Synergistic combinatorial anticancer potential of Tamoxifen with Naringin and Diosmetin in MCF-7 breast cancer cells and their liposomal delivery

synergistic-combinatorial-anticancer-potential-of-tamoxifen-with-naringin-and-diosmetin-in-mcf-7-breast-cancer-cells-and-their-liposomal-delivery
Synergistic combinatorial anticancer potential of Tamoxifen with Naringin and Diosmetin in MCF-7 breast cancer cells and their liposomal delivery

References

  1. Breast cancer. https://www.who.int/news-room/fact-sheets/detail/breast-cancer

  2. Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 74, 12–49 (2024).

    Google Scholar 

  3. Anderson, B. O. et al. The global breast cancer initiative: a strategic collaboration to strengthen health care for non-communicable diseases. Lancet Oncol. 22, 578–581 (2021).

    Google Scholar 

  4. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J. Clin. 71, 209–249 (2021).

    Google Scholar 

  5. Villela, L., Velez, A. K., Lopez-Sanc, R., Martínez-Cardona, J. & Hernandez, J. Advantages of drug selective distribution in cancer treatment: Brentuximab Vedotin. Int. J. Pharmacol. 13, 785–807 (2017).

    Google Scholar 

  6. Zafar, A., Khatoon, S., Khan, M. J., Abu, J. & Naeem, A. Advancements and limitations in traditional anti-cancer therapies: A comprehensive review of surgery, chemotherapy, radiation therapy, and hormonal therapy. Discov. Oncol. 16, 607 (2025).

    Google Scholar 

  7. Kang, L., Gao, Z., Huang, W., Jin, M. & Wang, Q. Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment. Acta Pharm. Sin B. 5, 169–175 (2015).

    Google Scholar 

  8. Liang, Y. et al. Nanoplatform-based natural products co-delivery system to surmount cancer multidrug-resistant. J. Controll. Release. 336, 396–409 (2021).

    Google Scholar 

  9. Al Bostami, R. D., Abuwatfa, W. H. & Husseini, G. A. Recent advances in nanoparticle-based co-delivery systems for cancer therapy. Nanomaterials (Basel). 12, 2672 (2022).

    Google Scholar 

  10. Xiong, R. et al. Selective human Estrogen receptor partial agonists (ShERPAs) for Tamoxifen-Resistant breast cancer. J. Med. Chem. 59, 219–237 (2016).

    Google Scholar 

  11. Rondón-Lagos, M., Villegas, V., Rangel, N., Sánchez, M. & Zaphiropoulos, P. Tamoxifen resistance: Emerging molecular targets. IJMS 17, 1357 (2016).

    Google Scholar 

  12. Emons, G., Mustea, A. & Tempfer, C. Tamoxifen and endometrial cancer: A Janus-Headed drug. Cancers 12, 2535 (2020).

    Google Scholar 

  13. He, J. & Zhang, H. P. Research progress on the anti-tumor effect of naringin. Front. Pharmacol. 14, 1217001 (2023).

    Google Scholar 

  14. Alhalmi, A., Amin, S., Ralli, T., Ali, K. S. & Kohli, K. Therapeutic role of naringin in cancer: molecular pathways, synergy with other agents, and nanocarrier innovations. Naunyn Schmiedebergs Arch. Pharmacol. 398, 3595–3615 (2025).

    Google Scholar 

  15. Ghanbari-Movahed, M., Jackson, G., Farzaei, M. H. & Bishayee, A. A systematic review of the preventive and therapeutic effects of naringin against human malignancies. Front. Pharmacol. 12, 639840 (2021).

  16. Wang, C. et al. Anti-proliferation and pro-apoptotic effects of Diosmetin via modulating cell cycle arrest and mitochondria-mediated intrinsic apoptotic pathway in MDA-MB-231 cells. Med. Sci. Monit. 25, 4639–4647 (2019).

