Quercetin (Que) is a kind of natural flavonoid compound. In recent years, Que has received great attention in anti-tumor research. However, the poor water solubility and low bioavailability of Que greatly limit its clinical application. Nanodelivery systems have made certain progress in improving the poor water solubility of Que and delaying its metabolism in the body, significantly enhancing its anti-cancer effects.  This article reviews the anti-tumor mechanism of Que and the research on the anti-tumor effect of Que nanomedicine in recent years in the literature at home and abroad, so as to provide a reference for further research on Que.

1.Erawati T, Isadiartuti D, Anggalih BD. The effect of polysorbate 20 and polysorbate 80 on the solubility of quercetin[J]. J Public Health Afr, 2023, 14(Suppl 1): 2503. DOI: 10.4081/jphia.2023.2503.

2.Ramešová S, Sokolová R, Degano I, et al. On the stability of the bioactive flavonoids quercetin and luteolin under oxygen-free conditions[J]. Anal Bioanal Chem, 2012, 402(2): 975-982. DOI: 10.1007/s00216-011-5504-3.

3.Prabhat S, Sharad S, Srikanta KR. A versatile flavonoid quercetin: study of its toxicity and differential gene expression in the liver of mice[J]. Phytomedicine Plus, 2022, 2(1): 100148. DOI: 10.1016/j.phyplu.2021.100148.

4.Li X, He X, Lin B, et al. Quercetin limits tumor immune escape through PDK1/CD47 axis in melanoma[J]. Am J Chin Med, 2024, 52(2): 541-543. DOI: 10.1142/S0192415X2450023X.

5.杨海玲, 苏国惠, 黄华枫, 等. 一测多评法同时测定广西桑叶及其炮制品中5种活性成分含量[J]. 亚太传统医药, 2023, 19(10): 33-38. [Yang HL, Su GH, Huang HF, et al. Simultaneous determination of 5 active ingredients in mulberry leaves from Guangxi by QAMS[J]. Asia-Pacific Traditional Medicine, 2023, 19(10): 33-38.] DOI: 10.11954/ytctyy.202310007.

6.师艺玮, 王洪玲, 黄慧莲, 等. UPLC-MS/MS法同时测定经典方剂槐花散中7个成分含量[J]. 药物分析杂志, 2023, 43(2):219-226. [Shi YW, Wang HL, Huang HL, et al. Simultaneous determination of 7 components in classic formula Huaihua powder by UPLC-MS/MS[J]. Chinese Journal of Pharmaceutical Analysis, 2023, 43(2): 219-226.] DOI: 10.16155/j.0254-1793.2023.02.05.

7.Hou DD, Zhang W, Gao YL, et al. Anti-inflammatory effects of quercetin in a mouse model of MC903-induced atopic dermatitis[J]. Int Immunopharmacol, 2019, 74: 105676. DOI: 10.1016/j.intimp.2019.105676.

8.Xu D, Hu MJ, Wang YQ, et al. Antioxidant activities of quercetin and its complexes for medicinal application[J]. Molecules, 2019, 24(6): 1123. DOI: 10.3390/molecules24061123.

9.Nguyen TLA, Bhattacharya D. Antimicrobial activity of quercetin: an approach to its mechanistic principle[J]. Molecules, 2022, 27(8): 2494. DOI: 10.3390/molecules27082494.

10.Saivish MV, de Lima Menezes G, da Silva RA, et al. Antiviral activity of quercetin hydrate against zika virus[J]. Int J Mol Sci, 2023, 24(8): 7504. DOI: 10.3390/ijms24087504.

11.Chekuri S, Vyshnava SS, Somisetti SL, et al. Isolation and anticancer activity of quercetin from Acalypha indica L. against breast cancer cell lines MCF-7 and MDA-MB-231[J]. 3 Biotech, 2023, 13(8): 289. DOI: 10.1007/s13205-023-03705-w.

12.Zu G, Sun K, Li L, et al. Mechanism of quercetin therapeutic targets for Alzheimer disease and type 2 diabetes mellitus[J]. Sci Rep, 2021, 11(1): 22959. DOI: 10.1038/s41598-021-02248-5.

13.Brüll V, Burak C, Stoffel-Wagner B, et al. Effects of a quercetin-rich onion skin extract on 24 h ambulatory blood pressure and endothelial function in overweight-to-obese patients with (pre-)hypertension: a randomised double-blinded placebo-controlled cross-over trial[J]. Br J Nutr, 2015, 114(8): 1263-1277. DOI: 10.1017/S0007114515002950.

