Skip to main content

Advertisement

SpringerLink
Log in

Enhancing Anticancer Efficacy of Formononetin Microspheres via Microfluidic Fabrication

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Formononetin is a flavonoid compound with anti-tumor and anti-inflammatory properties. However, its low solubility limits its clinical use. We employed microfluidic technology to prepare formononetin-loaded PLGA-PEGDA microspheres (Degradable polymer PLGA, Crosslinking agent PEGDA), which can encapsulate and release drugs in a controlled manner. We optimized and characterized the microspheres, and evaluated their antitumor effects. The microspheres had uniform size, high drug loading efficiency, high encapsulation efficiency, and stable release for 35 days. They also inhibited the proliferation, migration, and apoptosis. The antitumor mechanism involved the induction of reactive oxygen species and modulation of Bcl-2 family proteins. These findings suggested that formononetin-loaded PLGA-PEGDA microspheres, created using microfluidic technology, could be a novel drug delivery system that can overcome the limitations of formononetin and enhance its antitumor activity.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Zhang S, Sun J. Nano-drug delivery system for the treatment of acute myelogenous leukemia. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2022;51(2):233–40. https://doi.org/10.3724/zdxbyxb-2022-0084.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Qamar Z, Qizilbash FF, Iqubal MK, Ali A, Narang JK, Ali J, et al. Nano-based drug delivery system: recent strategies for the treatment of ocular disease and future perspective. Recent Pat Drug Deliv Formul. 2019;13(4):246–54. https://doi.org/10.2174/1872211314666191224115211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li B, Shao H, Gao L, Li H, Sheng H, Zhu L. Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a review. Drug Deliv. 2022;29(1):2130–61. https://doi.org/10.1080/10717544.2022.2094498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xie M, Xu Y, Shen H, Shen S, Ge Y, Xie J. Negative-charge-functionalized mesoporous silica nanoparticles as drug vehicles targeting hepatocellular carcinoma. Int J Pharm. 2014;474(1-2):223–31. https://doi.org/10.1016/j.ijpharm.2014.08.027.

    Article  CAS  PubMed  Google Scholar 

  5. Rui M, Xing Y, Li R, Ge Y, Feng C, Xu X. Targeted biomimetic nanoparticles for synergistic combination chemotherapy of paclitaxel and doxorubicin. Molecular Pharmaceutics. 2017;14(1):107–23. https://doi.org/10.1021/acs.molpharmaceut.6b00732.

    Article  CAS  PubMed  Google Scholar 

  6. Hussein HA, Nazir MS, Azra N, Qamar Z, Seeni A, Tengku Din T, et al. Novel drug and gene delivery system and imaging agent based on marine diatom biosilica nanoparticles. Mar Drugs. 2022;20(8) https://doi.org/10.3390/md20080480.

  7. Machado Dutra J, Espitia PJP, Andrade BR. Formononetin: biological effects and uses - a review. Food Chem. 2021;359:129975. https://doi.org/10.1016/j.foodchem.2021.129975.

    Article  CAS  PubMed  Google Scholar 

  8. Mendonça MAA, Ribeiro ARS, Lima AK, Bezerra GB, Pinheiro MS, Albuquerque-Júnior RLC, et al. Red propolis and its dyslipidemic regulator formononetin: evaluation of antioxidant activity and gastroprotective effects in rat model of gastric ulcer. Nutrients. 2020;12(10) https://doi.org/10.3390/nu12102951.

  9. Zhang B, Hao Z, Zhou W, Zhang S, Sun M, Li H, et al. Formononetin protects against ox-LDL-induced endothelial dysfunction by activating PPAR-γ signaling based on network pharmacology and experimental validation. Bioengineered. 2021;12(1):4887–98. https://doi.org/10.1080/21655979.2021.1959493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tian J, Wang XQ, Tian Z. Focusing on formononetin: recent perspectives for its neuroprotective potentials. Front Pharmacol. 2022;13:905898. https://doi.org/10.3389/fphar.2022.905898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tay KC, Tan LT, Chan CK, Hong SL, Chan KG, Yap WH, et al. Formononetin: a review of its anticancer potentials and mechanisms. Front Pharmacol. 2019;10:820. https://doi.org/10.3389/fphar.2019.00820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yu L, Zhang Y, Chen Q, He Y, Zhou H, Wan H, et al. Formononetin protects against inflammation associated with cerebral ischemia-reperfusion injury in rats by targeting the JAK2/STAT3 signaling pathway. Biomed Pharmacother. 2022;149:112836. https://doi.org/10.1016/j.biopha.2022.112836.

