt ro lle d re le as e, a nd m ai nt ai ni ng s pe ci fic ity w ith m in im al e ffe ct s on h ea lth y ce lls . Fa ra be go li et a l. 20 22 PHARMAceuticAl BioloGY 681 Ta bl e 2. P ol ym er -b as ed n an op ar tic le s. N an o ca rr ie rs ; m at er ia ls/ na m es Sy nt he tic m et ho d Pa rt ic le s iz e (n m ) ce ll lin es /a ni m al m od el s an tic an ce r eff ec t re fe re nc es W ga -e F- N P (e gc g an d 5- Fu ) io no tr op ic g el at io n 25 6. 6 ± 2. 3 ht -2 9 an d ct -2 6 ce lls tu m or -b ea rin g m ic e W ga -e F- N P en ha nc es t he t re at m en t of c ol on a de no ca rc in om a by pr ov id in g su st ai ne d dr ug r el ea se a nd im pr ov ed c el lu la r up ta ke , le ad in g to in cr ea se d an ti- tu m or a ct iv ity a nd a po pt os is w ith b et te r bi oa va ila bi lit y an d ci rc ul at io n tim e. W an g, h ua ng e t al . 2 01 9 Su -m N c (S u an d Pe g- eg cg ) Se lf- as se m bl y N ot e xp lic itl y st at ed hu Ve cs , hr Pt ec s , hr cc (a ch N a nd a 49 8) hr cc -x en og ra fte d m ou se Su -m N c en ha nc es t he t he ra pe ut ic e ffi ca cy a ga in st c an ce r by s pe ci fic al ly ta rg et in g en do th el ia l c el l p ro lif er at io n an d de m on st ra tin g su pe rio r an ti- an gi og en ic , a po pt ot ic , a nd a nt ip ro lif er at iv e eff ec ts w ith r ed uc ed to xi ci ty , d ue t o th e sy ne rg ist ic p ro pe rt ie s of it s Pe g- eg cg n an oc ar rie r. yo ng vo ng so on to rn et a l. 20 19 Fo la te d ec or at ed e gc g Pl ga -N Ps (F P- eg cg -N Ps ) N an o- pr ec ip ita tio n N ot e xp lic itl y st at ed m Da -m B- 23 1 an d m cF -7 c el ls nu de m ic e FP -e gc g- N Ps t ar ge t fo la te r ec ep to r-p os iti ve b re as t ca nc er c el ls, e nh an ci ng dr ug d el iv er y, cy to to xi ci ty , a nd t he ra pe ut ic e ffi ca cy , w hi le a lso de m on st ra tin g sig ni fic an t tu m or s el ec tiv ity a nd p ot en tia l f or c an ce r tr ea tm en t in p re -c lin ic al s tu di es . Ka zi e t al . 2 02 0 gl y- N Ps a nd e gc g m an ni ch c on de ns at io n 12 7 ± 20 4t 1 ce lls Ba lB /c f em al e m ic e gl y- N Ps a nd e gc g sh ow ed a s up er io r an tit um or e ffe ct c om pa re d to f re e eg cg , w ith a s ig ni fic an t in hi bi tio n of t um or g ro w th in v iv o yi , c he n, c he n, m a, 2 02 0 cc Ss (e gc g, c ys ), gc Ss (e gc g, g ly ) m an ni ch c on de ns at io n cc Ss 1 31 1, g cS s 47 6 m cF -7 Ba lb /c f em al e m ic e th es e na no pa rt ic le s ha ve t he p ot en tia l t o re vo lu tio ni ze b re as t ca nc er th er ap y by r ev er sin g dr ug r es ist an ce , t he re by s ig ni fic an tly e nh an ci ng tr ea tm en t ou tc om es . yi , c he n, c he n, D en g, et a l. 20 20 eg cg -l oa de d Pl ga -N Ps o il- in -w at er e m ul sio n so lv en t ev ap or at io n 17 5. 8 ± 3. 8 a5 49 a nd h 12 99 lu ng c an ce r ce lls hu m an lu ng c an ce r PD X m ou se m od el eg cg -l oa de d Pl ga -N Ps e nh an ce t he t he ra pe ut ic e ffi ca cy a ga in st lu ng ca nc er b y off er in g im pr ov ed b io av ai la bi lit y an d st ab ili ty , h ig he r en ca ps ul at io n effi ci en cy , a nd s up er io r in hi bi tio n of N F- κB s ig na lin g co m pa re d to f re e eg cg . Zh an g et a l. 20 20 eg cg -l oa de d Fa -P eg -N Ps Se lf- as se m bl y us in g po ly m er ic m at er ia ls N ot e xp lic itl y st at ed m Da -m B- 23 1 an d 4t 1 ce lls nu de m ic e eg cg -loa de d Fa -P eg -N Ps s ig ni fic an tly d el ay t he g ro w th o f t N Bc t um or s, an d th is de la yi ng e ffe ct is a ch ie ve d th ro ug h th e ac tiv at io n an d ex pr es sio n of c cN 5 D as e t al . 2 02 1 N P( eg cg ) π- π st ac ki ng 46 5 Bt 47 4 an d 4t 1c el ls 4t 1- tu m or b ea rin g m ic e N P( eg cg ) eff ec tiv el y ta rg et s ca nc er c el ls w ith e pi ga llo ca te ch in g al la te , en ha nc in g bi oa va ila bi lit y, re du ci ng s ys te m ic t ox ic ity , a nd m in im iz in g im pa ct o n he al th y ce lls . gu o et a l. 20 21 ua @ eg cg -a pt N Ps co -a ss em bl y an d ap ta m er c on ju ga tio n 16 0 he pg 2 an d he la c el ls h2 2 tu m or -b ea rin g m ic e ua @ eg cg -a pt N Ps e xh ib it st ab le p h- re sp on siv e de liv er y, st ro ng t um or tis su e pe ne tr at io n, a nd e nh an ce d ce llu la r up ta ke f or h cc t re at m en t, ac tiv at e in na te a nd a cq ui re d im m un ity , a nd o ffe r a sy ne rg ist ic th er ap eu tic e ffe ct w ith r ed uc ed s id e eff ec ts . Zh an g et a l. 20 21 m PD a- ic g/ eg cg / Da tS @ tD co -lo ad in g in to m es op or ou s po ly do pa m in e 25 0 4t 1 ce lls Ba lB /c m ic e m PD a- ic g@ tD p ro vi de s co nt ro lle d dr ug r el ea se t rig ge re d by n ea r-i nf ra re d lig ht , s ho w s ex ce lle nt p ho to th er m al c on ve rs io n fo r eff ec tiv e ca nc er tr ea tm en t, an d de m on st ra te s go od s ta bi lit y an d bi oc om pa tib ili ty w ith m in im al t ox ic ity in c el l a nd a ni m al m od el s. Zh ou e t al . 2 02 1 D au no -m N c se lf- as se m bl ed m ic el la r 68 hl -6 0 an d hl -6 0/ m X2 c el ls D au no -m N c eff ec tiv el y ta rg et s m ul tid ru g- re sis ta nt le uk em ia c el ls, en ha nc in g da un or ub ic in d el iv er y, in cr ea sin g in tr ac el lu la r ro S, a nd pr om ot in g ca sp as e- m ed ia te d ap op to sis , t he re by a m pl ify in g its ch em ot he ra pe ut ic e ffi ca cy . Ba e et a l. 20 22 m te (m Pa -t eg a nd e gc g) Se lf- as se m bl y of m t an d eg cg 15 0 he la c el ls m te n an op ar tic le s eff ec tiv el y en ha nc e ph ot ot he ra py b y in hi bi tin g an ti- ap op to sis p ro te in s an d re du ci ng t um or t he rm or es ist an ce , i m pr ov e tis su e pe ne tr at io n w ith r ed -s hi fte d ab so rp tio n, m ai nt ai n st ab ili ty in bi ol og ic al e nv iro nm en ts , o ffe r eff ec tiv e ro S sc av en gi ng , a nd e ns ur e m in im al s id e eff ec ts o n he al th y ce lls . ya ng e t al . 