    Google Scholar 

  17. Li, J. et al. Effects of citrus-derived Diosmetin on melanoma: Induction of apoptosis andautophagy mediated by PI3K/Akt/mTOR pathway inhibition. ACAMC 25, 921–933 (2025).

    Google Scholar 

  18. Shangguan, W. J. et al. Naringin inhibits vascular endothelial cell apoptosis via Endoplasmic reticulum stress– and mitochondrial–mediated pathways and promotes intraosseous angiogenesis in ovariectomized rats. Int. J. Mol. Med. 40, 1741–1749 (2017).

    Google Scholar 

  19. Azizpour, M., Changizzadeh, B., Golbashirzadeh, M. & Moradzadegan, A. Exploring the therapeutic potential of naringin and melatonin in breast cancer: A focus on SKBR3 and MCF-7 cell lines. Biomed. Res. Ther. 12, 7109–7117 (2025).

    Google Scholar 

  20. Roma, A., Rota, S. G. & Spagnuolo, P. A. Diosmetin induces apoptosis of acute myeloid leukemia cells. Mol. Pharm. 15, 1353–1360 (2018).

    Google Scholar 

  21. Raza, W., Meena, A. & Luqman, S. Diosmetin: A dietary flavone as modulator of signaling pathways in cancer progression. Mol. Carcinog. 63, 1627–1642 (2024).

    Google Scholar 

  22. Pandey, P. et al. An updated review summarizing the anticancer potential of flavonoids via targeting NF-kB pathway. Front. Pharmacol. 15, 1513422 (2025).

  23. Mokhtari, R. B. et al. Combination therapy in combating cancer. Oncotarget 8, 38022–38043 (2017).

    Google Scholar 

  24. Djamgoz, M. B. A. Combinatorial therapy of cancer: possible advantages of involving modulators of ionic mechanisms. Cancers (Basel). 14, 2703 (2022).

    Google Scholar 

  25. Damodaran, C., Cho, J. Y. & Güngör, C. Therapeutic resistance and combination therapy for cancer: recent developments and future directions. Sci. Rep. 15, 26881 (2025).

    Google Scholar 

  26. Foucquier, J. & Guedj, M. Analysis of drug combinations: current methodological landscape. Pharmacol. Res. Perspect. 3, e00149 (2015).

    Google Scholar 

  27. Banerjee, V. et al. Synergistic potential of dual Andrographolide and melatonin targeting of metastatic colon cancer cells: using the Chou-Talalay combination index method. Eur. J. Pharmacol. 897, 173919 (2021).

    Google Scholar 

  28. Duarte, D. & Vale, N. Evaluation of synergism in drug combinations and reference models for future orientations in oncology. Curr. Res. Pharmacol. Drug Discov. 3, 100110 (2022).

    Google Scholar 

  29. Din, F. et al. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int. J. Nanomed. 12, 7291–7309 (2017).

    Google Scholar 

  30. He, Q. et al. Tumor microenvironment responsive drug delivery systems. Asian J. Pharm. Sci. 15, 416–448 (2020).

    Google Scholar 

  31. Sun, L. et al. Smart nanoparticles for cancer therapy. Sig Transduct. Target. Ther. 8, 418 (2023).

    Google Scholar 

  32. Rosenblum, D., Joshi, N., Tao, W., Karp, J. M. & Peer, D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat. Commun. 9, 1410 (2018).

    Google Scholar 

  33. Deshpande, P. P., Biswas, S. & Torchilin, V. P. Current trends in the use of liposomes for tumor targeting. Nanomed. (Lond). 8, 1509–1528 https://doi.org/10.2217/nnm.13.118 (2013).

  34. Hamad, I., Harb, A. A. & Bustanji, Y. Liposome-based drug delivery systems in cancer research: An analysis of global landscape efforts and achievements. Pharmaceutics 16, 400 (2024).

    Google Scholar 

  35. Allahou, L. W., Madani, S. Y. & Seifalian, A. Investigating the application of liposomes as drug delivery systems for the diagnosis and treatment of cancer. Int. J. Biomater. 2021, 3041969 (2021).