    Article  CAS  PubMed  Google Scholar 

  13. Ma X, Wang J. Formononetin: a pathway to protect neurons. Front Integr Neurosci. 2022;16:908378. https://doi.org/10.3389/fnint.2022.908378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang QY, Meng QH, Zhang ZT, Tian ZJ, Liu H. Synthesis, solubility, lipids-lowering and liver-protection activities of sulfonated formononetin. Yao Xue Xue Bao. 2009;44(4):386–9.

    CAS  PubMed  Google Scholar 

  15. Ong SKL, Shanmugam MK, Fan L, Fraser SE, Arfuso F, Ahn KS, et al. Focus on formononetin: anticancer potential and molecular targets. Cancers (Basel). 2019;11(5) https://doi.org/10.3390/cancers11050611.

  16. Zhang J, Liu L, Wang J, Ren B, Zhang L, Li W. Formononetin, an isoflavone from Astragalus membranaceus inhibits proliferation and metastasis of ovarian cancer cells. J Ethnopharmacol. 2018;221:91–9. https://doi.org/10.1016/j.jep.2018.04.014.

    Article  CAS  PubMed  Google Scholar 

  17. Almatroodi SA, Almatroudi A, Khan AA, Rahmani AH. Potential therapeutic targets of formononetin, a type of methoxylated isoflavone, and its role in cancer therapy through the modulation of signal transduction pathways. Int J Mol Sci. 2023;24(11) https://doi.org/10.3390/ijms24119719.

  18. Yang Y, Zhao Y, Ai X, Cheng B, Lu S. Formononetin suppresses the proliferation of human non-small cell lung cancer through induction of cell cycle arrest and apoptosis. Int J Clin Exp Pathol. 2014;7(12):8453–61.

    PubMed  PubMed Central  Google Scholar 

  19. Zhang L, Gong Y, Wang S, Gao F. Anti-colorectal cancer mechanisms of formononetin identified by network pharmacological approach. Med Sci Monit. 2019;25:7709–14. https://doi.org/10.12659/msm.919935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li S, Zhu L, He Y, Sun T. Formononetin enhances the chemosensitivity of triple negative breast cancer via BTB domain and CNC homolog 1-mediated mitophagy pathways. Acta Biochim Pol. 2023;70(3):533–9. https://doi.org/10.18388/abp.2020_6466.

    Article  CAS  PubMed  Google Scholar 

  21. Wang Y, Deng Z, Wang X, Shi Y, Lu Y, Fang S, et al. Formononetin/methyl-β-cyclodextrin inclusion complex incorporated into electrospun polyvinyl-alcohol nanofibers: enhanced water solubility and oral fast-dissolving property. Int J Pharm. 2021;603:120696. https://doi.org/10.1016/j.ijpharm.2021.120696.

    Article  CAS  PubMed  Google Scholar 

  22. Kim JH, Kang DW, Cho SJ, Cho HY. Parent-metabolite pharmacokinetic modeling of formononetin and its active metabolites in rats after oral administration of formononetin formulations. Pharmaceutics. 2022;15(1) https://doi.org/10.3390/pharmaceutics15010045.

  23. Zhang HY, Firempong CK, Wang YW, Xu WQ, Wang MM, Cao X, et al. Ergosterol-loaded poly(lactide-co-glycolide) nanoparticles with enhanced in vitro antitumor activity and oral bioavailability. Acta Pharmacologica Sinica. 2016;37(6):834–44. https://doi.org/10.1038/aps.2016.37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cao X, Deng W, Wei Y, Su W, Yang Y, Wei Y, et al. Encapsulation of plasmid DNA in calcium phosphate nanoparticles: stem cell uptake and gene transfer efficiency. Int J Nanomedicine. 2011;6:3335–49. https://doi.org/10.2147/ijn.S27370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bian J, Cai F, Chen H, Tang Z, Xi K, Tang J, et al. Modulation of local overactive inflammation via injectable hydrogel microspheres. Nano Lett. 2021;21(6):2690–8. https://doi.org/10.1021/acs.nanolett.0c04713.

    Article  CAS  PubMed  Google Scholar 

  26. Yang J, Han Y, Lin J, Zhu Y, Wang F, Deng L, et al. Ball-bearing-inspired polyampholyte-modified microspheres as bio-lubricants attenuate osteoarthritis. Small. 2020;16(44):e2004519. https://doi.org/10.1002/smll.202004519.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Q, Yang T, Zhang R, Liang X, Wang G, Tian Y, et al. Platelet lysate functionalized gelatin methacrylate microspheres for improving angiogenesis in endodontic regeneration. Acta Biomater. 2021;136:441–55. https://doi.org/10.1016/j.actbio.2021.09.024.