2 02 2 ch ito sa n- ge la tin -e gc g N an op ar tic le s el ec tr os ta tic co m pl ex at io n 14 1 ± 21 gc c as es a t st ag e ii– iV hg c- 27 a nd m KN -4 5 ce lls cg e na no pa rt ic le s m ak e sir N a m or e st ab le a nd r es ist an t to t he b od y’s flu id s. th ey a lso m ak e it ea sie r fo r sir N a to e nt er c an ce r ce lls , w hi le ha vi ng li tt le e ffe ct o n he al th y ce lls . Zh ou , D on g, et a l. 20 22 Fe gc g@ m Pi N an op ar tic le s (F eg cg @ m Pi N Ps ) Se lf- as se m bl y of F eg cg an d m el itt in ( m Pi ) 29 9 he p3 B ce lls at hy m ic B al B/ c nu de m ic e Fe gc g@ m Pi N Ps t ar ge t ca nc er c el ls, r ed uc e sid e eff ec ts , r eg ul at e PD -l 1 ex pr es sio n, in du ce a po pt os is, in hi bi t tu m ou r gr ow th a nd m ai nt ai n hi gh s pe ci fic ity . Su n et a l. 20 23 lF N Ps 3- 3/ sit oX (F eg cg , 6F -l a, 6 F- Pe g an d sit oX ) m ic ro flu id ic s, po ly m er iz at io n 27 0 ct 26 c el ls; Ba lb /c m ic e lF N Ps 3- 3/ sit oX c om pl ex es e ffe ct iv el y in hi bi t PD -l 1 ex pr es sio n an d m iti ga te t c el l e xh au st io n, e nh an ci ng s ir N a st ab ili ty a nd t ar ge te d de liv er y, off er in g ro S/ ph -t rig ge re d re le as e, a nd m ai nt ai ni ng r ob us t im m un e re sp on se in du ct io n w ith m in im al e ffe ct s on h ea lth y ce lls . ha n et a l. 20 24 682 w. SuN et Al. shell to construct nanoparticles. This nanocapsule medication effectively targeted cancer cells, improved bioavailability, reduced systemic toxicity, and minimized impact on healthy cells. Innovatively, 2020 Yi, Chen, Chen, Deng, et al. (2020) devel- oped a method using amino acids to synthesize EGCG nanopar- ticles. They initiated a Mannich condensation reaction with amino acids to fix EGCG within the nanoparticles, resulting in Gly-NPs with enhanced antioxidant capacity and superior antitu- mor effects compared to those of free EGCG. This method sig- nificantly inhibited tumor growth in vivo. In addition to incorporating targeting ligands, nanocarriers are also designed with pH sensitivity to release drugs in the acidic environment of tumors, further optimizing the delivery system and reducing side effects. Zhang et al. (2021) used a self-assembly method to encapsulate uric acid (UA) and EGCG with an EpCAM-aptamer to enhance targeting, creating UA@ EGCG-Apt nanoparticles. These nanoparticles exhibit excellent pH responsiveness, tumor penetration, and cellular uptake, mak- ing them suitable for treating hepatocellular carcinoma (HCC). They can activate immune responses, reduce side effects, and improve therapeutic outcomes. Bae et al. (2022) developed a Daunorubicin-loaded Micellar NanoComplex (Dauno-MNC) nanocomposite made of daunorubicin (DNR) and EGCG, cova- lently bound via hyaluronic acid. This composite is stable at physiological pH and rapidly releases drugs in an acidic environ- ment, enhancing nuclear uptake and cytotoxicity in multidrug-resistant cell lines. Dauno-MNC promotes drug accu- mulation within cells, enhances reactive oxygen species (ROS) production, and stimulates apoptosis, displaying synergistically enhanced cytotoxicity. The pH-sensitive nature of these nanocarriers allows for pre- cise drug release in the unique acidic environment of tumors. This feature not only improves drug delivery targeting but also provides a solid foundation for subsequent photothermal ther- apy (PTT) and photodynamic therapy (PDT), enabling these treatments to be more effectively focused on tumor cells, enhancing therapeutic outcomes. Zhou et al. (2021) synthesized MPDA-ICG@TD nanoparticles containing EGCG, garlic extract diallyl trisulfide (DATS), and indocyanine green (ICG), capable of photothermal conversion and pH responsiveness. These nanoparticles allow for controllable drug release under near-infrared light, showing significant antiproliferative and pro-apoptotic effects in vitro. The BALB/c mouse 4T1 tumor model, the nanosystem effectively suppressed tumor growth and enhanced immune responses. Yang et al. (2022) constructed a self-assembling nanopolyphenol structure, MTE, by combining methyl-pheophorbide and MPa-TEG (MT) with EGCG. MTE is synthesized under mild conditions through π-π stacking interac- tions between EGCG and MT, exhibiting good stability at phys- iological pH and rapid drug release capabilities at acidic pH. These properties facilitate drug accumulation and cytotoxicity within cells. MTE also has dual therapeutic actions of antioxi- dation and heat shock protein (HSP)expression inhibition, reducing phototoxicity. Its synergistic effects on PDT and laser interstitial thermal therapy (LITT) offer new directions for clin- ical treatment. The application of nanotechnology in therapy is not limited to PTT and PDT. It also provides new avenues for gene therapy and immunotherapy. For instance, in research by Zhou, Dong, et al. (2022), a novel gene delivery system, Chitosan-Gelatin- EGCG (CGE), was developed through the interactions between chitosan, gelatin, and EGCG molecules, forming a proven stable nanocarrier. CGE-encapsulated siRNA targeting TMEM44-AS1 