    Google Scholar 

  36. Chen, J. et al. Recent advances and clinical translation of liposomal delivery systems in cancer therapy. Eur. J. Pharm. Sci. 193, 106688 (2024).

    Google Scholar 

  37. Zahednezhad, F. et al. Liposomal drug delivery systems for organ-specific cancer targeting: Early promises, subsequent problems, and recent breakthroughs. Expert Opin. Drug Deliv. 21, 1363–1384 (2024).

    Google Scholar 

  38. Adler-Moore, J., Proffitt, R. T. & AmBisome liposomal formulation, structure, mechanism of action and pre-clinical experience. J. Antimicrob. Chemother. 49, 21–30 (2002).

    Google Scholar 

  39. Barenholz, Y. (Chezy). Doxil®— The first FDA-approved nano-drug: Lessons learned. J. Controll. Release 160, 117–134 (2012).

  40. Fulton, M. D. & Najahi-Missaoui, W. Liposomes in cancer therapy: How Did we start and where are we now. IJMS 24, 6615 (2023).

  41. Zhao, Z., Jin, G., Ge, Y. & Guo, Z. Naringenin inhibits migration of breast cancer cells via inflammatory and apoptosis cell signaling pathways. Inflammopharmacol 27, 1021–1036 (2019).

    Google Scholar 

  42. Moon, S. Y. et al. Inhibition of STAT3 enhances sensitivity to Tamoxifen in Tamoxifen-resistant breast cancer cells. BMC Cancer. 21, 931 (2021).

    Google Scholar 

  43. Jalalpour Choupanan, M., Shahbazi, S. & Reiisi, S. Naringenin in combination with quercetin/fisetin shows synergistic anti-proliferative and migration reduction effects in breast cancer cell lines. Mol. Biol. Rep. 50, 7489–7500 (2023).

    Google Scholar 

  44. Abdelkarim, M. et al. 3,6-dichloro-1,2,4,5-Tetrazine assayed at high doses in the metastatic breast cancer cell line MDA-MB-231 reduces cell numbers and induces apoptosis. Curr. Bioact. Compd. 16, 546–550 (2020).

    Google Scholar 

  45. Limam, I. et al. Tunisian Artemisia Campestris L.: A potential therapeutic agent against myeloma—phytochemical and Pharmacological insights. Plant. Methods 20, 59 (2024).

    Google Scholar 

  46. Chou, T. C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70, 440–446 (2010).

    Google Scholar 

  47. Gaballah, A. I. et al. Dexamethasone–tamoxifen combination exerts synergistic therapeutic effects in tamoxifen-resistance breast cancer cells. Biosci. Rep. 44, BSR20240367 (2024).

    Google Scholar 

  48. Ling, L. U., Tan, K. B., Lin, H. & Chiu, G. N. C. The role of reactive oxygen species and autophagy in safingol-induced cell death. Cell. Death Dis. 2, e129–e129 (2011).

    Google Scholar 

  49. Shyamsivappan, S. et al. Novel phenyl and thiophene dispiro indenoquinoxaline pyrrolidine quinolones induced apoptosis via G1/S and G2/M phase cell cycle arrest in MCF-7 cells. New. J. Chem. 44, 15031–15045 (2020).

    Google Scholar 

  50. Alcon, C. et al. ER+ breast cancer strongly depends on MCL-1 and BCL-xL anti-apoptotic proteins. Cells 10, 1659 (2021).

    Google Scholar 

  51. Maitani, Y., Soeda, H., Junping, W. & Takayama, K. Modified ethanol injection method for liposomes containing β-sitosterol β-D-glucoside. J. Liposome Res. 11, 115–125 (2001).

    Google Scholar 

  52. Wong, M. Y. & Chiu, G. N. C. Simultaneous liposomal delivery of quercetin and vincristine for enhanced estrogen-receptor-negative breast cancer treatment. Anti-Cancer Drugs. 21, 401–410 (2010).