    Article  CAS  PubMed  Google Scholar 

  28. Wong CY, Al-Salami H, Dass CR. Microparticles, microcapsules and microspheres: a review of recent developments and prospects for oral delivery of insulin. Int J Pharm. 2018;537(1-2):223–44. https://doi.org/10.1016/j.ijpharm.2017.12.036.

    Article  CAS  PubMed  Google Scholar 

  29. Li W, Chen J, Zhao S, Huang T, Ying H, Trujillo C, et al. High drug-loaded microspheres enabled by controlled in-droplet precipitation promote functional recovery after spinal cord injury. Nat Commun. 2022;13(1):1262. https://doi.org/10.1038/s41467-022-28787-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang Y, Shen L, Wang T, Li H, Huang R, Zhang Z, et al. Taste masking of water-soluble drug by solid lipid microspheres: a child-friendly system established by reversed lipid-based nanoparticle technique. J Pharm Pharmacol. 2020;72(6):776–86. https://doi.org/10.1111/jphp.13245.

    Article  CAS  PubMed  Google Scholar 

  31. Gouerou H, Dain MP, Parrondo I, Poisson D, Bernades P. Alipase versus nonenteric-coated enzymes in pancreatic insufficiency. A French multicenter crossover comparative study. Int J Pancreatol. 1989;5(Suppl):45–50.

    PubMed  Google Scholar 

  32. Su Y, Liu J, Tan S, Liu W, Wang R, Chen C. PLGA sustained-release microspheres loaded with an insoluble small-molecule drug: microfluidic-based preparation, optimization, characterization, and evaluation in vitro and in vivo. Drug Deliv. 2022;29(1):1437–46. https://doi.org/10.1080/10717544.2022.2072413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ghosh Dastidar D, Saha S, Chowdhury M. Porous microspheres: synthesis, characterisation and applications in pharmaceutical & medical fields. Int J Pharm. 2018;548(1):34–48. https://doi.org/10.1016/j.ijpharm.2018.06.015.

    Article  CAS  PubMed  Google Scholar 

  34. Larsen LI, López GP, Selwyn R, Carroll NJ. Microfluidic fabrication of silica microspheres infused with positron emission tomography imaging agents. ACS Appl Bio Mater. 2023;6(2):712–21. https://doi.org/10.1021/acsabm.2c00940.

    Article  CAS  PubMed  Google Scholar 

  35. Cao X, Liu Q, Adu-Frimpong M, Shi W, Liu K, Deng T, et al. Microfluidic generation of near-infrared photothermal vitexin/ICG liposome with amplified photodynamic therapy. AAPS PharmSciTech. 2023;24(4):82. https://doi.org/10.1208/s12249-023-02539-2.

    Article  CAS  PubMed  Google Scholar 

  36. Zhao Q, Cui H, Wang Y, Du X. Microfluidic platforms toward rational material fabrication for biomedical applications. Small. 2020;16(9):e1903798. https://doi.org/10.1002/smll.201903798.

    Article  CAS  PubMed  Google Scholar 

  37. Lin Z, Rao Z, Chen J, Chu H, Zhou J, Yang L, et al. Bioactive decellularized extracellular matrix hydrogel microspheres fabricated using a temperature-controlling microfluidic system. ACS Biomater Sci Eng. 2022;8(4):1644–55. https://doi.org/10.1021/acsbiomaterials.1c01474.

    Article  CAS  PubMed  Google Scholar 

  38. Amini H, Lee W, Di Carlo D. Inertial microfluidic physics. Lab Chip. 2014;14(15):2739–61. https://doi.org/10.1039/c4lc00128a.

    Article  CAS  PubMed  Google Scholar 

  39. Yao Y, Lin JJ, Chee XYJ, Liu MH, Khan SA, Kim JE. Encapsulation of lutein via microfluidic technology: evaluation of stability and in vitro bioaccessibility. Foods. 2021;10(11) https://doi.org/10.3390/foods10112646.

  40. Seeto WJ, Tian Y, Pradhan S, Kerscher P, Lipke EA. Rapid production of cell-laden microspheres using a flexible microfluidic encapsulation platform. Small. 2019;15(47):e1902058. https://doi.org/10.1002/smll.201902058.

    Article  CAS  PubMed  Google Scholar 

  41. Bolze H, Erfle P, Riewe J, Bunjes H, Dietzel A, Burg TP. A microfluidic split-flow technology for product characterization in continuous low-volume nanoparticle synthesis. Micromachines (Basel). 2019;10(3) https://doi.org/10.3390/mi10030179.

