Novel PEGylated Cholephytosomes for Targeting Fisetin to Breast Cancer: in Vitro Appraisal and in Vivo Antitumoral Studies

Overview

Journal Drug Deliv Transl Res

Publisher Springer

Specialty Pharmacology

Date 2023 Aug 29

PMID 37644299

Authors

Sara M Talaat

Yosra S R Elnaggar

Mennatallah A Gowayed

Samar O El-Ganainy

Maram Allam

Ossama Y Abdallah

Affiliations

Soon will be listed here.

Abstract

Fisetin (FIS) is a multifunctional bioactive flavanol that has been recently exploited as anticancer drug against various cancers including breast cancer. However, its poor aqueous solubility has constrained its clinical application. In the current work, fisetin is complexed for the first time with soy phosphatidylcholine in the presence of cholesterol to form a novel biocompatible phytosomal system entitled "cholephytosomes." To improve fisetin antitumor activity against breast cancer, stearylamine bearing cationic cholephytosomes (mPHY) were prepared and furtherly modified with hyaluronic acid (HPHY) to allow their orientation to cancer cells through their surface exposed phosphatidylserine and CD-44 receptors, respectively. In vitro characterization studies revealed promising physicochemical properties of both modified vesicles (mPHY and HPHY) including excellent FIS complexation efficiency (˷100%), improved octanol/water solubility along with a sustained drug release over 24 h. In vitro cell line studies against MDA-MB-231 cell line showed about 10- and 3.5-fold inhibition in IC50 of modified vesicles compared with free drug and conventional drug-phospholipid complex, respectively. Preclinical studies revealed that both modified cholephytosomes (mPHY and HPHY) had comparable cytotoxicity that is significantly surpassing free drug cytotoxicity. TGF-β1and its non-canonical related signaling pathway; ERK1/2, NF-κB, and MMP-9 were involved in halting tumorigenesis. Thus, tailoring novel phytosomal nanosystems for FIS could open opportunity for its clinical utility against cancer.

Citing Articles

Fisetin as a chemoprotective and chemotherapeutic agent: mechanistic insights and future directions in cancer therapy.

Fatima R, Soni P, Sharma M, Prasher P, Kaverikana R, Mangalpady S Med Oncol. 2025; 42(4):104.

PMID: 40074915 DOI: 10.1007/s12032-025-02664-x.

The anticancer potential of tetrahydrocurcumin-phytosomes against oral carcinoma progression.

Raouf N, Darwish Z, Ramadan O, Barakat H, Elbanna S, Essawy M BMC Oral Health. 2024; 24(1):1126.

PMID: 39327561 PMC: 11430579. DOI: 10.1186/s12903-024-04856-9.

Hyaluronic Acid-Coated Nanoliposomes as Delivery Systems for Fisetin: Stability, Membrane Fluidity, and Bioavailability.

Sun Y, Shen X, Yang J, Tan C Foods. 2024; 13(15).

PMID: 39123596 PMC: 11311619. DOI: 10.3390/foods13152406.

Newly synthesized chitosan nanoparticles loaded with caffeine/moringa leaf extracts Halt Her2, BRCA1, and BRCA2 expressions.

Mohammed H, Karhib M, Al-Fahad K, Atef A, Eskandrani A, Darwish A Sci Rep. 2024; 14(1):18118.

PMID: 39103402 PMC: 11300450. DOI: 10.1038/s41598-024-67599-1.

Selected Flavonols Targeting Cell Death Pathways in Cancer Therapy: The Latest Achievements in Research on Apoptosis, Autophagy, Necroptosis, Pyroptosis, Ferroptosis, and Cuproptosis.

Wendlocha D, Kubina R, Krzykawski K, Mielczarek-Palacz A Nutrients. 2024; 16(8).

PMID: 38674891 PMC: 11053927. DOI: 10.3390/nu16081201.

References

Hussain Z, Khan S, Imran M, Sohail M, Ali Shah S, De Matas M . PEGylation: a promising strategy to overcome challenges to cancer-targeted nanomedicines: a review of challenges to clinical transition and promising resolution. Drug Deliv Transl Res. 2019; 9(3):721-734. DOI: 10.1007/s13346-019-00631-4. View

Kim S, Pham T, Bak Y, Ryu H, Oh S, Yoon D . Orientin inhibits invasion by suppressing MMP-9 and IL-8 expression via the PKCα/ ERK/AP-1/STAT3-mediated signaling pathways in TPA-treated MCF-7 breast cancer cells. Phytomedicine. 2018; 50:35-42. DOI: 10.1016/j.phymed.2018.09.172. View

Syed D, Adhami V, Khan N, Imran Khan M, Mukhtar H . Exploring the molecular targets of dietary flavonoid fisetin in cancer. Semin Cancer Biol. 2016; 40-41:130-140. PMC: 5067175. DOI: 10.1016/j.semcancer.2016.04.003. View