significantly reduced the expression of TMEM44-AS1 and statistically decreased the resistance of GC cells to 5-FU. Sun et al. (2023) created fluorinated EGCG (FEGCG) by introducing fluorine moieties into EGCG. When combined with melittin (MPI) to form FEGCG@MPI nanoparticles, these particles exhib- ited dose-dependent inhibitory effects on the growth of liver cancer cells. By co-releasing FEGCG and MPI, they regulated the PD-L1 signaling pathway while activating the expression of Bcl-2 and Bax, guiding tumor cell apoptosis. Han et al. (2024) used microfluidic technology to produce LFNPs3-3/siTOX nanoparti- cles, combining FEGCG with fluorinated long-chain amino acids (6 F-LA) and fluorinated polyethylene glycol (6 F-PEG), enhanc- ing the stability and transport efficiency of the nanoparticles. These nanoparticles leverage ROS and acidic pH shifts to trigger drug release, precisely modulating PD-L1 expression on tumor cell surfaces. This mechanism alleviates T cell exhaustion, stimu- lates immune responses, and effectively combats tumor growth and metastasis. Metal-based nanoparticles The application of metal nanoparticles in cancer treatment is an active area of research. These nanoparticles are ideal for drug delivery systems because of their unique physical and chemical properties, such as small size, large surface-to-volume ratio, and high reactive activity. For example, gold nanoparticles (AuNPs) improve drug stability and optimize their distribution in the body through surface modification and drug carrier design, enhancing the efficacy of the drug and reducing side effects. AuNPs have been extensively studied in photothermal therapy for their excellent photothermal conversion efficiency. They absorb near-infrared light and convert light into heat energy, kill- ing cancer cells. In photodynamic therapy, AuNPs generate cyto- toxic ROS, damaging the structure and function of cancer cells. Beyond phototherapy, AuNPs are also used in chemodynamic treatment (CDT) and sonodynamic therapy, utilizing their cata- lytic properties to produce ROS and inhibit tumor growth. When combined with certain anticancer drugs, metal nanoparticles have been shown to enhance the biological activity and bioavail- ability of the drugs. Metal nanoparticles also serve as imaging agents in cancer treatment. Their high atomic number and X-ray absorption rate provide greater imaging contrast, crucial for can- cer diagnosis. Some metal nanoparticles have magnetic resonance imaging (MRI) or positron emission tomography (PET) capabil- ities, making them potentially valuable for multimodal cancer imaging. Metal nanoparticles, serving as carriers for EGCG, have demonstrated tremendous potential in various cancer treatments, drug delivery and therapy, and diagnostic imaging. Details are shown in Table 3. Gold nanoparticles (AuNPs) Because of their excellent optical and electrochemical properties, AuNPs are widely used in biosensing, photothermal therapy, and drug delivery. In the study by Chavva et al. (2019), E-GNPs were designed and synthesized by reducing chloroauric acid (HAuCl4) with EGCG to enhance cellular uptake and stability of EGCG, prolong its release time in target cells, and more effectively use EGCG’s antitumor properties. Compared to normal cells, E-GNPs are more effectively internalized by various cancer cells, inhibit the nuclear translocation and transcriptional activity of NF-κB, and induce apoptosis in cancer cells. Mostafa et al. (2020) syn- thesized EGCG-AuNPs using the same method but specifically investigated the effects of the nanoparticles on tumor-suppressive miRNAs. In addition to demonstrating more potent cytotoxicity PHARMAceuticAl BioloGY 683 Ta bl e 3. m et al -b as ed n an op ar tic le s.1 15 .2 0 nm ± 1 .4 5 N an o ca rr ie rs ; m at er ia ls/ na m es Sy nt he tic m et ho d Pa rt ic le s iz e (n m ) ce ll lin es /a ni m al m od el s an tic an ce r eff ec t re fe re nc es eg cg -g ol d na no pa rt ic le s (e -g N Ps ) re du ct io n 90 .3 a3 75 Sm , m Da -m B- 2 31 , m ia P ac a, a nd P c- 3 ce lls e- gN Ps a re m or e eff ec tiv el y in te rn al iz ed b y ca nc er c el ls, e na bl in g su st ai ne d eg cg r el ea se , i nh ib iti ng N F- κB a ct iv ity , a nd in du ci ng ap op to sis in c an ce r ce lls . ch av va e t al . 2 01 9 eg cg -r ea lg ar N an op ar tic le s( eg cg -r N Ps ) ch em ic al c o- pr ec ip ita tio n 20 0. 3 ± 1. 23 hl -6 0 ce lls N o D /S ci D n ud e m ic e eg cg -r N Ps e nh an ce t he a nt ic an ce r effi ca cy a ga in st a cu te p ro m ye lo cy tic le uk em ia b y fa ci lit at in g in cr ea se d up ta ke a nd p ro lo ng ed r et en tio n of re al ga r in c an ce r ce lls , l ea di ng t o sig ni fic an t in hi bi tio n of c el l g ro w th an d tu m or v ol um e re du ct io n. Fa ng e t al . 2 01 9 lu :N d@ N iS 2- eg cg m od ifi ed s ol vo th er m al ad so rp tio n 15 0 hu m an c ol or ec ta l ad en oc ar ci no m a hc t1 16 c el ls; tu m or -b ea rin g m ic e th e lu :N d@ N iS 2- eg cg n an op ar tic le s ac t as a m ul tif un ct io na l a ge nt f or du al -m od e im ag in g gu id ed P tt , s ig ni fic an tly e nh an ci ng t he th er ap eu tic e ffe ct a ga in st t um or s w ith m in im al s id e eff ec ts b y re le as in g eg cg t o in hi bi t hS P9 0 un de r in fra re d irr ad ia tio n. . Jia ng e t al . 2 01 9 FD eP N Ps ( eg cg @ D oX F e na no pa rt ic le s) co or di na tio n ch em ist ry FD eP 30 N Ps : 7 7. 4 ± 13 FD eP 50 N Ps : 1 26 ± 2 4 FD eP 80 N Ps : 2 96 ± 1 9. 