Inhibition of P-Glycoprotein Pumps by PEO–PPO Amphiphiles: Branched Versus Linear Derivatives

Abstract

Inhibition of the activity of efflux transporters may relevantly improve the chemotherapy of cancer and infectious diseases. Aim: To explore the ability of poloxamines (Tetronic^®, X-shaped structure with a central ethylendiamine group and four branches of poly[ethylene oxide]–poly[propylene oxide] [PEO–PPO]) to inhibit the activity of P-glycoprotein (P-gp) on Caco-2 cell monolayers and to elucidate the incidence of the molecular architecture of PEO–PPO block copolymers on the intracellular accumulation of a relevant substrate, doxorubicin, by comparison with poloxamers (Pluronic^®, linear triblock copolymers), well-known inhibitors of this efflux transporter. Methods: Both pristine and N-methylated poloxamines displaying a wide range of molecular weights and EO/PO ratios were tested regarding cytocompatibility and accumulation of doxorubicin in Caco-2 monolayers. Verapamil was used as a control. Results: The most active anti-P-gp poloxamines (which enhanced two- to three-fold doxorubicin accumulation compared with verapamil) resulted to be pristine medium-to-high hydrophobic T304, T904, T1301, T901 and T150R1. A notable dependence of the anti-P-gp activity on the copolymer concentration was found. A joint diagram of the inhibitory activity of poloxamers and poloxamines as a function of the effective length of the PPO block is proposed. Conclusion: The anti-P-gp activity is maxima for block copolymers possessing a low-to-medium hydrophilic–lipophilic balance and an ‘effective number’ of PO units ranging from 30 to 50.

Keywords::

• cancer
• doxorubicin
• drug efflux
• HIV/AIDS
• P-glycoprotein inhibition
• poloxamer
• poloxamine
• polymeric micelle
• transport

Financial & competing interests disclosure

This work was financed by the Ministerio de Asuntos Exteriores (AECID Grant A/016343/08) and the Ministerio de Ciencia e Innovación (SAF2008–01679) Spain and FEDER. Alejandro Sosnik received partial financial support from the University of Buenos Aires (Grant UBACyT-B424). The authors express their gratitude to BASF Corporation (Verena Geiselhart) for providing poloxamer and poloxamine samples. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

The authors would like to thank the staff of the Screening Unit USEF of the University of Santiago de Compostela for their technical assistance.

Additional information

Funding

This work was financed by the Ministerio de Asuntos Exteriores (AECID Grant A/016343/08) and the Ministerio de Ciencia e Innovación (SAF2008–01679) Spain and FEDER. Alejandro Sosnik received partial financial support from the University of Buenos Aires (Grant UBACyT-B424). The authors express their gratitude to BASF Corporation (Verena Geiselhart) for providing poloxamer and poloxamine samples. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.