  42. Wu S, Wang Z, Wang Y, Guo M, Zhou M, Wang L, et al. Peptide-grafted microspheres for mesenchymal stem cell sorting and expansion by selective adhesion. Front Bioeng Biotechnol. 2022;10:873125. https://doi.org/10.3389/fbioe.2022.873125.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Zhou W, Dou M, Timilsina SS, Xu F, Li X. Recent innovations in cost-effective polymer and paper hybrid microfluidic devices. Lab Chip. 2021;21(14):2658–83. https://doi.org/10.1039/d1lc00414j.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Siavashy S, Soltani M, Ghorbani-Bidkorbeh F, Fallah N, Farnam G, Mortazavi SA, et al. Microfluidic platform for synthesis and optimization of chitosan-coated magnetic nanoparticles in cisplatin delivery. Carbohydr Polym. 2021;265:118027. https://doi.org/10.1016/j.carbpol.2021.118027.

    Article  CAS  PubMed  Google Scholar 

  45. Hernández-Giottonini KY, Rodríguez-Córdova RJ, Gutiérrez-Valenzuela CA, Peñuñuri-Miranda O, Zavala-Rivera P, Guerrero-Germán P, et al. PLGA nanoparticle preparations by emulsification and nanoprecipitation techniques: effects of formulation parameters. RSC Adv. 2020;10(8):4218–31. https://doi.org/10.1039/c9ra10857b.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang S, Liang WF, Dong ZL, Lee VGB, Li WJ. Fabrication of micrometer- and nanometer-scale polymer structures by visible light induced dielectrophoresis (DEP) force. Micromachines. 2011;2(4):431–42. https://doi.org/10.3390/mi2040431.

    Article  Google Scholar 

  47. Blasi P. Poly(lactic acid)/poly(lactic-co-glycolic acid)-based microparticles: an overview. Journal of Pharmaceutical Investigation. 2019;49(4):337–46. https://doi.org/10.1007/s40005-019-00453-z.

    Article  CAS  Google Scholar 

  48. He C, Zeng W, Su Y, Sun R, Xiao Y, Zhang B, et al. Microfluidic-based fabrication and characterization of drug-loaded PLGA magnetic microspheres with tunable shell thickness. Drug Deliv. 2021;28(1):692–9. https://doi.org/10.1080/10717544.2021.1905739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chen M, Aluunmani R, Bolognesi G, Vladisavljević GT. Facile microfluidic fabrication of biocompatible hydrogel microspheres in a novel microfluidic device. Molecules. 2022:27(13). https://doi.org/10.3390/molecules27134013.

  50. Wang X, Wang L, Qi F, Zhao J. The effect of a single injection of uniform-sized insulin-loaded PLGA microspheres on peri-implant bone formation. RSC Adv. 2018;8(70):40417–25. https://doi.org/10.1039/c8ra08505f.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li X, Xia X, Zhang J, Adu-Frimpong M, Shen X, Yin W, et al. Preparation, physical characterization, pharmacokinetics and anti-hyperglycemic activity of esculetin-loaded mixed micelles. J Pharm Sci. 2023;112(1):148–57. https://doi.org/10.1016/j.xphs.2022.06.022.

    Article  CAS  PubMed  Google Scholar 

  52. Zhu Z, Liu J, Yang Y, Adu-Frimpong M, Ji H, Toreniyazov E, et al. SMEDDS for improved oral bioavailability and anti-hyperuricemic activity of licochalcone A. J Microencapsul. 2021;38(7-8):459–71. https://doi.org/10.1080/02652048.2021.1963341.

    Article  CAS  PubMed  Google Scholar 

  53. Jafarifar E, Hajialyani M, Akbari M, Rahimi M, Shokoohinia Y, Fattahi A. Preparation of a reproducible long-acting formulation of risperidone-loaded PLGA microspheres using microfluidic method. Pharm Dev Technol. 2017;22(6):836–43. https://doi.org/10.1080/10837450.2016.1221426.

    Article  CAS  PubMed  Google Scholar 

  54. El-Didamony SE, Amer RI, El-Osaily GH. Formulation, characterization and cellular toxicity assessment of a novel bee-venom microsphere in prostate cancer treatment. Sci Rep. 2022;12(1):13213. https://doi.org/10.1038/s41598-022-17391-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cao X, Zhu Q, Wang QL, Adu-Frimpong M, Wei CM, Weng W, et al. Improvement of oral bioavailability and anti-tumor effect of zingerone self-microemulsion drug delivery system. J Pharm Sci. 2021;110(7):2718–27. https://doi.org/10.1016/j.xphs.2021.01.037.