7 u8 7m g xe no gr af t m od el (e xp re ss es h ig h le ve ls of c Br 1 pr ot ei n) FD eP N Ps s ig ni fic an tly im pr ov e th e th er ap eu tic e ffi ca cy o f D oX in c an ce r tr ea tm en t by in hi bi tin g th e pr od uc tio n of it s to xi c m et ab ol ite , re du ci ng c ar di ac t ox ic ity , a nd e nh an ci ng t um or t ar ge tin g th ro ug h pr ol on ge d bl oo d ci rc ul at io n. Sh an e t al . 2 01 9 tc l@ eg cg /a l m ic ro pa rt ic le s co or di na tio n 13 00 0 B1 6, m B4 9, c t2 6, 4 t1 , hl -6 0 Fe m al e c5 7B l/ 6 m ic e th e tc l@ eg cg /a l m ic ro pa rt ic le s en ca ps ul at e tu m or c el ls fo r pe rs on al iz ed im m un ot he ra py , e nh an ci ng a nt ig en u pt ak e an d de nd rit ic c el l ac tiv at io n, a nd s ho w c om pa ra bl e an tit um or e ffe ct s to P ol yi :c in a pu lm on ar y m et as ta sis m od el . W an g, c he n, e t al . 20 19 ei N P@ D oX (e gc g, ir on io ns a nd D oX ) co or di na tio n 16 5. 1 ± 0. 4 co S7 a nd 4 t1 c el ls fe m al e Ba lB /c m ic e ei N P@ D oX d em on st ra te d an o ut st an di ng c ap ab ili ty in d ia gn os in g tu m or s an d exhi bi te d su pe rio r th er ap eu tic e ffe ct iv en es s, su cc es sf ul ly c ur bi ng th e m et as ta sis o f tu m or c el ls. ch en , F an , et a l. 20 20 eg cg @ Zi F- PD a- Pe g- D oX (e ZP PD ) N ot s pe ci fie d 24 0 ± 10 he la c el ls nu de m ic e eZ PP D d em on st ra te d a po te nt a nt ic an ce r eff ec t th ro ug h a co m bi na tio n of t ar ge te d dr ug d el iv er y, ph -re sp on siv e re le as e, a nd p ho to th er m al th er ap y, sig ni fic an tly r ed uc in g tu m or s iz e an d im pr ov in g th er ap eu tic ou tc om es in b ot h ce ll cu ltu re a nd a ni m al m od el s. ch en , t on g, e t al . 20 20 eg cg -a uN Ps N ot s pe ci fie d 35 he pg 2 ce lls eg cg -a uN Ps e nh an ce t he c yt ot ox ic e ffe ct o n he pg 2 liv er c an ce r ce lls , in cr ea se t um or -s up pr es sin g m ir -3 4a a nd le t- 7a , a nd m od ul at e ce ll de at h m ed ia to rs , s ho w in g pr om ise a s an e ffe ct iv e an ti- ca nc er a ge nt . m os ta fa e t al . 2 02 0 D oX /F e3+ /e gc g N Ps ( D F N Ps ) gr ee n on e- po t m et ho d N ot e xp lic itl y st at ed ll 2 an d a5 49 c el ls c5 7 m ic e th e D F N Ps a re e ng in ee re d to d el iv er c he m ot he ra py a nd ir on io ns t o tu m or s, in du ci ng b ot h ap op to sis a nd f er ro pt os is, t he re by e nh an ci ng th e an tic an ce r effi ca cy . m u et a l. 20 20 eg cg -l oa de d Fh P- c- Pl ga N Ps W at er -in -o il em ul sifi ca tio n 21 7. 19 ± 1 1. 37 th re e- di m en sio na l P c3 ce lls Sc iD m ic e eg cg -l oa de d Fh P- c- Pl ga N Ps e ffe ct iv el y in hi bi t pr os ta te c an ce r ce ll gr ow th a nd d em on st ra te s ig ni fic an t an tit um or a ct iv ity in v iv o, off er in g en ha nc ed im ag in g an d th er ap eu tic p ot en tia l. Pe ng e t al . 2 02 0 Pt cg N Ps (e gc g an d Pt -o h) co or di na tio n po ly m er iz at io n 60 -1 10 he pg 2 ce lls Pt cg N Ps s yn er gi ze c he m ot he ra py a nd c he m od yn am ic t he ra py , le ve ra gi ng p la tin um -in du ce d hy dr og en p er ox id e pr od uc tio n an d iro n- ba se d Fe nt on r ea ct io ns t o en ha nc e an tic an ce r effi ca cy w hi le re du ci ng s ys te m ic t ox ic ity . re n et a l. 20 20 Sa m N @ eg cg ul tr as on ic at io n 11 5. 20 ± 1 .4 5 he la c el ls th e Sa m N @ eg cg n an oh yb rid d el iv er s en ha nc ed s ta bi lit y an d ta rg et ed de liv er y of e gc g to c an ce r ce lls , i nh ib iti ng p ro te in k in as e cK 2 eff ec tiv el y an d off er in g po te nt ia l a s an a lte rn at iv e ca nc er t he ra py w ith b ro ad er a nt im ic ro bi al a pp lic at io ns . (F as ol at o et a l. 20 21 ) l- eg cg -m n N Ps re ve rs e m ic ro em ul sio n 27 7. 4 ± 5. 5 h2 2 ce lls h2 2 tu m or -b ea rin g m ic e l- eg cg -m n na no pa rt ic le s m ay s er ve a s a po te nt ia l m ri c on tr as t ag en t w ith e nh an ce d ca pa bi lit ie s fo r tu m or im ag in g an d th er ap y li e t al . 2 02 1 lm Pe ( li qu id m et al -P la sm a am in e o xi da se -e gc g) ca sc ad e ca ta ly tic 30 0 ct 26 c el ls ct 26 t um or b ea rin g m ou se lm Pe e ffi ci en tly t ar ge ts c an ce r ce lls , c on ve rt in g tu m or p ol ya m in es in to cy to to xi c ag en ts , e nh an ci ng p ho to th er m al c on ve rs io n, r ed uc in g off -t ar ge t eff ec ts , a nd in hi bi tin g tu m or g ro w th w ith m in im al in v iv o to xi ci ty . li u et a l. 20 21 D oX @ m tP /h a- eg cg co or di na tio n N ot e xp lic itl y st at ed gl 26 1 ce lls Fe m al e c5 7B l/ 6 m ic e D oX @ m tP /h a- eg cg n an or ea ct or s en ha nc e tu m or t ar ge tin g an d th er ap eu tic a ge nt r el ea se w ith in t um or c el ls, a m pl ify in g ch em od yn am ic t he ra py b y effi ci en tly d ep le tin g gl ut at hi on e an d ov er co m in g th e bl oo d- br ai n ba rr ie r. m u et a l. 20 21 fa u@ Zi F- Fe e la ye re d as se m bl y 13 7 m cF -7 c el ls fa u@ Zi F- Fe e pr ec ise ly lo ca liz es c he m ot he ra py a ge nt s w ith in c an ce r ce lls , en su re s co nt ro lle d dr ug r el ea se , a nd t ar ge ts d ru g- re sis ta nt t um or s, en ha nc in g tr ea tm en t effi ca cy a nd s af et y. W an g, h ua ng , X in , et a l. 20 21 (C on tin ue d) 684 w. SuN et Al. toward liver cancer cells, they significantly increased levels of miR-34a and let-7a in HepG2 cells, affecting the expression of the target genes Caspase-3 and c-Myc. This study filled the