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Polymeric Micellar Formulation Enhances Antimicrobial and Anticancer Properties of Salinomycin

  • Carolina Sousa
  • Luís F. Gouveia
  • Bruna Kreutzer
  • Beatriz Silva-Lima
  • Retsepile E. Maphasa
  • Admire Dube
  • Mafalda VideiraEmail author
Research Paper

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.

Keywords

Antibiotics cancer stem cells nanomedicines polymeric micelles quality by design salinomycin 

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

Notes

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.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pharmacological and Regulatory Sciences Group (PharmaRegSci), Research Institute for Medicines (iMed.ULisboa)Faculdadde de Farmácia da Universidade de LisboaLisbonPortugal
  2. 2.Discipline of Pharmaceutics, School of PharmacyUniversity of the Western CapeBellvilleSouth Africa
  3. 3.iMed.ULisboa – Research Institute for Medicines and Pharmaceutical Sciences, Faculty of PharmacyUniversity of LisbonLisbonPortugal

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