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P2X7 receptor as a novel drug delivery system to increase the entrance of hydrophilic drugs into cells during photodynamic therapy

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Abstract

The second-generation photosensitizer methylene blue (MB) exhibits photochemical and photophysical properties suitable for photodynamic therapy (PDT)-based cancer treatment. However, the clinical application of MB is limited because of its high hydrophilicity, which hinders its penetration into tumor tissues. Therefore, new methods to improve the entry of MB into the cytoplasm of target cells are necessary. Because MB has a mass of 319 Da, transient pores on the plasma membrane, such as the pore induced by the P2X7 receptor (P2X7R) that allows the passage of molecules up to 900 Da, could be used. Using MTT viability assays, flow cytometry experiments, and fluorescence microscopy, we evaluated the toxicity and phototoxicity of MB and potentiation effects of ATP and MB on cell death processes in the J774 cell line (via a P2X7-associated pore). We observed that treatment with 5 μM MB for 15 min promoted the rate of entry of MB into the cytoplasm to 4.7 %. However, treatment with 5 μM MB and 1 mM ATP for the same amount of time increased this rate to 90.2 %. However, this effect was inhibited by pretreatment with a P2X7 antagonist. We used peritoneal macrophages and a cell line that does not express P2X7R as controls. These cells were more resistant to PDT with MB under the same experimental conditions. Taken together, these results suggest the use of the pore associated with P2X7R as a drug delivery system to increase the passage of hydrophilic drugs into cells that express this receptor, thus facilitating PDT.

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Abbreviations

PDT:

Photodynamic Therapy

P2X7R:

P2X7 receptor

MB:

Methylene Blue

PI:

Propidium iodide

BBG:

Brilliant Blue G

DMEM:

Dulbecco’s Modified Eagle Medium

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Acknowledgments

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), PAPES VI – CNPq, Oswaldo Cruz Institute and FAPERJ. The experiments using HEK 293 cells were carried out in the Laboratory of Inflammation, Oswaldo Cruz Institute.

Author contributions

PAFP carried out the phototherapy and toxicity assays, participated in the sequence alignment and drafted the manuscript. LBGF carried out the phototherapy and toxicity assays and participated in the sequence alignment of the manuscript. DNMF and JPS carried out the phototherapy and toxicity assays. JPS carried out the phototherapy and toxicity assays. RXF participated in the design of the study and helped to revise the manuscript. PCNT conceived of the study, and participate in its design. LAA participated in its design and coordination of the study. All authors read and approved the final manuscript.

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  1. Laboratório de Comunicação Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brasil

    Paulo Anastácio Furtado Pacheco, Leonardo Mendonça, Dinarte Neto M Ferreira, Pedro Celso Nogueira Teixeira & Luiz Anastacio Alves

  2. Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brasil

    Leonardo Braga Gomes Ferreira

  3. Laboratório de Toxoplasmose, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz – FIOCRUZ, Av. Brasil, 4365 Manguinhos – CEP, :21045-900, Rio de Janeiro, RJ, Brasil

    Juliana Pimenta Salles & Robson Xavier Faria

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  1. Paulo Anastácio Furtado Pacheco
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Pacheco, P.A.F., Ferreira, L.B.G., Mendonça, L. et al. P2X7 receptor as a novel drug delivery system to increase the entrance of hydrophilic drugs into cells during photodynamic therapy. J Bioenerg Biomembr 48, 397–411 (2016). https://doi.org/10.1007/s10863-016-9668-6

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