    Google Scholar 

  53. Kesharwani, P., Md, S., Alhakamy, N. A., Hosny, K. M. & Haque, A. QbD enabled Azacitidine loaded liposomal nanoformulation and its in vitro evaluation. Polymers 13, 250 (2021).

    Google Scholar 

  54. Saad, A. S. Novel spectrophotometric method for selective determination of compounds in ternary mixtures (dual wavelength in ratio spectra). Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 147, 257–261 (2015).

    Google Scholar 

  55. Borman, P., Elder, D. & Q2(R1. ) Validation of analytical procedures. In ICH Quality Guidelines 127–166 (John Wiley & Sons, Ltd, 2017). https://doi.org/10.1002/9781118971147.ch5

    Google Scholar 

  56. Holsæter, A. M. et al. How docetaxel entrapment, vesicle size, zeta potential and stability change with liposome composition–A formulation screening study. Eur. J. Pharm. Sci. 177, 106267 (2022).

    Google Scholar 

  57. Sebaaly, C., Greige-Gerges, H., Stainmesse, S., Fessi, H. & Charcosset, C. Effect of composition, hydrogenation of phospholipids and lyophilization on the characteristics of eugenol-loaded liposomes prepared by ethanol injection method. Food Biosci. 15, 1–10 (2016).

    Google Scholar 

  58. Sandhu, P. S. et al. Natural lipids enriched self-nano-emulsifying systems for effective co-delivery of Tamoxifen and naringenin: systematic approach for improved breast cancer therapeutics. Nanomed. Nanotechnol. Biol. Med. 13, 1703–1713 (2017).

    Google Scholar 

  59. Prathyusha, E. et al. Investigation of ROS generating capacity of curcumin-loaded liposomes and its in vitro cytotoxicity on MCF-7 cell lines using photodynamic therapy. Photodiagn. Photodyn. Ther. 40, 103091 (2022).

    Google Scholar 

  60. Wright, R. H. G., Vastolo, V., Oliete, J. Q., Carbonell-Caballero, J. & Beato, M. Global signalling network analysis of luminal T47D breast cancer cells in response to progesterone. Front. Endocrinol. (Lausanne). 13, 888802 (2022).

    Google Scholar 

  61. Płonka-Czerw, J., Żyrek, L. & Latocha, M. Changes in the sensitivity of MCF-7 and MCF-7/DX breast cancer cells to cytostatic in the presence of Metformin. Molecules 29, 3531 (2024).

    Google Scholar 

  62. Matsuyoshi, S., Shimada, K., Nakamura, M. & Ishida, E. Konishi, N. FADD phosphorylation is critical for cell cycle regulation in breast cancer cells. Br. J. Cancer. 94, 532–539 (2006).

    Google Scholar 

  63. Kalabay, M. et al. Investigation of the antitumor effects of Tamoxifen and its ferrocene-linked derivatives on pancreatic and breast cancer cell lines. Pharmaceuticals (Basel). 15, 314 (2022).

    Google Scholar 

  64. Chen, C. H. et al. Naringin induces ROS-stimulated G1 cell-cycle arrest and apoptosis in nasopharyngeal carcinoma cells. Environ. Toxicol. 39, 5059–5073 (2024).

    Google Scholar 

  65. Ge, A. et al. Diosmetin prevents TGF-β1-induced epithelial-mesenchymal transition via ROS/MAPK signaling pathways. Life Sci. 153, 1–8 (2016).

    Google Scholar 

  66. Yuan, Y., Long, H., Zhou, Z., Fu, Y. & Jiang, B. PI3K-AKT-targeting breast cancer treatments: Natural products and synthetic compounds. Biomolecules 13, 93 (2023).

    Google Scholar 

  67. Pan, Z. et al. Diosmetin induces apoptosis and protective autophagy in human gastric cancer HGC-27 cells via the PI3K/Akt/FoxO1 and MAPK/JNK pathways. Med. Oncol. 40, 319 (2023).

