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.
Highlights
Glioma is one of the most malignant forms of brain cancer
The specificity of internalization of the designed folic acid (FA)-Cyt c NP constructs by cultured glioma cells was tested by using FA-Cyt c NPs modified with fluorescein isothiocyanate (FITC) via the amine
A172, U87, mouse Gl261 glioma cells, and mouse cultured astrocytes was tested by using FA-Cyt c NPs modified with fluorescein isothiocyanate (FITC) via the amine treated with FITC–labeled FA-Cyt c NPs, added to the culture medium for a final concentration of group
Summary
Glioma is one of the most malignant forms of brain cancer. Current chemotherapeutic treatments typically lack specificity against cancer cells and are associated with significant toxicity on healthy tissues, affecting the overall health of the patient. Therapeutic approaches based on targeted nanoparticulate drug delivery open a new avenue for cancer treatment and allow selective binding to cancer cells, with minor effects on healthy tissues [1,2,3]. The system is based on conjugation of nano-particulate cytochrome c (Cyt c NPs) to ligands, which are specific for receptors in tumors, in order to enhance selective cellular uptake and initiate apoptosis. This designed system demonstrated an increased potential therapeutic benefit, based on the ability to deliver high drug concentrations to the tumor site without the need for excessive systemic exposure [7]
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