Skip to main content

Advertisement

SpringerLink
Log in

Polymeric Micellar Formulation Enhances Antimicrobial and Anticancer Properties of Salinomycin

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Salinomycin (SAL) is a polyether compound that exhibits strong antimicrobial as well as anticancer activity. Nanomedicine has been at the forefront of drug delivery research with the aim of increasing the efficacy, specificity and reduce toxicity of drugs. There is an intersection between infection and cancer, and cancer patients are prone to bacterial infections. In this study, polymeric micelles were prepared using Pluronic® F127 (PM) to encapsulate SAL (PM_SAL) with the view of enhancing antimicrobial and anticancer activity.

Methods

A Quality by Design (QbD) approach was utilized to synthesize PM_SAL, and nanoformulation activity was determined against bacterial (S. aureus, MRSA and E. coli). Effects on cancer cell line A549, i.e. cell viability, prevention of P-gp efflux, vimentin expression, effects on migratory ability of A549 cells. Anticancer activity was determined by ability to eradicate cancer stem-like cells.

Results

PM_SAL demonstrated only efficacy against MRSA, being even higher than that obtained with SAL. In A549 cells, a 15-fold increase in P-gp’s expression as well as a significant decrease of the cell’s migration, was observed.

Conclusions

PM_SAL can interfere with the oncogenic protein VIM, involved in the crucial mechanisms EMT, downregulating its expression. Altogether data obtained indicates that this antibiotic and the developed polymeric micelle system is a very promising inhibitor of tumor cell growth.

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

Similar content being viewed by others

Abbreviations

ABC:

ATP-binding cassette

Akt:

Serine/threonine protein Kinase

BCRP/ABCG2:

Breast cancer resistance protein

BCS:

Biopharmaceutical Classification System

CMA:

Critical Material Attributes

CPP:

Critical Process Parameters

CQAs:

Critical quality attributes

CSC:

Cancer stem-like cells

DLS:

Dynamic light scattering

DNP:

2,4 Dinitrophenyl Hydrazine

DoE:

Design of Experiments

E. coli :

Escherichia coli

EE:

Encapsulation Efficiency

EMT:

Epithelial to mesenchymal transition

h:

Hour

ICH :

International Conference on Harmonisation

IC50:

Half Maximal Inhibitory concentration

MD:

Mean Diameter

MDR:

Multidrug resistance

min:

Minutes

MRP1:

Multidrug resistance-associated protein 1

MRSA :

Methicillin-resistant Staphylococcus aureus

PDI:

Polydispersity Index

PEG:

Polyethylene Glycol

P-gp:

P-glycoprotein

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

PM:

Pluronic® F127-based polymeric micelles

PM_SAL:

Polymeric micelles with encapsulated Salinomycin

QbD:

Quality by Design

QTPP:

Quality Target product profile

RES:

Reticuloendothelial System

RT:

Room Temperature

SAL:

Salinomycin

S. aureus :

Staphylococcus aureus

SD:

Standard Deviation

TCA:

Trichloroacetic acid

VIM:

Vimentin

ZP:

Zeta Potential

References

  1. Ii DAK, Meujo DA, Hamann MT. Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites. Expert Opin Drug Discovery. 2009;4(2):109–46.

    Article  Google Scholar 

  2. Naujokat C, Steinhart R. Salinomycin as a drug for targeting human cancer stem cells. J Biomed Biotechnol. 2012;2012:44–6.

    Article  Google Scholar 

  3. Mager DL. Bacteria and cancer: cause, coincidence or cure? A review. J Transl Med. 2006;4(14):1–18.

    Google Scholar 

  4. Jacqueline C, Tasiemski A, Sorci G, Ujvari B, Maachi F, Missé D, et al. Infections and cancer: the “fifty shades of immunity” hypothesis. BioMed Cent. 2017;17(257):1–11.

    Google Scholar 

  5. Martin NO, Nishiuchi Y, Jonathan Baell J, Franco OL, Felício MR, Silva ON, et al. Peptides with dual antimicrobial and anticancer activities. Front Chem. 2017;5(5):1–9.

    Google Scholar 

  6. Zhou S, Wang F, Wong ET, Fonkem E, Hsieh T-C, Wu JM, et al. Salinomycin: a novel anti-Cancer agent with known anti- Coccidial activities. Curr Med Chem. 2013;20(33):4095–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wu D, Zhang Y, Huang J, Fan Z, Shi F, Wang S. Salinomycin inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cell in vitro and suppresses tumor growth in vivo. Biochem Biophys Res Commun. Elsevier Inc; 2014;443(2):712–717.

    Article  CAS  PubMed  Google Scholar 

  8. An H, Kim JY, Lee N, Cho Y, Oh E, Seo JH. Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via an apoptosis-independent pathway. Biochem Biophys Res Commun. Elsevier Ltd; 2015;466(4):696–703.