    Google Scholar 

  68. Lee, H. J. & Choi, C. H. Characterization of SN38-resistant T47D breast cancer cell sublines overexpressing BCRP, MRP1, MRP2, MRP3, and MRP4. BMC Cancer. 22, 446 (2022).

    Google Scholar 

  69. Farhadi, P. et al. Cell line-directed breast cancer research based on glucose metabolism status. Biomed. Pharmacother. 146, 112526 (2022).

    Google Scholar 

  70. Chou, T. C. The combination index (CI < 1) as the definition of synergism and of synergy claims. Synergy 7, 49–50 (2018).

    Google Scholar 

  71. Kalkan, F. N. et al. Synergistic and antagonistic drug interactions are prevalent but not conserved across acute myeloid leukemia cell lines. Sci. Rep. 15, 19431 (2025).

    Google Scholar 

  72. Benderski, K., Lammers, T. & Sofias, A. M. Analysis of multi-drug cancer nanomedicine. Nat. Nanotechnol. https://doi.org/10.1038/s41565-025-01932-1 (2025).

  73. Hu, C. et al. Optimizing drug combination and mechanism analysis based on risk pathway crosstalk in pan cancer. Sci. Data 11, 74 (2024).

    Google Scholar 

  74. Ahmed, N. S., Samec, M., Liskova, A., Kubatka, P. & Saso, L. Tamoxifen and oxidative stress: An overlooked connection. Discov. Oncol. 12, 17 (2021).

    Google Scholar 

  75. Tan, D., Ma, N., Wang, Y., Li, X. & Xu, M. Reactive oxygen species in cancer: mechanistic insights and therapeutic innovations. Cell. Stress Chaperones 30, 100108 https://doi.org/10.1016/j.cstres.2025.100108 (2025).

    Google Scholar 

  76. El-Kersh, D. M. et al. Anti-estrogenic and anti-aromatase activities of citrus peels major compounds in breast cancer. Sci. Rep. 11, 7121 (2021).

    Google Scholar 

  77. Tiwari, R. et al. Reactive oxygen species (ROS) and their profound influence on regulating diverse aspects of cancer: A concise review. Drug Dev. Res. 86, e70107 (2025).

    Google Scholar 

  78. Yuan, L. et al. Promoting apoptosis, a promising way to treat breast cancer with natural products: A comprehensive review. Front. Pharmacol. 12, 801662 (2022).

  79. Utpal, B. K. et al. Exploring natural products as apoptosis modulators in cancers: insights into natural product-based therapeutic strategies. Naunyn-Schmiedeberg’s Arch. Pharmacol. 398, 8189–8214 (2025).

    Google Scholar 

  80. Panche, A. N., Diwan, A. D. & Chandra, S. R. Flavonoids: An overview. J. Nutr. Sci. 5, e47 (2016).

    Google Scholar 

  81. Imran, M. et al. Exploring the remarkable chemotherapeutic potential of polyphenolic antioxidants in battling various forms of cancer. Molecules 28, 3475 (2023).

    Google Scholar 

  82. Bisht, P. et al. Naringin and Temozolomide combination suppressed the growth of glioblastoma cells by promoting cell apoptosis: Network pharmacology, in-vitro assays and metabolomics based study. Front. Pharmacol. 15, 1431085 (2024).

    Google Scholar 

  83. Kang, M. H. & Reynolds, C. P. Bcl-2 inhibitors: Targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res. 15, 1126–1132 (2009).

    Google Scholar 

  84. Bharti, V. et al. BCL-xL Inhibition potentiates cancer therapies by redirecting the outcome of p53 activation from senescence to apoptosis. Cell. Rep. 41, 111826 (2022).

    Google Scholar 

  85. Erdogan, S., Doganlar, O., Doganlar, Z. B. & Turkekul, K. Naringin sensitizes human prostate cancer cells to paclitaxel therapy. Prostate Int. 6, 126–135 (2018).

    Google Scholar 

  86. Ajji, P. K., Walder, K. & Puri, M. Combination of balsamin and flavonoids induce apoptotic effects in liver and breast cancer cells. Front. Pharmacol. 11, 574496 (2020).

