Combination Therapy Comprising Paclitaxel and 5-Fluorouracil by Using Folic Acid Functionalized Bovine Milk Exosomes Improves the Therapeutic Efficacy Against Breast Cancer

Overview

Journal Life (Basel)

Specialty Biology

Date 2022 Aug 26

PMID 36013322

Authors

Dulla Naveen Kumar

Aiswarya Chaudhuri

Deepa Dehari

Anusmita Shekher

Subash C Gupta

Shreyasi Majumdar

Sairam Krishnamurthy

Sanjay Singh

Dinesh Kumar

Ashish Kumar Agrawal

Affiliations

Soon will be listed here.

Abstract

Paclitaxel (PAC) has been approved by FDA for clinical use (Taxol), yet dose-dependent severe toxicity due to the adjuvant Cremophor EL in combination with ethanol is a major drawback. The drawbacks of the current therapy can be overcome by (i) finding a suitable vehicle that cannot only bypass the above adjuvant but also be used to deliver drugs orally and (ii) combining the PAC with some other chemotherapeutics to have the enhanced therapeutic efficacy. In the current work, we have used folic acid (FA) functionalized bovine milk-derived exosomes for oral delivery of PAC in combination with 5-fluorouracil (5-FU). Exosomes before and after the drug loading were found to have a particle size in the range of 80-100 nm, polydispersity index (PDI ~0.20), zeta potential (~-25 mV), entrapment efficiency (~82%), practical drug loading (~28%) and sustained drug release for 48 h. Significant decreases in IC were observed in the case of exosomes loaded drugs which further improved following the FA functionalization. FA functionalized coumarin-6-loaded exosomes showed remarkably higher cellular uptake in comparison with free coumarin-6. Moreover, FA-functionalized drug-loaded exosomes showed a higher apoptotic index with better control over cell migration. Collectively, data suggested the enhanced efficacy of the combination following its loading to the folic acid functionalized exosomes against breast cancer.

Citing Articles

Extracellular Vesicles as Mediators and Potential Targets in Combating Cancer Drug Resistance.

Zhang H, Wu B, Wang Y, Du H, Fang L Molecules. 2025; 30(3).

PMID: 39942602 PMC: 11819960. DOI: 10.3390/molecules30030498.

Synergistic Anti-Aging Effects of Adipose-Derived Stem Cell Extracellular Vesicles Loaded With Natural Compounds.

Vo N, Vu D, Tran N, Nguyen D, Phung P, Nguyen H J Cosmet Dermatol. 2025; 24(2):e70021.

PMID: 39924347 PMC: 11807792. DOI: 10.1111/jocd.70021.

αvβ3 Integrin and Folate-Targeted pH-Sensitive Liposomes with Dual Ligand Modification for Metastatic Breast Cancer Treatment.

Pandey P, Arya D, Deepak P, Ali D, Alarifi S, Srivastava S Bioengineering (Basel). 2024; 11(8).

PMID: 39199757 PMC: 11352135. DOI: 10.3390/bioengineering11080800.

An Investigation of In Vitro Anti-Cancer Efficacy of Dihydroartemisinin-Loaded Bovine Milk Exosomes Against Triple-Negative Breast Cancer.

Kumar D, Chaudhuri A, Shiromani U, Kumar D, Agrawal A AAPS J. 2024; 26(5):91.

PMID: 39107504 DOI: 10.1208/s12248-024-00958-y.

Hypoxia-preconditioned WJ-MSC spheroid-derived exosomes delivering miR-210 for renal cell restoration in hypoxia-reoxygenation injury.

Toghiani R, Azimian Zavareh V, Najafi H, Mirian M, Azarpira N, Abolmaali S Stem Cell Res Ther. 2024; 15(1):240.

PMID: 39080774 PMC: 11289969. DOI: 10.1186/s13287-024-03845-7.

References

Aqil F, Munagala R, Jeyabalan J, Agrawal A, Gupta R . Exosomes for the Enhanced Tissue Bioavailability and Efficacy of Curcumin. AAPS J. 2017; 19(6):1691-1702. DOI: 10.1208/s12248-017-0154-9. View

Zeng X, Zhang Y, Nystrom A . Endocytic uptake and intracellular trafficking of bis-MPA-based hyperbranched copolymer micelles in breast cancer cells. Biomacromolecules. 2012; 13(11):3814-22. DOI: 10.1021/bm301281k. View

Bondhopadhyay B, Sisodiya S, Alzahrani F, Bakhrebah M, Chikara A, Kasherwal V . Exosomes: A Forthcoming Era of Breast Cancer Therapeutics. Cancers (Basel). 2021; 13(18). PMC: 8464658. DOI: 10.3390/cancers13184672. View

Nunez C, Capelo J, Igrejas G, Alfonso A, Botana L, Lodeiro C . An overview of the effective combination therapies for the treatment of breast cancer. Biomaterials. 2016; 97:34-50. DOI: 10.1016/j.biomaterials.2016.04.027. View