14.Dehghani F, Jandaghi SHSS, Janani L, et al. Effects of quercetin supplementation on inflammatory factors and quality of life in post-myocardial infarction patients: a double blind, placebo-controlled, randomized clinical trial[J]. Phytother Res, 2021, 35(4): 2085-2098. DOI: 10.1002/ptr.6955.

15.Chekalina N, Burmak Y, Petrov Y, et al. Quercetin reduces the transcriptional activity of NF-κB in stable coronary artery disease[J]. Indian Heart J, 2018, 70(5): 593-597. DOI: 10.1016/j.ihj.2018.04.006.

16.Loshaj AS, Ilaria A, Basholli MS, et al. Quercetin and its nano-formulations for brain tumor therapy-current developments and future perspectives for paediatric studies[J]. Pharmaceutics, 2023, 15(3): 963. DOI: 10.3390/pharmaceutics15030963.

17.Wang Q, Ma C, Wang N, et al. Effects of quercetin on the DNA methylation pattern in tumor therapy: an updated review[J]. Food Funct, 2024, 15(8): 3897-3907. DOI: 10.1039/d3fo03831a.

18.Kamal R, Paul P, Thakur S, et al. Quercetin in oncology: a phytochemical with immense therapeutic potential[J]. Curr Drug Targets, 2024, 25(11): 740-751. DOI: 10.2174/0113894501292466240627050638.

19.Graña X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth sup pressor genes and cyclin-dependent kinase inhibitors (CKIs)[J]. Oncogene, 1995, 11(2): 211-219. https://pubmed.ncbi.nlm.nih.gov/7624138/.

20.Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin dependent kinases[J]. Genes Dev, 1995, 9(10): 1149. DOI: 10.1101/gad.9.10.1149.

21.Mu C, Jia P, Yan Z, et al. Quercetin induces cell cycle G1 arrest through elevating Cdk inhibitors p21 and p27 in human hepatoma cell line (HepG2)[J]. Methods Find Exp Clin Pharmacol, 2007, 29(3): 179-183. DOI: 10.1358/mf.2007.29.3.1092095.

22.Yoshida M, Sakai T, Hosokawa N, et al. The effect of quercetin on cell cycle progression and growth of human gastric cancer cells[J]. FEBS Lett, 1990, 260(1): 10-13. DOI: 10.1016/0014-5793(90)80053-l.

23.Shafabakhsh R, Asemi Z. Quercetin: a natural compound for ovarian cancer treatment[J]. J Ovarian Res, 2019, 12(1): 55. DOI: 10.1186/s13048-019-0530-4.

24.Chan CY, Hong SC, Chang CM, et al. Oral squamous cell carcinoma cells with acquired resistance to erlotinib are sensitive to anti-cancer effect of quercetin via pyruvate kinase M2 (PKM2)[J]. Cells, 2023, 12(1): 179. DOI: 10.3390/cells12010179.

25.Azizi E, Fouladdel S, Movahhed TK, et al. Quercetin effects on cell cycle arrest and apoptosis and doxorubicin activity in T47D cancer stem cells[J]. Asian Pac J Cancer Prev, 2022, 23(12): 4145-4154. DOI: 10.31557/APJCP.2022.23.12.4145.

26.Hu SA, Cheng J, Zhao WH, et al. Quercetin induces apoptosis in meningioma cells through the miR-197/IGFBP5 cascade[J]. Environ Toxicol Pharmacol, 2020, 80: 103439. DOI: 10.1016/j.etap.2020.103439.

27.Lu X, Yang F, Chen D, et al. Quercetin reverses docetaxel resistance in prostate cancer via androgen receptor and PI3K/Akt signaling pathways[J]. Int J Biol Sci, 2020, 16(7): 1121-1134. DOI: 10.7150/ijbs.41686.

28.Wang W, Yuan X, Mu J, et al. Quercetin induces MGMT+glioblastoma cells apoptosis via dual inhibition of Wnt3a/β-catenin and Akt/NF-κB signaling pathways[J]. Phytomedicine, 2023, 118: 154933. DOI: 10.1016/j.phymed.2023.154933.

29.Ward AB, Mir H, Kapur N, et al. Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways[J]. World J Surg Oncol, 2018, 16(1): 108. DOI: 10.1186/s12957-018-1400-z.

30.Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer[J]. Mol Cancer, 2020, 19(1): 12. DOI: 10.1186/s12943-020-1138-4.

31.Xiao J, Zhang B, Yin S, et al. Quercetin induces autophagy-associated death in HL-60 cells through CaMKKβ/AMPK/mTOR signal pathway[J]. Acta Biochim Biophys Sin (Shanghai), 2022, 54(9): 1244-1256. DOI: 10.3724/abbs.2022117.