    Google Scholar 

  87. Quintieri, L., Palatini, P., Moro, S. & Floreani, M. Inhibition of cytochrome P450 2C8-mediated drug metabolism by the flavonoid Diosmetin. Drug Metab. Pharmacokinet. 26, 559–568 (2011).

    Google Scholar 

  88. Effat, H., Abosharaf, H. A. & Radwan, A. M. Combined effects of naringin and doxorubicin on the JAK/STAT signaling pathway reduce the development and spread of breast cancer cells. Sci. Rep. 14, 2824 (2024).

    Google Scholar 

  89. Kim, H. & Lee, D. G. Naringin-generated ROS promotes mitochondria-mediated apoptosis in Candida albicans. IUBMB Life. 73, 953–967 (2021).

    Google Scholar 

  90. Crosley, P. et al. Procaspase-activating compound-1 synergizes with TRAIL to induce apoptosis in established granulosa cell tumor cell line (KGN) and explanted patient granulosa cell tumor cells in vitro. Int. J. Mol. Sci. 22, 4699 (2021).

    Google Scholar 

  91. Abachi, M., Salati, M., Araghi, S., Shirkoohi, R. & Eslamifar, A. Molecular analysis of acquired Tamoxifen resistance in breast cancer cell line. Asian Pac. J. Cancer Biology. 2, 41–49 (2017).

    Google Scholar 

  92. Williams, M. M. et al. Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers. Cell. Death Dis. 9, 21 (2018).

    Google Scholar 

  93. Albayrak, D. et al. Naringin combined with NF-κB Inhibition and Endoplasmic reticulum stress induces apoptotic cell death via oxidative stress and the PERK/eIF2α/ATF4/CHOP axis in HT29 colon cancer cells. Biochem. Genet. 59, 159–184 (2021).

    Google Scholar 

  94. Xu, C. et al. Naringin induces apoptosis of gastric carcinoma cells via blocking the PI3K/AKT pathway and activating pro–death autophagy. Mol. Med. Rep. 24, 772 (2021).

    Google Scholar 

  95. Qiao, J. et al. Diosmetin triggers cell apoptosis by activation of the p53/Bcl-2 pathway and inactivation of the Notch3/NF-κB pathway in HepG2 cells. Oncol. Lett. 12, 5122–5128 (2016).

    Google Scholar 

  96. Ning, R. et al. Diosmetin inhibits cell proliferation and promotes apoptosis through STAT3/c-Myc signaling pathway in human osteosarcoma cells. Biol. Res. 54, 40 (2021).

    Google Scholar 

  97. Gouda, A., Sakr, O. S., Nasr, M. & Sammour, O. Ethanol injection technique for liposomes formulation: An insight into development, influencing factors, challenges and applications. J. Drug Deliv. Sci. Technol. 61, 102174 (2021).

    Google Scholar 

  98. Pittiu, A. et al. Production of liposomes by microfluidics: the impact of post-manufacturing dilution on drug encapsulation and lipid loss. Int. J. Pharm. 664, 124641 (2024).

    Google Scholar 

  99. Qi, X., Wang, J., Chen, C. & Wang, L. Optimal design of micromixer for preparation of nanoliposomes. Chem. Eng. Process. Process. Intensif. 196, 109677 (2024).

    Google Scholar 

  100. Carugo, D., Bottaro, E., Owen, J., Stride, E. & Nastruzzi, C. Liposome production by microfluidics: Potential and limiting factors. Sci. Rep. 6, 25876 (2016).

    Google Scholar 

  101. Zhang, G., Wang, L. & Pan, J. Probing the binding of the flavonoid Diosmetin to human serum albumin by multispectroscopic techniques. J. Agric. Food Chem. 60, 2721–2729 (2012).

    Google Scholar 

  102. Hakim, A., Loka, I. & Prastiwi, N. New method for isolation of naringin compound from citrus maxima. Nat. Resour. 10, 299–304 (2019).