    Article  CAS  PubMed  Google Scholar 

  9. Li R, Dong T, Hu C, Lu J, Dai J, Liu P. Salinomycin repressed the epithelial-mesenchymal transition of epithelial ovarian cancer cells voa downregulating Wnt/B-catenin pathway. OncoTargets and Therapy 2017;10:1317–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kidd ME, Shumaker DK, Ridge KM. The role of vimentin intermediate filaments in the progression of lung cancer. Am J Respir Cell Mol Biol. 2014;50(1):1–6.

    PubMed  PubMed Central  Google Scholar 

  11. Cogli L, Progida C, Bramato R, Bucci C. Vimentin phosphorylation and assembly are regulated by the small GTPase Rab7a. Biochim Biophys Acta, Mol Cell Res Elsevier B.V.; 2013;1833(6):1283–1293.

    Article  CAS  Google Scholar 

  12. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull. 2017;7(3):339–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Amin L. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights. 2013;7:27–34.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Fda, Cder, Purdie, Florine P. Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid Oral dosage forms based on a biopharmaceutics classification system guidance for industry. 2017 [cited 2018 Jun 21]; Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Accessed 20 June 2018.

  15. Biswas S, Torchilin VP. Nanopreparations for organelle-specific delivery in cancer. Adv Drug Deliv Rev. 2014;66:26–41.

    Article  CAS  PubMed  Google Scholar 

  16. Li J, Qiao Y. Wu Z. Nanosystem trends in drug delivery using quality-by-design concept. J Control Release. 2017 Jun;256:9–18.

    Article  CAS  PubMed  Google Scholar 

  17. Rizvi SAA, Saleh AM. Applications of nanoparticle systems in drug delivery technology. Saudi Pharm J. King Saud University; 2017;26(1):64–70.

    Article  PubMed  Google Scholar 

  18. Almeida M, Magalhães M, Veiga F, Figueiras A. Poloxamers, poloxamines and polymeric micelles: definition, structure and therapeutic applications in cancer. J Polym Res. 2018;25(1):1–14.

    Article  CAS  Google Scholar 

  19. Chowdhury P, Nagesh PKB, Kumar S, Jaggi M, Chauhan SC, Yallapu MM. Bioactivity of engineered nanoparticles. 2017. 207–237 p.

  20. Ai X, Zhong L, Niu H, He Z. Thin-film hydration preparation method and stability test of DOX-loaded disulfide-linked polyethylene glycol 5000-lysine-di-tocopherol succinate nanomicelles. Asian J Pharm Sci. 2014;9(5):244–50.

    Article  Google Scholar 

  21. Bastogne T. Quality-by-design of nanopharmaceuticals. A state of the art. In: Bridging communitie in the field of nanomedicine. European Commission JRC ; 2017. p. 1–12.

  22. Dusi G, Gamba V. Liquid chromatography with ultraviolet detection of lasalocid, monensin, salinomycin and narasin in poultry feeds using pre-column derivatization. J Chromatogr A. Elsevier; 1999;835(1–2):243–246.

    Article  CAS  PubMed  Google Scholar 

  23. Lu GW, Gao P. Emulsions and microemulsions for topical and transdermal drug delivery. In: Handbook of non-invasive drug delivery systems: Elsevier; 2010. p. 59–94.

    Chapter  Google Scholar 

  24. Shaarani S, Hamid SS, Mohd Kaus NH. The influence of Pluronic F68 and F127 Nanocarrier on physicochemical properties, in vitro release, and Antiproliferative activity of Thymoquinone drug. Pharmacognosy res. 2017;9(1):12–20.

  25. Sotoudegan F, Amini M, Faizi M, Aboofazeli R. Nimodipine-loaded Pluronic® block copolymer micelles: preparation, characterization, in-vitro and in-vivo studies. Iran J Pharm Res IJPR. Shahid Beheshti University of Medical Sciences; 2016;15(4):641–661.

  26. Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. J Control Release Elsevier; 2001;73(2–3):137–172.

    Article  CAS  PubMed  Google Scholar 

  27. Antoszczak M, Maj E, Napiórkowska A, Stefańska J, Augustynowicz-Kopeć E, Wietrzyk J, et al. Synthesis, anticancer and antibacterial activity of salinomycin N-benzyl amides. Molecules. 2014;19(12):19435–59.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ghai I, Ghai S. Understanding antibiotic resistance via outer membrane permeability. Infect Drug Resist. 2018;11:523–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Fu D, Nobili S, William Murray B. Where is it and how does it get there – intracellular localization and traffic of P-glycoprotein. Front Oncol. 2013;3:1–5.