    Article  CAS  PubMed  Google Scholar 

  56. Yi C, Zhong H, Tong S, Cao X, Firempong CK, Liu H, et al. Enhanced oral bioavailability of a sterol-loaded microemulsion formulation of Flammulina velutipes, a potential antitumor drug. International Journal of Nanomedicine. 2012;7:5067–78. https://doi.org/10.2147/ijn.S34612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Marulanda K, Brokaw D, Gambarian M, Pareta R, McQuilling JP, Opara EC, et al. Controlled delivery of Slit3 proteins from alginate microbeads inhibits in vitro angiogenesis. J Surg Res. 2021;264:90–8. https://doi.org/10.1016/j.jss.2021.01.025.

    Article  CAS  PubMed  Google Scholar 

  58. Pijuan J, Barceló C, Moreno DF, Maiques O, Sisó P, Marti RM, et al. In vitro cell migration, invasion, and adhesion assays: from cell imaging to data analysis. Front Cell Dev Biol. 2019;7:107. https://doi.org/10.3389/fcell.2019.00107.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ayyanaar S, Kesavan MP, Balachandran C, Rasala S, Rameshkumar P, Aoki S, et al. Iron oxide nanoparticle core-shell magnetic microspheres: applications toward targeted drug delivery. Nanomedicine. 2020;24:102134. https://doi.org/10.1016/j.nano.2019.102134.

    Article  CAS  PubMed  Google Scholar 

  60. Sun C, Li W, Liu Y, Deng W, Adu-Frimpong M, Zhang H, et al. In vitro/in vivo hepatoprotective properties of 1-O-(4-hydroxymethylphenyl)-α-L-rhamnopyranoside from Moringa oleifera seeds against carbon tetrachloride-induced hepatic injury. Food Chem Toxicol. 2019;131:110531. https://doi.org/10.1016/j.fct.2019.05.039.

    Article  CAS  PubMed  Google Scholar 

  61. Hu W, Xiao Z. Formononetin induces apoptosis of human osteosarcoma cell line U2OS by regulating the expression of Bcl-2, Bax and MiR-375 in vitro and in vivo. Cell Physiol Biochem. 2015;37(3):933–9. https://doi.org/10.1159/000430220.

    Article  CAS  PubMed  Google Scholar 

  62. Aladaileh SH, Hussein OE, Abukhalil MH, Saghir SAM, Bin-Jumah M, Alfwuaires MA, et al. Formononetin upregulates Nrf2/HO-1 signaling and prevents oxidative stress, inflammation, and kidney injury in methotrexate-induced rats. Antioxidants (Basel). 2019;8(10) https://doi.org/10.3390/antiox8100430.

  63. Sun X, Lv W, Wang Y, Zhang X, Ouyang Z, Yin R, et al. Mrgprb2 gene plays a role in the anaphylactoid reactions induced by Houttuynia cordata injection. Journal of Ethnopharmacology. 2022:289. https://doi.org/10.1016/j.jep.2022.115053.

  64. Shi W, Cao X, Liu Q, Zhu Q, Liu K, Deng T, et al. Hybrid membrane-derived nanoparticles for isoliquiritin enhanced glioma therapy. Pharmaceuticals (Basel). 2022;15(9) https://doi.org/10.3390/ph15091059.

  65. Cao X, Deng T, Zhu Q, Wang J, Shi W, Liu Q, et al. Photothermal therapy mediated hybrid membrane derived nano-formulation for enhanced cancer therapy. AAPS PharmSciTech. 2023;24(6):146. https://doi.org/10.1208/s12249-023-02594-9.

    Article  CAS  PubMed  Google Scholar 

  66. Ding D, Zhu Q. Recent advances of PLGA micro/nanoparticles for the delivery of biomacromolecular therapeutics. Mater Sci Eng C Mater Biol Appl. 2018;92:1041–60. https://doi.org/10.1016/j.msec.2017.12.036.

    Article  CAS  PubMed  Google Scholar 

  67. Mahar R, Chakraborty A, Nainwal N, Bahuguna R, Sajwan M, Jakhmola V. Application of PLGA as a biodegradable and biocompatible polymer for pulmonary delivery of drugs. AAPS PharmSciTech. 2023;24(1):39. https://doi.org/10.1208/s12249-023-02502-1.

    Article  CAS  PubMed  Google Scholar 

  68. Hajavi J, Ebrahimian M, Sankian M, Khakzad MR, Hashemi M. Optimization of PLGA formulation containing protein or peptide-based antigen: recent advances. J Biomed Mater Res A. 2018;106(9):2540–51. https://doi.org/10.1002/jbm.a.36423.

    Article  CAS  PubMed  Google Scholar 

  69. Abdul Rahim R, Jayusman PA, Muhammad N, Ahmad F, Mokhtar N, Naina Mohamed I, et al. Recent advances in nanoencapsulation systems using PLGA of bioactive phenolics for protection against chronic diseases. Int J Environ Res Public Health. 2019;16(24) https://doi.org/10.3390/ijerph16244962.

