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Open AccessArticle

Targeted Delivery of Nanoparticulate Cytochrome C into Glioma Cells Through the Proton-Coupled Folate Transporter

1
Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Bayamon, PR 00956, USA
2
Universidad Central del Caribe, School of Medicine, Bayamon, PR 00956, USA
3
Department of Physiology, Universidad Central del Caribe, School of Medicine, Bayamon, PR 00956, USA
4
HIMA San Pablo Hospital, Caguas, PR 00726, USA
5
Department of Neurosurgery, University of Puerto Rico, Medical Sciences Campus, Rio Piedras, PR 00935, USA
6
Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(4), 154; https://doi.org/10.3390/biom9040154
Received: 4 March 2019 / Revised: 11 April 2019 / Accepted: 15 April 2019 / Published: 18 April 2019
(This article belongs to the Special Issue Nanoparticles for Cancer Therapy)
In this study, we identified the proton-coupled folate transporter (PCFT) as a route for targeted delivery of drugs to some gliomas. Using the techniques of confocal imaging, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and small interfering (siRNA) knockdown against the PCFT, we demonstrated that Gl261 and A172 glioma cells, but not U87 and primary cultured astrocytes, express the PCFT, which provides selective internalization of folic acid (FA)-conjugated cytochrome c-containing nanoparticles (FA-Cyt c NPs), followed by cell death. The FA-Cyt c NPs (100 µg/mL), had no cytotoxic effects in astrocytes but caused death in glioma cells, according to their level of expression of PCFT. Whole-cell patch clamp recording revealed FA-induced membrane currents in FA-Cyt c NPs-sensitive gliomas, that were reduced by siRNA PCFT knockdown in a similar manner as by application of FA-Cyt c NPs, indicating that the PCFT is a route for internalization of FA-conjugated NPs in these glioma cells. Analysis of human glioblastoma specimens revealed that at least 25% of glioblastomas express elevated level of either PCFT or folate receptor (FOLR1). We conclude that the PCFT provides a mechanism for targeted delivery of drugs to some gliomas as a starting point for the development of efficient methods for treating gliomas with high expression of PCFT and/or FOLR1. View Full-Text
Keywords: glioma; proton-coupled folate transporter; folate receptor 1 glioma; proton-coupled folate transporter; folate receptor 1
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Kucheryavykh, Y.V.; Davila, J.; Ortiz-Rivera, J.; Inyushin, M.; Almodovar, L.; Mayol, M.; Morales-Cruz, M.; Cruz-Montañez, A.; Barcelo-Bovea, V.; Griebenow, K.; Kucheryavykh, L.Y. Targeted Delivery of Nanoparticulate Cytochrome C into Glioma Cells Through the Proton-Coupled Folate Transporter. Biomolecules 2019, 9, 154.

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