Zanardi E, Bregni G, De Braud F, Di Cosimo S . Better Together: Targeted Combination Therapies in Breast Cancer. Semin Oncol. 2015; 42(6):887-95. DOI: 10.1053/j.seminoncol.2015.09.029. View

Aqil F, Kausar H, Agrawal A, Jeyabalan J, Kyakulaga A, Munagala R . Exosomal formulation enhances therapeutic response of celastrol against lung cancer. Exp Mol Pathol. 2016; 101(1):12-21. DOI: 10.1016/j.yexmp.2016.05.013. View

Kushwah V, Katiyar S, Dora C, Agrawal A, Lamprou D, Gupta R . Co-delivery of docetaxel and gemcitabine by anacardic acid modified self-assembled albumin nanoparticles for effective breast cancer management. Acta Biomater. 2018; 73:424-436. DOI: 10.1016/j.actbio.2018.03.057. View

Kushwah V, Jain D, Agrawal A, Jain S . Improved antitumor efficacy and reduced toxicity of docetaxel using anacardic acid functionalized stealth liposomes. Colloids Surf B Biointerfaces. 2018; 172:213-223. DOI: 10.1016/j.colsurfb.2018.08.047. View

Shilpi D, Kushwah V, Agrawal A, Jain S . Improved Stability and Enhanced Oral Bioavailability of Atorvastatin Loaded Stearic Acid Modified Gelatin Nanoparticles. Pharm Res. 2017; 34(7):1505-1516. DOI: 10.1007/s11095-017-2173-8. View

10.

Agrawal A, Aqil F, Jeyabalan J, Spencer W, Beck J, Gachuki B . Milk-derived exosomes for oral delivery of paclitaxel. Nanomedicine. 2017; 13(5):1627-1636. DOI: 10.1016/j.nano.2017.03.001. View

11.

Jain S, Patil S, Swarnakar N, Agrawal A . Oral delivery of doxorubicin using novel polyelectrolyte-stabilized liposomes (layersomes). Mol Pharm. 2012; 9(9):2626-35. DOI: 10.1021/mp300202c. View

12.

Fader A, Rose P . Abraxane for the treatment of gynecologic cancer patients with severe hypersensitivity reactions to paclitaxel. Int J Gynecol Cancer. 2009; 19(7):1281-3. DOI: 10.1111/IGC.0b013e3181a38e2f. View

13.

Oosthuyzen W, Sime N, Ivy J, Turtle E, Street J, Pound J . Quantification of human urinary exosomes by nanoparticle tracking analysis. J Physiol. 2013; 591(23):5833-42. PMC: 3872755. DOI: 10.1113/jphysiol.2013.264069. View

14.

Gaihre B, Khil M, Lee D, Kim H . Gelatin-coated magnetic iron oxide nanoparticles as carrier system: drug loading and in vitro drug release study. Int J Pharm. 2008; 365(1-2):180-9. DOI: 10.1016/j.ijpharm.2008.08.020. View

15.

Lee A, Djamgoz M . Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies. Cancer Treat Rev. 2017; 62:110-122. DOI: 10.1016/j.ctrv.2017.11.003. View

16.

Cameron D, Gabra H, Leonard R . Continuous 5-fluorouracil in the treatment of breast cancer. Br J Cancer. 1994; 70(1):120-4. PMC: 2033324. DOI: 10.1038/bjc.1994.259. View

17.

Bari E, Perteghella S, Catenacci L, Sorlini M, Croce S, Mantelli M . Freeze-dried and GMP-compliant pharmaceuticals containing exosomes for acellular mesenchymal stromal cell immunomodulant therapy. Nanomedicine (Lond). 2019; 14(6):753-765. DOI: 10.2217/nnm-2018-0240. View

18.

Jain S, Sharma J, Agrawal A, Mahajan R . Surface stabilized efavirenz nanoparticles for oral bioavailability enhancement. J Biomed Nanotechnol. 2013; 9(11):1862-74. DOI: 10.1166/jbn.2013.1683. View

19.

Mesia R, Vazquez S, Grau J, Garcia-Saenz J, Lozano A, Garcia C . A Phase 2 Open Label, Single-Arm Trial to Evaluate the Combination of Cetuximab Plus Taxotere, Cisplatin, and 5-Flurouracil as an Induction Regimen in Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck. Int J Radiat Oncol Biol Phys. 2015; 94(2):289-96. DOI: 10.1016/j.ijrobp.2015.10.019. View

20.

Kyakulaga A, Aqil F, Munagala R, Gupta R . Withaferin A inhibits Epithelial to Mesenchymal Transition in Non-Small Cell Lung Cancer Cells. Sci Rep. 2018; 8(1):15737. PMC: 6200817. DOI: 10.1038/s41598-018-34018-1. View