32.Guo H, Ding H, Tang X, et al. Quercetin induces pro-apoptotic autophagy via SIRT1/AMPK signaling pathway in human lung cancer cell lines A549 and H1299 in vitro[J]. Thorac Cancer, 2021, 12(9): 1415-1422. DOI: 10.1111/1759-7714.13925.

33.Hasan AAS, Kalinina EV, Tatarskiy VV, et al. Suppression of the antioxidant system and PI3K/Akt/mTOR signaling pathway in cisplatin-resistant cancer cells by quercetin[J]. Bull Exp Biol Med, 2022, 173(6): 760-764. DOI: 10.1007/s10517-022-05626-9. 

34.Liao Y, Xie X, Zhang C, et al. Quercetin exerts anti-tumor immune mechanism by regulating IL-6/JAK2/STAT3 signaling pathway to deplete Treg cells[J]. Toxicon, 2024, 243: 107747. DOI: 10.1016/j.toxicon.2024.107747.

35.Li T, Li Y. Quercetin acts as a novel anti-cancer drug to suppress cancer aggressiveness and cisplatin-resistance in nasopharyngeal carcinoma (NPC) through regulating the yes-associated protein/Hippo signaling pathway[J]. Immunobiology, 2023, 228(2): 152324. DOI: 10.1016/j.imbio.2022.152324.

36.Huang J, Chen J, Li J. Quercetin promotes ATG5-mediating autophagy-dependent ferroptosis in gastric cancer[J]. J Mol Histol, 2024, 55(2): 211-225. DOI: 10.1007/s10735-024-10186-5.

37.Li B, Shao H, Gao L, et al. Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a review[J]. Drug Deliv, 2022, 29(1): 2130-2161. DOI: 10.1080/10717544.2022.2127213.

38.Elzayat A, Adam-Cervera I, Álvarez-Bermúdez O, et al. Nanoemulsions for synthesis of biomedical nanocarriers[J]. Colloids Surf B Biointerfaces, 2021, 203: 111764. DOI: 10.1016/j.colsurfb.2021.111764.

39.Das SS, Sarkar A, Chabattula SC, et al. Food-Grade Quercetin-loaded nanoemulsion ameliorates effects associated with parkinson's disease and cancer: studies employing a transgenic c. elegans model and human cancer cell lines[J]. Antioxidants (Basel), 2022, 11(7): 1378. DOI: 10.3390/antiox11071378.

40.Oskooei FA, Mehrzad J, Asoodeh A, et al. Olive oil-based quercetin nanoemulsion (QuNE)'s interactions with human serum proteins (HSA and HTF) and its anticancer activity[J]. J Biomol Struct Dyn, 2023, 41(3): 778-791. DOI: 10.1080/07391102.2021.2012514.

41.Chitkara A, Mangla B, Kumar P, et al. Design-of-experiments (DoE)-assisted fabrication of quercetin-loaded nanoemulgel and its evaluation against human skin cancer cell lines[J]. Pharmaceutics, 2022, 14(11): 2517. DOI: 10.3390/pharmaceutics14112517.

42.Moghassemi S, Dadashzadeh A, Azevedo RB, et al. Nanoemulsion applications in photodynamic therapy[J]. J Control Release, 2022, 351: 164-173. DOI: 10.1016/j.jconrel.2022.09.035.

43.Roy A, Nishchaya K, Rai VK. Nanoemulsion-based dosage forms for the transdermal drug delivery applications: a review of recent advances[J]. Expert Opin Drug Deliv, 2022, 19(3): 303-319. DOI: 10.1080/17425247.2022.2045944.

44.Elsebay MT, Eissa NG, Balata GF, et al. Nanosuspension: a formulation technology for tackling the poor aqueous solubility and bioavailability of poorly soluble drugs[J]. Curr Pharm Des, 2023, 29(29): 2297-2312. DOI: 10.2174/1381612829666230911105922.

45.Tian Y, Wang S, Yu Y, et al. Review of nanosuspension formulation and process analysis in wet media milling using microhydrodynamic model and emerging characterization methods[J]. Int J Pharm, 2022, 623: 121862. DOI: 10.1016/j.ijpharm.2022.121862.

46.Qiao Y, Cao Y, Yu K, et al. Preparation and antitumor evaluation of quercetin nanosuspensions with synergistic efficacy and regulating immunity[J]. Int J Pharm, 2020, 589: 119830. DOI: 10.1016/j.ijpharm.2020.119830.