knowledge gap on the impact of EGCG-AuNPs on miRNA expression in cancer cells. Building on previous reduction meth- ods for synthesizing gold nanoparticles, Cunha et al. (2022) enhanced the delivery of EGCG to pancreatic cancer cells through functionalization and conjugation, achieving therapeutic effects at lower drug concentrations while maintaining antioxi- dant activity. Wang, Huang, Xin, et al. (2021) adopted a more complex nanostructure, using gold nanoparticles as the core, encapsulated by a pH-sensitive metal-organic framework (MOF, ZIF-8) to form a core-shell structure, and covered with a coor- dination complex layer of EGCG and Fe3+. This multifunctional nanostructure, responsive to changes in TME through its inter- actions with hydroxides, protons, and telomerases, enables pre- cise drug release and treatment. Additionally, this structure integrates CDT and telomerase-driven chemotherapy, showing exceptional therapeutic effects against drug-resistant cancer cells. Gao et al. (2022) further advanced the application of nanotech- nology by designing and synthesizing AuNCs-EGCG, a nano-complex that can be controlled through near-infrared response for EGCG release. Using the photothermal effect and synergistic action of EGCG, they significantly enhanced the inhi- bition of liver cancer cell proliferation and promoted apoptosis. Li et al. (2022) synthesized iRGD-PEG-PLGA@AuNCs/EGCG (PAuE) nanoparticles, innovatively coating the gold nanocages (AuNCs) with maleimide-poly(diols)-poly(lactic-co-glycolic acid) (Mal-PEG-PLGA), greatly enhancing the targeting ability to tumor cells. To ensure the stability and functionality of the nanoparticles, the research team quenched unreacted maleimide groups on the surface of PAuE NPs with cysteine. These nanopar- ticles demonstrated synergistic effects of PTT and chemotherapy, aiming to integrate mild PTT, enhanced drug loading, in vivo tracking, and tumor targeting. In vivo experiments showed that mild PTT promoted the release of EGCG, which enhanced apop- tosis by inhibiting HIF-1α expression. Gene expression analysis also supported the combination of mild phototherapy and che- motherapy to induce necrosis and apoptosis synergistically. Iron nanoparticles Iron nanoparticles are extensively researched and applied in bio- medical engineering, with applications that include MRI, bioca- talysis, magnetic hyperthermia, photo-responsive therapy, immunotherapy, and drug delivery. Specifically, iron metal-phenolic networks (MPNs) are nanomaterials formed through chemical coordination between iron ions and polyphe-nolic substances, exhibiting good biocompatibility, high drug-loading capacity, low immunogenicity, and minimal toxicity. Iron nanoparticles have demonstrated promising therapeutic out- comes and clinical application prospects in cancer therapy, par- ticularly in inducing iron-dependent cell death (ferroptosis) and integrated disease diagnostics and treatment. These characteris- tics provide a solid foundation for further applications of iron nanoparticles in cancer treatment. With the excellent biocompatibility and drug-loading capacity of iron nanoparticles, Shan et al. (2019) used self-assembly tech- niques to encapsulate DOX and EGCG within a nano platform using coordination between Fe3+ and polyphenols. EGCG enhanced DOX’s efficacy and reduced cardiac toxicity by inhib- iting carbonyl reductase1 (CBR1) expression and dox-orubicinol (DOXOL) production. The improved stability of the blood circu- lation resulted in a high accumulation of fabrication of EGCG@N an o ca rr ie rs ; m at er ia ls/ na m es Sy nt he tic m et ho d Pa rt ic le s iz e (n m ) ce ll lin es /a ni m al m od el s an tic an ce r eff ec t re fe re nc es eg cg -c ys ta uN Ps eg cg -c ha uN Ps fu nc tio na liz at io n an d co nj ug at io n 11 1 ± 1 12 5 ± 13 Bx Pc 3 ce lls eg cg -c ha uN Ps a nd e gc g- cy st au NP s im pr ov e th e de liv er y of e pi ga llo ca te ch in ga lla te t o pa nc re at ic ca nc er c el ls, re qu iri ng lo w er d ru g co nc en tra tio ns fo r eff ec tiv en es s, pr es er vi ng a nt io xid an t ac tiv ity , d em on st ra tin g sc al ab ilit y, an d m ai nt ai ni ng n on -to xic ity t o ca nc er c el ls. cu nh a et a l. 20 22 au N cs -e gc g co nj ug at io n N ot e xp lic itl y st at ed he pg 2 ce lls au N cs -e gc g lo ad ed w ith e gc g eff ec tiv el y ta rg et c an ce r ce lls t hr ou gh ph ot ot he rm al t he ra py , e nh an ci ng e gc g st ab ili ty a nd b io av ai la bi lit y, off er in g co nt ro lle d re le as e, a nd m ai nt ai ni ng s pe ci fic ity w ith m in im al eff ec ts o n he al th y ce lls . ga o et a l. 20 22 ir gD -P eg -P lg a@ au N cs /e gc g (P au e) N Ps N an op re ci pi ta tio n 14 0. 1 ± 3. 6 m Da -m B- 23 1 ce lls Fe m al e Ba lb /c N ud e m ic e ir gD -P eg -P lg a@ au N cs /e gc g (P au e) n an op ar tic le s eff ec tiv el y ta rg et ca nc er c el ls th ro ug h re ce pt or -m ed ia te d en do cy to sis , e nh an ci ng e gc g st ab ili ty a nd b io av ai la bi lit y, off er in g co nt ro lle d re le as e, a nd e ns ur in g sp ec ifi ci ty w ith m in im al e ffe ct s on h ea lth y ce lls . li e t al . 