  70. Butreddy A, Gaddam RP, Kommineni N, Dudhipala N, Voshavar C. PLGA/PLA-based long-acting injectable depot microspheres in clinical use: production and characterization overview for protein/peptide delivery. Int J Mol Sci. 2021;22(16) https://doi.org/10.3390/ijms22168884.

  71. Muddineti OS, Omri A. Current trends in PLGA based long-acting injectable products: the industry perspective. Expert Opin Drug Deliv. 2022;19(5):559–76. https://doi.org/10.1080/17425247.2022.2075845.

    Article  CAS  PubMed  Google Scholar 

  72. McAvoy K, Jones D, Thakur RRS. Synthesis and characterisation of photocrosslinked poly(ethylene glycol) diacrylate implants for sustained ocular drug delivery. Pharm Res. 2018;35(2):36. https://doi.org/10.1007/s11095-017-2298-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sabel-Grau T, Tyushina A, Babalik C, Lensen MC. UV-VIS curable PEG hydrogels for biomedical applications with multifunctionality. Gels. 2022;8(3) https://doi.org/10.3390/gels8030164.

  74. Bhardwaj VK, Purohit R. A comparative study on inclusion complex formation between formononetin and β-cyclodextrin derivatives through multiscale classical and umbrella sampling simulations. Carbohydr Polym. 2023;310:120729. https://doi.org/10.1016/j.carbpol.2023.120729.

    Article  CAS  PubMed  Google Scholar 

  75. Obaidat R, BaniAmer F, Assaf SM, Yassin A. Fabrication and evaluation of transdermal delivery of carbamazepine dissolving microneedles. AAPS PharmSciTech. 2021;22(8):253. https://doi.org/10.1208/s12249-021-02136-1.

    Article  CAS  PubMed  Google Scholar 

  76. Liu J, Wang Q, Omari-Siaw E, Adu-Frimpong M, Liu J, Xu X, et al. Enhanced oral bioavailability of bisdemethoxycurcumin-loaded self-microemulsifying drug delivery system: formulation design, in vitro and in vivo evaluation. Int J Pharm. 2020;590:119887. https://doi.org/10.1016/j.ijpharm.2020.119887.

    Article  CAS  PubMed  Google Scholar 

  77. Wang Q, Wei Q, Yang Q, Cao X, Li Q, Shi F, et al. A novel formulation of [6]-gingerol: proliposomes with enhanced oral bioavailability and antitumor effect. Int J Pharm. 2018;535(1-2):308–15. https://doi.org/10.1016/j.ijpharm.2017.11.006.

    Article  CAS  PubMed  Google Scholar 

  78. Löf D, Schillén K, Nilsson L. Flavonoids: precipitation kinetics and interaction with surfactant micelles. J Food Sci. 2011;76(3):N35–9. https://doi.org/10.1111/j.1750-3841.2011.02103.x.

    Article  CAS  PubMed  Google Scholar 

  79. Kim MS, Park JS, Chung YC, Jang S, Hyun CG, Kim SY. Anti-inflammatory effects of formononetin 7-O-phosphate, a novel biorenovation product, on LPS-stimulated RAW 264.7 macrophage cells. Molecules. 2019;24(21) https://doi.org/10.3390/molecules24213910.

  80. Karmakar J, Mukherjee K, Mandal C. Siglecs modulate activities of immune cells through positive and negative regulation of ROS generation. Front Immunol. 2021;12:758588. https://doi.org/10.3389/fimmu.2021.758588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. He L, He T, Farrar S, Ji L, Liu T, Ma X. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell Physiol Biochem. 2017;44(2):532–53. https://doi.org/10.1159/000485089.

    Article  PubMed  Google Scholar 

  82. Li T, Gao SJ. KSHV hijacks FoxO1 to promote cell proliferation and cellular transformation by antagonizing oxidative stress. J Med Virol. 2023;95(3):e28676. https://doi.org/10.1002/jmv.28676.

    Article  CAS  PubMed  Google Scholar 

  83. Rahman MA, Ahmed KR, Haque F, Park MN, Kim B. Recent advances in cellular signaling interplay between redox metabolism and autophagy modulation in cancer: an overview of molecular mechanisms and therapeutic interventions. Antioxidants (Basel). 2023;12(2) https://doi.org/10.3390/antiox12020428.

  84. Zhan Y, Zhang Z, Liu Y, Fang Y, Xie Y, Zheng Y, et al. NUPR1 contributes to radiation resistance by maintaining ROS homeostasis via AhR/CYP signal axis in hepatocellular carcinoma. BMC Med. 2022;20(1):365. https://doi.org/10.1186/s12916-022-02554-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sun C, Li W, Ma P, Li Y, Zhu Y, Zhang H, et al. Development of TPGS/F127/F68 mixed polymeric micelles: enhanced oral bioavailability and hepatoprotection of syringic acid against carbon tetrachloride-induced hepatotoxicity. Food Chem Toxicol. 2020;137:111126. https://doi.org/10.1016/j.fct.2020.111126.

