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

Biomolecules. 2019 Apr 18;9(4):154. doi: 10.3390/biom9040154.

Abstract

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.

Keywords: folate receptor 1; glioma; proton-coupled folate transporter.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytochromes c / chemistry*
  • Cytochromes c / pharmacology
  • Folic Acid / chemistry
  • Folic Acid / pharmacology
  • Glioma / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Nanoconjugates / adverse effects
  • Nanoconjugates / chemistry*
  • Proton-Coupled Folate Transporter / metabolism*

Substances

  • Nanoconjugates
  • Proton-Coupled Folate Transporter
  • SLC46A1 protein, human
  • Cytochromes c
  • Folic Acid