2 02 2 Fe gc g/ Zn /c y5 -s ir N a/ er yt hr oc yt e Fl uo rin at ed -c oo rd in at iv e- eg cg sy nt he sis N ot e xp lic itl y st at ed he p1 -6 , m hc c- 97 h, 4 t1 ce lls he p1 -6 t um or -b ea rin g m ic e c5 7B l/ 6 m ic e Fe gc g/ Zn /c y5 -s ir N a/ er yt hr oc yt e eff ec tiv el y ta rg et s ca nc er c el ls, en ha nc es t he s ta bi lit y an d tu m or a cc um ul at io n of s ir N a, o ffe rs co nt ro lle d re le as e th ro ug h er yt hr oc yt e in te gr at io n, a nd m ai nt ai ns sp ec ifi ci ty w ith m in im al e ffe ct s on h ea lth y ce lls , t he re by im pr ov in g th e effi ca cy o f im m un ot he ra py b y re gu la tin g PD -l 1 ex pr es sio n. W u et a l. 20 22 Sm -e gc g- Se N Ps re du ct io n, f re ez e- dr yi ng N ot e xp lic itl y st at ed he pg 2 ce lls Sm -e gc g- Se N Ps e ffe ct iv el y ta rg et c an ce r ce lls t hr ou gh e nh an ce d ap op to sis in du ct io n, in cr ea sin g st ab ili ty a nd b io ac tiv ity o f se le ni um , off er in g sy ne rg ist ic a nt ic an ce r eff ec ts , a nd m ai nt ai ni ng h ig he r cy to to xi ci ty w ith m in im al e ffe ct s on h ea lth y ce lls . Zh ou , l iu , et a l. 20 22 m et al -e nr ic he d hS P9 0 na no in hi bi to r (m ne gc g) Fl as h na no co m pl ex at io n (F N c) 20 8 hc t1 16 , g Se 1, h m rS V5 , m gc 80 3, h gc -2 7, ct 26 c el ls Ba lB /c m ic e m od el m ne gc g na no pa rti cle s eff ec tiv el y in hi bi t he at s tre ss re sis ta nc e in t um or c el ls, in du ce p yr op to sis , a nd t ar ge t ca nc er c el ls sp ec ifi ca lly , e nh an cin g th e effi ca cy o f h yp er th er m ic in tra pe rit on ea l c he m ot he ra py w hi le p ro m ot in g im m un og en ic ce ll de at h an d m ai nt ai ni ng m in im al t ox ici ty t o he al th y ce lls . W an g et a l. 20 23 Ta bl e 3. c on tin ue d. PHARMAceuticAl BioloGY 685 DOX Fe (FDEP) nanoparticles in tumors. Furthermore, com- pared to the free drug group, both FDEP30 and FDEP50 nanoparticles inhibited tumor growth and extended the survival time of tumor-bearing mice, demonstrating a synergistic enhance- ment effect. Fasolato et al. (2021) developed a self-assembled core-shell nanocomposite named SAMN@EGCG, combining sur- factant maghemite nanoparticles (SAMN) with intrinsic dual sig- naling functions and EGCG. This innovative design protected EGCG from degradation and autoxidation and effectively deliv- ered EGCG into cancer cells. SAMN@EGCG significantly improved the targeted inhibition of endogenous protein kinase CK2 in HeLa cells, rivaling the effects of the specific protein kinase CK2 inhibitor CX-4945, showing potential applications in cancer therapy. For targeted glioblastoma therapy, Mu et al. (2021) employed a natural derivative of EGCG, HA-EGCG, and developed a DOX@MTP/HA-EGCG nano-reactor based on MTP. With its pH and GSH dual-responsive release mechanism, this nano-reactor achieved tumor-specific payload delivery and ROS production. In vitro, blood-brain barrier models showed that DOX@MTP/HA-EGCG could penetrate the blood-brain barrier and deliver drugs to brain tumors. After cellular uptake via the CD44 receptor, the nano-reactor is released from the lysosomes, triggering the sustained release of DOX, Fe3+, and EGCG, achieving chemotherapy and CDT effects. Mu et al. (2020) also encapsulated DOX and EGCG in a nanocarrier and achieved selective release of DOX and Fe3+ under specific pH or GSH conditions. Their research focused more on the mechanisms of action. DOX-induced apoptosis by binding to nuclear DNA, while EGCG chemically reduced Fe3+ to Fe2+. The generated Fe2+ reacted with H2O2, initiating ferroptosis, a combination of apop- tosis and ferroptosis that demonstrated significant antitumor effects. Liu et al. (2021) developed the LMPE technique, a mul- timodal therapy platform combining CDT and PTT, enhancing enzyme catalytic efficiency through the morphological transfor- mation of liquid metal. CDT was implemented through PAO catalysis, producing H2O2 and utilizing Fe3+ catalyzed Fenton reaction, generating hydroxyl radicals. The outer EGCG-Fe3+ complex absorbed near-infrared light to generate heat, imple- menting PTT, effectively eliminating tumor cells while minimiz- ing damage to surrounding healthy tissue. Iron nanoparticles have multiple potentials in targeted cancer therapy and make significant contributions to diagnostics. Chen, Fan, et al. (2020) developed an innovative multifunctional drug delivery system composed of EGCG, Fe3+, and DOX. It effec- tively inhibited tumor growth and prevented tumor metastasis by inhibiting the epithelial-mesenchymaltransition (EMT) and reducing levels of matrix metalloproteinases (MMPs). Using iron ions as an MRI contrast agent, the system provided precise imag- ing in tumor diagnostics and therapy, enhancing its potential for clinical applications. Peng et al. (2020) successfully constructed an EGCG-loaded FHP-c-PLGA NPs nanocarrier system. This system, covered with polyethylene glycol-gelatin composite mate- rial, contained EGCG, biodegradable polymer PLGA, and stable iron oxide nanoparticles (IOs). This composite nanostructure tar- geted prostate cancer cells and suppressed tumor growth by inducing programmed cell death. In MRI, IOs served as a T2-weighted negative contrast imaging agent, significantly reduc- ing signal intensity in the tumor area, thus prominently high- lighting the tumor. It possessed fluorescent labeling capabilities that allow real-time tracking and localization via in vivo fluores- cence imaging and computed tomography. This integrated diag- nostic and therapeutic nanotechnology offers new strategies and directions for future cancer treatments. Other metal nanoparticles The application of metal nanoparticles in cancer research is a highly active field, including gold, iron, zinc, manganese, nickel, and