    Article  CAS  Google Scholar 

  30. Mealey KL, Barhoumi R, Burghardt RC, Safe S, Kochevar DT. Doxycycline induces expression of P glycoprotein in MCF-7 breast carcinoma cells. Antimicrob Agents Chemother. 2002;46(3):755–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ihnat MA, Lariviere JP, Warren AJ, La RN, Blaxall JRN, Pierre KM, et al. Suppression of P-glycoprotein expression and multidrug resistance by DNA cross-linking agents. Clin Cancer Res. 1997;3:1339–46.

    CAS  PubMed  Google Scholar 

  32. Sulová Z, Šereš M, Barančík M, Gibalová L, Uhrík B, Poleková L, et al. Does any relationship exist between P-glycoprotein-mediated multidrug resistance and intracellular calcium homeostasis. Gen Physiol Biophys. 2009;28:89–95.

    Google Scholar 

  33. Hermawan A, Wagner E, Roidl A. Consecutive salinomycin treatment reduces doxorubicin resistance of breast tumor cells by diminishing drug efflux pump expression and activity. Oncol Rep. 2016;35(3):1732–40.

    Article  CAS  PubMed  Google Scholar 

  34. Summers MA, Moore JL, McAuley JW. Use of verapamil as a potential P-glycoprotein inhibitor in a patient with refractory epilepsy. Ann Pharmacother. SAGE PublicationsSage CA: Los Angeles, CA; 2004;38(10):1631–1634.

    Article  PubMed  Google Scholar 

  35. Kusunoki S, Kato K, Tabu K, Inagaki T, Okabe H, Kaneda H, et al. The inhibitory effect of salinomycin on the proliferation, migration and invasion of human endometrial cancer stem-like cells. Gynecol Oncol. 2013 Jun;129(3):598–605.

    Article  CAS  PubMed  Google Scholar 

  36. Qu H, Ma B, Yuan H-F, Wang Z-Y, Guo S-J, Zhang J. Effect of salinomycin on metastasis and invasion of bladder cancer cell line T24. Asian Pac J Trop Med No longer published by Elsevier; 2015;8(7):578–582.

    Article  CAS  PubMed  Google Scholar 

  37. Zhu Q-S, Rosenblatt K, Huang K-L, Lahat G, Brobey R, Bolshakov S, et al. Vimentin is a novel AKT1 target mediating motility and invasion. Oncogene. 2011;30(4):457–70.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rai G, Suman S, Mishra S, Shukla Y. Evaluation of growth inhibitory response of resveratrol and Salinomycin combinations against triple negative breast cancer cells. Biomed Pharmacother. Elsevier Masson; 2017 May 1;89:1142–1151.

  39. Satelli A, Li S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci. 2011;68(18):3033–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kuo SZ, Blair KJ, Rahimy E, Kiang A, Abhold E, Fan J-B, et al. Salinomycin induces cell death and differentiation in head and neck squamous cell carcinoma stem cells despite activation of epithelial-mesenchymal transition and Akt. BMC Cancer. 2012;12(1):556.

  41. Lee HG, Lee JM, Shin SJ, Kwon SH, Lee GS, Song CH. Salinomycin inhibited cell proliferation and induced apoptosis in human uterine leiomyoma cells. Obstet Gynecol Sci 2014;57(6):501–6.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments and Disclosures

Professor Mafalda Videira acknowledges the European Comission and the Fundação para a Ciência e Tecnologia (FCT), Portugal, for funding the projects “NanoGlio - Nanotechnology based immunotherapy for glioblastoma” (ENMed/0065/2016) and “Target4Cancer - (Nano) systems with active targeting to sensitize colorectal cancer stem cells to anti-tumoral treatment”. (ENMed/0009/2015): March 2016–2019″ and COST Action MP1404, “SimInhale”.

The work was funded, in part, by iMed.ULisboa (UID/DTP/04138/2013) from Fundação para a Ciência e a Tecnologia (FCT), Portugal.

Author information

Authors and Affiliations

  1. Pharmacological and Regulatory Sciences Group (PharmaRegSci), Research Institute for Medicines (iMed.ULisboa), Faculdadde de Farmácia da Universidade de Lisboa, Lisbon, Portugal

    Carolina Sousa, Luís F. Gouveia, Bruna Kreutzer, Beatriz Silva-Lima & Mafalda Videira

  2. Discipline of Pharmaceutics, School of Pharmacy, University of the Western Cape, Bellville, South Africa

    Retsepile E. Maphasa & Admire Dube

  3. iMed.ULisboa – Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal

    Mafalda Videira

Authors
  1. Carolina Sousa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luís F. Gouveia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruna Kreutzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beatriz Silva-Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Retsepile E. Maphasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Admire Dube
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mafalda Videira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mafalda Videira.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sousa, C., Gouveia, L.F., Kreutzer, B. et al. Polymeric Micellar Formulation Enhances Antimicrobial and Anticancer Properties of Salinomycin. Pharm Res 36, 83 (2019). https://doi.org/10.1007/s11095-019-2615-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-019-2615-6

Keywords

Search

Navigation