    Article  CAS  PubMed  Google Scholar 

  86. Lai PK, Chan JY, Cheng L, Lau CP, Han SQ, Leung PC, et al. Isolation of anti-inflammatory fractions and compounds from the root of Astragalus membranaceus. Phytother Res. 2013;27(4):581–7. https://doi.org/10.1002/ptr.4759.

    Article  CAS  PubMed  Google Scholar 

  87. Wang DS, Yan LY, Yang DZ, Lyu Y, Fang LH, Wang SB, et al. Formononetin ameliorates myocardial ischemia/reperfusion injury in rats by suppressing the ROS-TXNIP-NLRP3 pathway. Biochem Biophys Res Commun. 2020;525(3):759–66. https://doi.org/10.1016/j.bbrc.2020.02.147.

    Article  CAS  PubMed  Google Scholar 

  88. Fan TJ, Han LH, Cong RS, Liang J. Caspase family proteases and apoptosis. Acta Biochim Biophys Sin (Shanghai). 2005;37(11):719–27. https://doi.org/10.1111/j.1745-7270.2005.00108.x.

    Article  CAS  PubMed  Google Scholar 

  89. Xiong Y, Tang YD, Zheng C. The crosstalk between the caspase family and the cGAS–STING signaling pathway. J Mol Cell Biol. 2021;13(10):739–47. https://doi.org/10.1093/jmcb/mjab071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Van Opdenbosch N, Lamkanfi M. Caspases in cell death, inflammation, and disease. Immunity. 2019;50(6):1352–64. https://doi.org/10.1016/j.immuni.2019.05.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang X, Bi L, Ye Y, Chen J. Formononetin induces apoptosis in PC-3 prostate cancer cells through enhancing the Bax/Bcl-2 ratios and regulating the p38/Akt pathway. Nutr Cancer. 2014;66(4):656–61. https://doi.org/10.1080/01635581.2014.894098.

    Article  CAS  PubMed  Google Scholar 

  92. Zha Q, Zhang L, Guo Y, Bao R, Shi F, Shi Y. Preparation and study of folate modified albumin targeting microspheres. J Oncol. 2022;2022:3968403. https://doi.org/10.1155/2022/3968403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang L, Wang YS, Chen RY, Feng CL, Wang H, Zhu XW, et al. PLGA microspheres as a delivery vehicle for sustained release of tetracycline: biodistribution in mice after subcutaneous administration. J Drug Deliv Sci Technol. 2013;23(6):547–53. https://doi.org/10.1016/s1773-2247(13)50083-9.

    Article  CAS  Google Scholar 

  94. Lv S, Jing R, Liu X, Shi H, Shi Y, Wang X, et al. One-step microfluidic fabrication of multi-responsive liposomes for targeted delivery of doxorubicin synergism with photothermal effect. Int J Nanomedicine. 2021;16:7759–72. https://doi.org/10.2147/ijn.S329621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cao X, Liu Q, Shi W, Liu K, Deng T, Weng X, et al. Microfluidic fabricated bisdemethoxycurcumin thermosensitive liposome with enhanced antitumor effect. Int J Pharm. 2023;641:123039. https://doi.org/10.1016/j.ijpharm.2023.123039.

    Article  CAS  PubMed  Google Scholar 

  96. Schuster B, Junkin M, Kashaf SS, Romero-Calvo I, Kirby K, Matthews J, et al. Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids. Nat Commun. 2020;11(1):5271. https://doi.org/10.1038/s41467-020-19058-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nguyen HQ, Seo TS. A 3D printed size-tunable flow-focusing droplet microdevice to produce cell-laden hydrogel microspheres. Anal Chim Acta. 2022;1192:339344. https://doi.org/10.1016/j.aca.2021.339344.

    Article  CAS  PubMed  Google Scholar 

  98. Liu H, Singh RP, Zhang Z, Han X, Liu Y, Hu L. Microfluidic assembly: an innovative tool for the encapsulation, protection, and controlled release of nutraceuticals. J Agric Food Chem. 2021;69(10):2936–49. https://doi.org/10.1021/acs.jafc.0c05395.

    Article  CAS  PubMed  Google Scholar 

  99. Rajput MS, Agrawal P. Microspheres in cancer therapy. Indian J Cancer. 2010;47(4):458–68. https://doi.org/10.4103/0019-509x.73547.