sele- nium. These nanoparticles exhibit great potential in cancer therapy because of their unique physicochemical properties and biological activities. Fang et al. (2019) developed nanoparticles encapsulated with EGCG using a chemical co-precipitation method. These nanoparticles, EGCG-wrapped realgar nanoparticles (EGCG-RNPs), in which the amorphous transformation of EGCG enhances its sta- bility and antitumor activity in HL-60 cells, demonstrated significant inhibitory effects on acute promyelocytic leukemia (APL) HL-60 cells. Zhou, Liu, et al. (2022) used starch microspheres (SM) and EGCG as templates to prepare monodispersed selenium nanoparti- cles (SeNPs), named SM-EGCG-SeNPs, through Se-O bonding and polysaccharide-polyphenol interactions. These nanoparticles induced apoptosis in cancer cells by activating multiple caspases and generat- ing excess ROS. Building on these studies, Chen, Tong, et al. (2020) created a nano-drug carrier named EZPPD, which combines the chemo- therapy drug DOX with EGCG. EZPPD’s design allows con- trolled drug release under the acidic conditions of the tumor microenvironment and 808 nm laser-induced photothermal effects. This nanocarrier releases the drug in response to acidic pH and further promotes release through the photothermal effect of the polydopamine (PDA) layer under laser illumination. The combined effect of DOX and EGCG stimulates autophagy and autophagosome formation in tumor cells, effectively inhibiting tumor growth in a mouse model of HeLa tumor, demonstrating its superior therapeutic effects. In the latest work by Wang et al. (2023), they constructed a unique nanotherapeutic agent formed through the self-assembly process of manganese ions with EGCG, which has dual functions of chemotherapy and immunotherapy. In the application of hyperthermic intraperitoneal chemotherapy (HIPEC), this nan- otherapeutic agent can intervene in the energy metabolism of tumor cells, significantly reduce ATP levels, and inhibit the activ- ity of colon tumor cells by inhibiting the function of HSP90. The agent can induce the oxidative stress response and activation of caspase-1, triggering gasdermin D (GSDMD)-mediated cell pyro- ptosis, releasing tumor antigens, and activating an immune response. This process ultimately promotes dendritic cell matura- tion, enhancing the effects of immunotherapy. This study pro- vides new information on the design of nanomedicines combining chemotherapy and immunotherapy. Wang, Chen, et al. (2019) employed a metal-organic coordi- nation strategy to rapidly form an EGCG-Al (III) layer, achieving efficient encapsulation of tumor cells for personalized immuno- therapy. This encapsulation method can efficiently load antigens, protect them, and activate dendritic cells, improving Th1-related cytokines production. This method has shown broad applicability in six tumor cell types and significant antitumor effects in a lung metastasis model, providing a new direction for personalized therapy. Wu et al. (2022) introduced gene therapy into chemo- therapy and immunotherapy. They designed and synthesized a new delivery system named FEGCG/Zn, creating enhanced anti-PD-L1 immunotherapy through a FEGCG/Zn/siPD-L1/red blood cell biomimetic system. The red blood cell component increased siPD-L1 accumulation in tumors, and the combination of FEGCG/Zn and siPD-L1 could improve T cell ability to kill tumors and attenuate the activity of infiltrating CD8+ T cells, thus improving therapeutic effects. This study suggests that FEGCG/Zn can serve both as a PD-L1 inhibitor and a carrier of immunobiological molecules, potentially becoming an effective platform for improving cancer treatment. 686 w. SuN et Al. Building on previous research, nanoparticles containing EGCG have made significant progress in cancer treatment and shown great potential in the diagnostic field. Li et al. (2021) synthesized L-EGCG-Mn nanoparticles using the reverse microemulsion method as MRI contrast agents. These nanoparticles are particu- larly notable for their safety and pH sensitivity, adapting well to changes in pH in TME. In both in vitro and in vivo experiments, L-EGCG-Mn nanoparticles demonstrated excellent MRI contrast performance, particularly in hypoxic environments such as the H22 tumor cell model and mouse model, confirming their effec- tiveness as potential tumor-targeting contrast agents. Continuing this research line, Ren et al. (2020) developed PTCG nanoparti- cles that combine EGCG and a platinum (IV) prodrug (Pt-OH) through metal-polyphenol coordination, creating an innovative theranostic nanomedicine. Once ingested by cancer cells, these nanoparticles release anticancer drugs and ROS, achieving a syn- ergistic effect of chemotherapy and photodynamic therapy. The introduced gadolinium (Gd) element provides imaging capabili- ties to track drug delivery and release processes. In vivo experi- ments show that PTCG nanoparticles possess synergistic anticancer effects and good biocompatibility. The hybrid metal-ligand strategy significantly improves anticancer efficacy and improves theranostic capabilities. Jiang et al. (2019) reported for the first time on NiS2-modified NaLuF4:Nd (Lu:Nd@NiS2) core-shell nanoparticles. These multifunctional Lu:Nd@NiS2 nanoparticles were successfully applied in T2-weighted MRI and short-wave infrared (SWIR) luminescence imaging-guided photo- thermal therapy. Cells and animals treated with Lu:Nd@NiS2 