Mehta P, Pawar A, Mahadik K, Bothiraja C . Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. Biomed Pharmacother. 2018; 106:1282-1291. DOI: 10.1016/j.biopha.2018.07.079. View

Sabra S, Elzoghby A, Sheweita S, Haroun M, Helmy M, Eldemellawy M . Self-assembled amphiphilic zein-lactoferrin micelles for tumor targeted co-delivery of rapamycin and wogonin to breast cancer. Eur J Pharm Biopharm. 2018; 128:156-169. DOI: 10.1016/j.ejpb.2018.04.023. View

Li Y, Zhou X, Liu J, Gao N, Yang R, Wang Q . Dihydroartemisinin inhibits the tumorigenesis and metastasis of breast cancer via downregulating CIZ1 expression associated with TGF-β1 signaling. Life Sci. 2020; 248:117454. DOI: 10.1016/j.lfs.2020.117454. View

Seguin J, Brulle L, Boyer R, Lu Y, Ramos Romano M, Touil Y . Liposomal encapsulation of the natural flavonoid fisetin improves bioavailability and antitumor efficacy. Int J Pharm. 2013; 444(1-2):146-54. DOI: 10.1016/j.ijpharm.2013.01.050. View

Li J, Gong X, Jiang R, Lin D, Zhou T, Zhang A . Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway. Front Pharmacol. 2018; 9:772. PMC: 6080104. DOI: 10.3389/fphar.2018.00772. View

Gao Z, Li Y, Zhang Y, An P, Chen F, Chen J . A CD44-targeted Cu(ii) delivery 2D nanoplatform for sensitized disulfiram chemotherapy to triple-negative breast cancer. Nanoscale. 2020; 12(15):8139-8146. DOI: 10.1039/d0nr00434k. View

10.

Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P . Breast cancer. Nat Rev Dis Primers. 2019; 5(1):66. DOI: 10.1038/s41572-019-0111-2. View

11.

Chen S, Han Y, Huang J, Dai L, Du J, McClements D . Fabrication and Characterization of Layer-by-Layer Composite Nanoparticles Based on Zein and Hyaluronic Acid for Codelivery of Curcumin and Quercetagetin. ACS Appl Mater Interfaces. 2019; 11(18):16922-16933. DOI: 10.1021/acsami.9b02529. View

12.

Liu X, Long H, Miao X, Liu G, Yao H . Fisetin inhibits liver cancer growth in a mouse model: Relation to dopamine receptor. Oncol Rep. 2017; 38(1):53-62. PMC: 5492805. DOI: 10.3892/or.2017.5676. View

13.

Agarwal V, Bajpai M, Sharma A . Patented and Approval Scenario of Nanopharmaceuticals with Relevancy to Biomedical Application, Manufacturing Procedure and Safety Aspects. Recent Pat Drug Deliv Formul. 2018; 12(1):40-52. DOI: 10.2174/1872211312666180105114644. View

14.

Khatik R, Dwivedi P, Shukla A, Srivastava P, Rath S, Paliwal S . Development, characterization and toxicological evaluations of phospholipids complexes of curcumin for effective drug delivery in cancer chemotherapy. Drug Deliv. 2014; 23(3):1067-78. DOI: 10.3109/10717544.2014.936988. View

15.

Noh E, Park Y, Kim J, Kim M, Kim H, Song H . Fisetin regulates TPA-induced breast cell invasion by suppressing matrix metalloproteinase-9 activation via the PKC/ROS/MAPK pathways. Eur J Pharmacol. 2015; 764:79-86. DOI: 10.1016/j.ejphar.2015.06.038. View

16.

Talaat S, Elnaggar Y, El-Ganainy S, Gowayed M, Abdel-Bary A, Abdallah O . Novel bio-inspired lipid nanoparticles for improving the anti-tumoral efficacy of fisetin against breast cancer. Int J Pharm. 2022; 628:122184. DOI: 10.1016/j.ijpharm.2022.122184. View

17.

Docea A, Mitrut P, Grigore D, Pirici D, Calina D, Gofita E . Immunohistochemical expression of TGF beta (TGF-β), TGF beta receptor 1 (TGFBR1), and Ki67 in intestinal variant of gastric adenocarcinomas. Rom J Morphol Embryol. 2012; 53(3 Suppl):683-92. View

18.

Wendt M, Allington T, Schiemann W . Mechanisms of the epithelial-mesenchymal transition by TGF-beta. Future Oncol. 2009; 5(8):1145-68. PMC: 2858056. DOI: 10.2217/fon.09.90. View

19.

Wu Y, Sarkissyan M, Vadgama J . Epithelial-Mesenchymal Transition and Breast Cancer. J Clin Med. 2016; 5(2). PMC: 4773769. DOI: 10.3390/jcm5020013. View

20.

Kashyap D, Sharma A, Sak K, Tuli H, Buttar H, Bishayee A . Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy. Life Sci. 2017; 194:75-87. DOI: 10.1016/j.lfs.2017.12.005. View