    Google Scholar 

  103. Khan, Z. et al. Preparation and in vitro evaluation of Tamoxifen-conjugated, eco-friendly, agar-based hybrid magnetic nanoparticles for their potential use in breast cancer treatment. ACS Omega. 8, 25808–25816 (2023).

    Google Scholar 

  104. Gupta, S. R. N. Determination of lecithin from egg yolk, milk, Soyabean seed, sunflower oil calorimetrically and its FTIR study (2024). https://doi.org/10.5281/ZENODO.12702228

  105. Romano, E. et al. Identification of cholesterol in different media by using the FT-IR, FT-Raman and UV–visible spectra combined with DFT calculations. J. Mol. Liq. 403, 124879 (2024).

    Google Scholar 

  106. Mohebbi, S., Shariatipour, M., Shafie, B. & Amini, M. M. Encapsulation of Tamoxifen citrate in functionalized mesoporous silica and investigation of its release. J. Drug Deliv. Sci. Technol. 62, 102406 (2021).

    Google Scholar 

  107. Taghon, G. J., Rowe, J. B., Kapolka, N. J. & Isom, D. G. Predictable cholesterol binding sites in GPCRs lack consensus motifs. Structure 29, 499–506e3 (2021).

    Google Scholar 

  108. Chaki, R. et al. Biocompatible nanocarriers of bioactive flavonoid naringin: Design, formulation, and comprehensive characterization. J. App Pharm. Sci. 15, 117–126 (2025).

    Google Scholar 

  109. Xie, D. et al. Convenient and highly efficient adsorption of Diosmetin from lemon peel by magnetic surface molecularly imprinted polymers. J. Mater. Sci. Technol. 211, 159–170 (2025).

    Google Scholar 

  110. Halevas, E. G., Avgoulas, D. I., Katsipis, G. & Pantazaki, A. A. Flavonoid-liposomes formulations: Physico-chemical characteristics, biological activities and therapeutic applications. Eur. J. Med. Chem. Rep. 5, 100059 (2022).

    Google Scholar 

  111. Mehta, M. et al. Lipid-based nanoparticles for drug/gene delivery: An overview of the production techniques and difficulties encountered in their industrial development. ACS Mater. Au. 3, 600–619 (2023).

    Google Scholar 

  112. Sani, A. et al. Revolutionizing anticancer drug delivery: Exploring the potential of tamoxifen-loaded nanoformulations. J. Drug Deliv. Sci. Technol. 86, 104642 (2023).

    Google Scholar 

  113. Ashfaq, R. et al. Lipid nanoparticles: an effective tool to improve the bioavailability of nutraceuticals. Int. J. Mol. Sci. 24, 15764 (2023).

    Google Scholar 

  114. Midekessa, G. et al. Zeta potential of extracellular vesicles: Toward understanding the attributes that determine colloidal stability. ACS Omega. 5, 16701–16710 (2020).

    Google Scholar 

  115. Németh, Z. et al. Quality by Design-Driven zeta potential optimisation study of liposomes with charge imparting membrane additives. Pharmaceutics 14, 1798 (2022).

    Google Scholar 

  116. Rizwan, S. B., Dong, Y. D., Boyd, B. J., Rades, T. & Hook, S. Characterisation of bicontinuous cubic liquid crystalline systems of phytantriol and water using cryo field emission scanning electron microscopy (cryo FESEM). Micron 38, 478–485 (2007).

    Google Scholar 

  117. Rashidinejad, A., Birch, E. J., Sun-Waterhouse, D. & Everett, D. W. Delivery of green tea catechin and epigallocatechin gallate in liposomes incorporated into low-fat hard cheese. Food Chem. 156, 176–183 (2014).

    Google Scholar 

  118. Şahin Bektay, H., Sağıroğlu, A. A., Bozali, K., Güler, E. M. & Güngör, S. The design and optimization of ceramide NP-loaded liposomes to restore the skin barrier. Pharmaceutics 15, 2685 (2023).