showed no significant toxicity. This material was also used to load EGCG. Under near-infrared irradiation, EGCG was released from Lu:Nd@NiS2-EGCG, interacted with HSP90, and reduced cell heat tolerance, achieving better therapeutic outcomes at the same temperature increase. Carbohydrate-based nanoparticles Polysaccharides are natural high-molecular-weight polymers with ten or more monosaccharides linked by glycosidic bonds. Their abundance of functional groups, such as hydroxyl, amino, sulfate, and carboxyl groups, makes them ideal templates for synthesiz- ing nanoparticles in modern nanotechnology. Due to their bio- compatibility, degradability, renewability, and ease of modification, polysaccharide nanoparticles are widely used in biomedicine, particularly as drug delivery systems for transporting anticancer drugs, genes, and vaccines. Common polysaccharides such as cyclodextrin, chitosan, and alginate have shown significant poten- tial in these applications. Details are shown in Table 4. In terms of carbohydrate-based nanoparticles carrying EGCG, researchers have made several breakthroughs. Chen, Lai, et al. (2020) utilized hyaluronic acid conjugated with TPGS (a vitamin E derivative) to successfully encapsulate EGCGof strong antioxidative, therapeutic nanoparticles based on amino acid-induced ultrafast assembly of tea polyphenols. ACS Appl Mater Interfaces. 12(30):33550–33563. doi:10.1021/acsami.0c10282. Yongvongsoontorn N, Chung JE, Gao SJ, Bae KH, Yamashita A, Tan MH, Ying JY, Kurisawa M. 2019. Carrier-enhanced anticancer efficacy of sunitinib-loaded green tea-based micellar nanocomplex beyond tumor-targeted delivery. ACS Nano. 13(7):7591–7602. doi:10.1021/acsnano.9b00467. Yuan H, Li Y, Ling F, Guan Y, Zhang D, Zhu Q, Liu J, Wu Y, Niu Y. 2020. The phytochemical epigallocatechin gallate prolongs the lifespan by improving lipid metabolism, reducing inflammation and oxidative stress in high-fat diet-fed obese rats. Aging Cell. 19(9):e13199. doi:10.1111/acel.13199. Zeng W, Lao S, Guo Y, Wu Y, Huang M, Tomlinson B, Zhong G. 2022. The in- fluence of EGCG on the pharmacokinetics and pharmacodynamics of bisopr- olol and a new method for simultaneous determination of EGCG and bisopr- olol in rat plasma. Front Nutr. 9:907986. doi:10.3389/fnut.2022.907986. Zhang L, Chen W, Tu G, Chen X, Lu Y, Wu L, Zheng D. 2020. Enhanced chemotherapeutic efficacy of PLGA-encapsulated epigallocatechin gallate (EGCG) against human lung cancer. Int J Nanomedicine. 15:4417–4429. doi:10.2147/IJN.S243657. Zhang B, Jiang J, Wu P, Zou J, Le J, Lin J, Li C, Luo B, Zhang Y, Huang R, et al. 2021. A smart dual-drug nanosystem based on co-assembly of plant and food-derived natural products for synergistic HCC immunotherapy. Acta Pharm Sin B. 11(1):246–257. doi:10.1016/j.apsb.2020.07.026. Zhao J, Blayney A, Liu X, Gandy L, Jin W, Yan L, Ha JH, Canning AJ, Connelly M, Yang C, et al. 2021. EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction. Nat Commun. 12(1):986. doi:10.1038/s41467-021-21258-5. Zhou M, Dong J, Huang J, Ye W, Zheng Z, Huang K, Pan Y, Cen J, Liang Y, Shu G, et al. 2022. Chitosan-gelatin-EGCG nanoparticle-meditated LncRNA TMEM44-AS1 silencing to activate the P53 signaling pathway for the synergistic reversal of 5-FU resistance in gastric cancer. Adv Sci (Weinh). 9(22):e2105077. doi:10.1002/advs.202105077. Zhou X, Liang J, Liu Q, Huang D, Xu J, Gu H, Xue W. 2021. Codelivery of epigallocatechin-3-gallate and diallyl trisulfide by near-infrared light-responsive mesoporous polydopamine nanoparticles for enhanced an- titumor efficacy. Int J Pharm. 592:120020. doi:10.1016/j.ijpharm.2020.120020. Zhou J, Liu Y, Hu Y, Zhang D, Xu W, Chen L, He J, Cheng S, Cai J. 2022. Selenium nanoparticles synergistically stabilized by starch microgel and EGCG: synthesis, characterization, and bioactivity. Foods. 12(1):13. doi:10.3390/foods12010013. https://doi.org/10.1080/10408398.2019.1565490 https://doi.org/10.1021/acsami.0c11650 https://doi.org/10.1021/acsami.0c11650 https://doi.org/10.1021/acsami.0c10282 https://doi.org/10.1021/acsnano.9b00467 https://doi.org/10.1111/acel.13199 https://doi.org/10.3389/fnut.2022.907986 https://doi.org/10.2147/IJN.S243657 https://doi.org/10.1016/j.apsb.2020.07.026 https://doi.org/10.1038/s41467-021-21258-5 https://doi.org/10.1002/advs.202105077 https://doi.org/10.1016/j.ijpharm.2020.120020 https://doi.org/10.3390/foods12010013 Epigallocatechin-3-gallate at the nanoscale: a new strategy for cancer treatment ABSTRACT Introduction Materials and methods Results The role of EGCG in cancer research and its potential therapeutic mechanisms Challenges of EGCG bioavailability, pharmacokinetic properties, and stability EGCG-loaded nanoparticles Lipid-based nanoparticles in cancer therapy Polymer-based nanoparticles in cancer therapy Metal-based nanoparticles Gold nanoparticles (AuNPs) Iron nanoparticles Other metal nanoparticles Carbohydrate-based nanoparticles Discussion Authors contributions Disclosure statement Funding References
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- Onde a resposta: Radares são emissores e receptores de ondas de rádio e têm aplicações, por exemplo, na determinação de velocidades de veículos nas ru
- qual a resposta: Radares são emissores e receptores de ondas de rádio e têm aplicações, por exemplo, na determinação de velocidades de veículos nas ru
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- Geradores CA
- 1.Introdução.a.Transferência.de.Massa