47.Vithani K, Jannin V, Pouton CW, et al. Colloidal aspects of dispersion and digestion of self-dispersing lipid-based formulations for poorly water-soluble drugs[J]. Adv Drug Deliv Rev, 2019, 142: 16-34. DOI: 10.1016/j.addr.2019.01.008.

48.Hsieh CM, Yang TL, Putri AD, et al. Application of design of experiments in the development of self-microemulsifying drug delivery systems[J]. Pharmaceuticals (Basel), 2023, 16(2): 283. DOI: 10.3390/ph16020283. 

49.Patcharawalai J, Subhaphorn W, Surasak L, et al. Enhanced oral bioavailability and improved biological activities of a quercetin/resveratrol combination using a liquid self-microemulsifying drug delivery system[J]. Planta medica, 2020, 87(4): 336-346. DOI: 10.1055/a-1270-7606.

50.Zhang M, Du Y, Wang S, et al. A review of biomimetic nanoparticle drug delivery systems based on cell membranes[J]. Drug Des Devel Ther, 2020, 14: 5495-5503. DOI: 10.2147/DDDT.S282368.

51.Liu Z, Xia Q, Ma D, et al. Biomimetic nanoparticles in ischemic stroke therapy[J]. Discov Nano, 2023, 18(1): 40. DOI: 10.1186/s11671-023-03824-6.

52.李萌, 余玲玲, 邱新云, 等. 载槲皮素仿生纳米粒诱导结直肠癌细胞凋亡的研究[J]. 上海中医药大学学报, 2023, 37(1): 10-16. [Li M, Yu LL, Qiu XY, et al. Quercetin-loaded biomimetic nanoparticles induce apoptosis in colorectal cancer cells[J]. Acta Universitatis Traditionis Medicalis Sinensis Pharmacologiaeque Shanghai, 2023, 37(1): 10-16.] DOI: 10.16306/j.1008-861x.2023.01.002.

53.Díaz-González M, de la Escosura-Muñiz A, Fernandez-Argüelles MT, et al. Quantum dot bioconjugates for diagnostic applications[J]. Top Curr Chem (Cham), 2020, 378(2): 35. DOI: 10.1007/s41061-020-0296-6.

54.Zhang LJ, Xia L, Xie HY, et al. Quantum dot based biotracking and biodetection[J]. Anal Chem, 2019, 91(1): 532-547. DOI: 10.1021/acs.analchem.8b04721.

Pourmadadi M, Shabestari MS, Abdouss H, et al. Green synthesis of pH-sensitive carboxymethyl cellulose/agarose/carbon quantum dots nanocarriers for quercetin delivery to A549 lung cancer using an emulsification method[J]. BioNanoScience, 2024, 14(4): 4570-4584. DOI: 10.1007/s12668-024-01426-9.

55.Li J, Gao Y, Liu S, et al. Aptamer-functionalized Quercetin thermosensitive liposomes for targeting drug delivery and antitumor therapy[J]. Biomed Mater, 2022, 17(6): 065003. DOI: 10.1088/1748-605X/ac8c75.

56.Demirbolat GM, Erdoğan Ö, Coşkun GP, et al. PEG4000 modified liposomes enhance the solubility of quercetin and improve the liposome functionality: in vitro characterization and the cellular efficacy[J]. Turk J Chem, 2022, 46(4): 1011-1023. DOI: 10.55730/1300-0527.3411.

57.Qi X, Gao C, Yin C, et al. Development of Quercetin-loaded PVCL-PVA-PEG micelles and application in inhibiting tumor angiogenesis through the PI3K/Akt/VEGF pathway[J]. Toxicol Appl Pharmacol, 2022, 437: 115889. DOI: 10.1016/j.taap.2022.115889.

58.Li K, Zang X, Meng X, et al. Targeted delivery of quercetin by biotinylated mixed micelles for non-small cell lung cancer treatment[J]. Drug Deliv, 2022, 29(1): 970-985. DOI: 10.1080/10717544.2022.2055225.

59.Dogan M. Assessment of mechanism involved in the apoptotic and anti-cancer activity of quercetin and quercetin-loaded chitosan nanoparticles[J]. Med Oncol, 2022, 39(11): 176. DOI: 10.1007/s12032-022-01820-x.

60.Mohammed HA, Sulaiman GM, Anwar SS, et al. Quercetin against MCF7 and CAL51 breast cancer cell lines: apoptosis, gene expression and cytotoxicity of nano-quercetin[J]. Nanomedicine (Lond), 2021, 16(22): 1937-1961. DOI: 10.2217/nnm-2021-0070.