    Google Scholar 

  119. Dejeu, I. L. et al. Innovative approaches to enhancing the biomedical properties of liposomes. Pharmaceutics 16, 1525 (2024).

    Google Scholar 

  120. Lee, Y. & Thompson, D. H. Stimuli-Responsive liposomes for drug delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 9 https://doi.org/10.1002/wnan.1450 (2017).

  121. Eugster, R., Luciani, P. & Liposomes Bridging the gap from lab to pharmaceuticals. Curr. Opin. Colloid Interface Sci. 75, 101875 (2025).

    Google Scholar 

  122. Bai, X., Smith, Z. L., Wang, Y., Butterworth, S. & Tirella, A. Sustained drug release from smart nanoparticles in cancer therapy: A comprehensive review. Micromachines (Basel). 13, 1623 (2022).

    Google Scholar 

  123. Mircioiu, C. et al. Mathematical modeling of release kinetics from supramolecular drug delivery systems. Pharmaceutics 11, 140 (2019).

    Google Scholar 

  124. Ahmadzadegan, A., Zhang, J., Ardekani, A. & Vlachos, P. Spatiotemporal Measurement of Concentration-Dependent Diffusion Coefficient. (2022). https://doi.org/10.22541/au.164873358.86144442/v1

  125. Ahmed, L. et al. Study the using of nanoparticles as drug delivery system based on mathematical models for controlled release. IJLTEMAS 8, 52–56 (2019).

  126. Askarizadeh, M., Esfandiari, N., Honarvar, B., Sajadian, S. A. & Azdarpour, A. Kinetic modeling to explain the release of medicine from drug delivery systems. ChemBioEng Rev. 10, 1006–1049 (2023).

  127. Sawaftah, N. A., Paul, V., Awad, N. & Husseini, G. A. Modeling of Anti-Cancer drug release kinetics from liposomes and micelles: A review. IEEE Trans. Nanobiosci. 20, 565–576 (2021).

    Google Scholar 

  128. AlMajed, Z., Salkho, N. M., Sulieman, H. & Husseini, G. A. Modeling of the in vitro release kinetics of sonosensitive targeted liposomes. Biomedicines 10, 3139 (2022).

    Google Scholar 

  129. Izadiyan, Z. et al. Advancements in liposomal nanomedicines: innovative formulations, therapeutic applications, and future directions in precision medicine. Int. J. Nanomed. 20, 1213–1262 (2025).

    Google Scholar 

  130. Kozak, A., Lavrih, E., Mikhaylov, G. & Turk, B. Vasiljeva, O. Navigating the clinical landscape of liposomal therapeutics in cancer treatment. Pharmaceutics 17, 276 (2025).

    Google Scholar 

  131. Xiao, D. (Zoe) Liposomal drug delivery: comparative kinetics, efficacy, and applications in targeted therapeutics. Theor. Nat. Sci. 69, 140–149 (2025).

    Google Scholar 

  132. Farhan, M. Naringin’s prooxidant effect on tumor cells: Copper’s role and therapeutic implications. Pharmaceuticals (Basel). 15, 1431 (2022).

    Google Scholar 

  133. Liu, C. Y. et al. Tamoxifen induces apoptosis through cancerous inhibitor of protein phosphatase 2A–dependent phospho-Akt inactivation in Estrogen receptor–negative human breast cancer cells. Breast Cancer Res. 16, 431 (2014).

    Google Scholar 

  134. Koosha, S., Mohamed, Z., Sinniah, A. & Alshawsh, M. A. Investigation into the molecular mechanisms underlying the Anti-proliferative and anti-tumorigenesis activities of Diosmetin against HCT-116 human colorectal cancer. Sci. Rep. 9, 5148 (2019).

    Google Scholar 

  135. Yen, C., Zhao, F., Yu, Z., Zhu, X. & Li, C. G. Interactions between natural products and Tamoxifen in breast cancer: A comprehensive literature review. Front. Pharmacol. 13, 847113 (2022).

    Google Scholar 

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