# Drastic Impact of Donor Substituents on Xanthenes in the PDT of Glioblastoma

## TL;DR

This paper explores how changing donor groups in xanthene-based dyes significantly affects their effectiveness in photodynamic therapy for glioblastoma.

## Contribution

The study introduces two new selenium-containing xanthene-based photosensitizers with improved PDT efficacy and selectivity for glioblastoma.

## Key findings

- NSeMorph and NSeAze show absorption over 650 nm with molecular weights under 420 g/mol.
- NSeAze achieved IC50 values of 456 nM and 461 nM for glioblastoma cell lines.
- NSeAze demonstrated high phototoxicity indices, indicating strong activity under illumination.

## Abstract

Even though significant progress has been made in treating
various
cancer types, brain cancers lag drastically. Several factors contribute,
led by operational difficulties, the blood-brain barrier, and the
tendency of recurrence. Alternative therapies are needed, and photodynamic
therapy (PDT) offers several advantages. However, PDT has rarely been
explored for brain cancers since, for achieving near-infrared range
activation, photosensitizers should have longer conjugation lengths
and thus higher molecular weight, which then limits blood-brain barrier
penetration. Here, we describe the syntheses and PDT action of two
new selenium-containing xanthane-based photosensitizers (NSeMorph and NSeAze) that show absorption over 650 nm with molecular
weights lower than 420 g/mol. It has been demonstrated that both NSeMorph and NSeAze showed PDT activity against
glioblastoma cell lines (U87MG and U118MG), and more interestingly,
the efficacy and selectivity of the photosensitizers were significantly
different depending on the donor side groups. NSeMorph, utilizing morpholine donors, showed IC50 values of 15.8
μM for U87MG and 8.0 μM for U118MG cell lines. Surprisingly,
the IC50 was not reached at a 20 μM concentration
in the healthy cell line (L929), indicating the selective nature of NSeMorph even though no activation-based cage groups or targeting
groups were present. Upon switching the donor units to azetidine,
IC50 values of 456 nM for U87MG and 461 nM for U118MG cell
lines were achieved; to the best of our knowledge, these are the lowest
IC50 values reported in literature against glioblastoma
(U87MG and U118MG) that combine NIR absorption in aqueous media and
low molecular weight (<400 g/mol). Additionally, NSeAze showed one of the highest phototoxicity indices, the ratio of cell
viabilities under dark and light conditions, showing the remarkable
activity of NSeAze under illumination. Overall, this
study represents one of the first examples of the drastic effect on
PDT action by altering only the donor side groups of xanthene-based
dyes.