    Article  CAS  PubMed  Google Scholar 

  100. Hu C, He Y. Formononetin inhibits non-small cell lung cancer proliferation via regulation of mir-27a-3p through p53 pathway. Oncologie. 2021;23(2):241–50.

    Article  Google Scholar 

  101. Yu X, Gao F, Li W, Zhou L, Liu W, Li M. Formononetin inhibits tumor growth by suppression of EGFR-Akt-Mcl-1 axis in non-small cell lung cancer. J Exp Clin Cancer Res. 2020;39(1):62. https://doi.org/10.1186/s13046-020-01566-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the Ethics Committee of University for the guidance on animal experiments. The authors also thank the Institute of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China for the necessary facilities support to generate the manuscript.

Funding

This work was funded by the National Key R&D Program of China (2018YFE0208600), Key planning social development projects of Zhenjiang in Jiangsu Province (SH2021024), National Natural Science Foundation of China (81720108030 and 82173785), Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (18KJB360001), Natural Science Foundation of Jiangsu Province (BK20180866), and Postdoctoral Research Fund of Jiangsu Province in 2021 category A (2021K010A).

Author information

Author notes

  1. Xia Cao and Qingwen Li contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Centre for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, People’s Republic of China

    Xia Cao, Qingwen Li, Xiaoli Li, Qi Liu, Kai Liu, Tianwen Deng, Xuedi Weng, Qintong Yu, Wenwen Deng, Jiangnan Yu, Qilong Wang & Ximing Xu

  2. Medicinal function development of new food resources, Jiangsu Provincial Research Center, Jiangsu, People’s Republic of China

    Xia Cao, Qingwen Li, Xiaoli Li, Qi Liu, Kai Liu, Tianwen Deng, Qintong Yu, Wenwen Deng, Jiangnan Yu, Qilong Wang & Ximing Xu

  3. College of Environment and Safety Engineering, Fuzhou University, Fuzhou, 350108, Fujian, People’s Republic of China

    Gao Xiao

Authors
  1. Xia Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qingwen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoli Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kai Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tianwen Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xuedi Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qintong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wenwen Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiangnan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qilong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gao Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ximing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XC, XX, and QW: conceptualization. QL, QL, TD, and XW: data curation and methodology. QL, XL, and KL: formal analysis and validation. QY, WD, and GX: supervision. XC, QL, QW, and XG: writing of the manuscript. XC, JY, and XX: funding acquisition.

Corresponding authors

Correspondence to Qilong Wang, Gao Xiao or Ximing Xu.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Fig. S1

Optimization of microsphere prescription. A, Histogram of particle size distribution at different levels of factors PLGA (0%, 0.5%, 2%) and the corresponding level microscope. B, Histogram of particle size distribution at different levels of factor PEGDA (0%, 5%, 10%) and the corresponding level microscope. C, Histogram of particle size distribution at different levels (0%, 1%, 2%) of factor PI and the corresponding microscope images. D, Histogram of particle size distribution at different levels (0%, 1%, 3%) of factor PVA and the corresponding microscope images. (mean ± SD, n = 100) (PNG 966 kb)

High resolution image (PDF 298 kb)

Fig. S2

A chemistry illustration for the crosslinking reaction of PEGDA with PI under UV light (PNG 55 kb)

High resolution image (TIF 1151 kb)

Fig. S3

Cumulative release curve of free formononetin and formononetin-loaded microsphere in pH 5.0 buffer solutions containing 1% Tween 80 at 37°C (A, 0 d–7 d; B, 8 d–14 d; C, 15 d–21 d; D, 22 d–28 d; E, 29 d–35 d) (PNG 128 kb)

High resolution image (TIF 2017 kb)

Fig. S4

Cumulative release curve of free formononetin and formononetin-loaded microsphere in pH 6.8 buffer solutions containing 1% Tween 80 at 37°C. (A, 0 d–7 d; B, 8 d–14 d; C, 15 d–21 d; D, 22 d–28 d; E, 29 d–35 d) (PNG 142 kb)

High resolution image (TIF 2091 kb)

Fig. S5

Cumulative release curve of free formononetin and formononetin-loaded microsphere in pH 7.4 buffer solutions containing 1% Tween 80 at 37°C (A, 0 d–7 d; B, 8 d–14 d; C, 15 d–21 d; D, 22 d–28 d; E, 29 d–35 d) (PNG 141 kb)

High resolution image (TIF 2040 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, X., Li, Q., Li, X. et al. Enhancing Anticancer Efficacy of Formononetin Microspheres via Microfluidic Fabrication. AAPS PharmSciTech 24, 241 (2023). https://doi.org/10.1208/s12249-023-02691-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-023-02691-9

Keywords

Search

Navigation