Efficient cell death induction in human glioblastoma cells by photodynamic treatment with Tetrahydroporphyrin-Tetratosylat (THPTS) and ionizing irradiation

Abstract

BackgroundSo far, glioblastomas cannot be cured by standard therapy and have an extremely poor median survival of about 15 months. The photodynamic therapy (PDT) with next generation photosensitizers, reaching a higher therapeutic depth, might offer a new, adjuvant treatment strategy in brain cancer therapy. Here, we investigated the effect of THPTS-PDT combined with ionizing irradiation (IR) on glioblastoma cells in vitro and in vivo.ResultsTHPTS colocalized to mitochondria and was not found in the nucleus. THPTS (2–20 μg/ml)-PDT significantly reduced the proliferation, metabolic activity and clonogenic survival and induced cell death mainly through apoptosis and autophagy. THPTS-PDT combined with IR decreased the clonogenicity significantly compared to single treatments. THPTS (≤ 300 μg/ml) alone showed no dark toxicity. The maximum therapeutic depth of THPTS-PDT in C6 glioblastomas was 13 mm.Materials and MethodsThree human glioblastoma cell lines (U-87 MG, A-172, DBTRG-05MG) were incubated with THPTS (1–300 μg/ml) 3–24 hours before laser treatment (760 nm, 30 J/cm2). THPTS localization and effects on metabolic activity, proliferation, cell death mechanisms and long-term reproductive survival were assessed. IR was conducted on an X-ray unit (0.813 Gy/min). Results were verified in vivo on a subcutaneous C6 glioblastoma model in Wistar rats.ConclusionsThis study demonstrated efficient THPTS-PDT in glioblastoma cells, in vitro and in vivo. The combinatorial effects of THPTS-PDT and IR are of specific clinical interest as enhanced eradication of infiltrating glioblastoma cells in the tumor surrounding tissue might possibly reduce the commonly occurring local relapses.

Co-Administered Polymeric Nano-Antidotes for Improved Photo-Triggered Response in Glioblastoma

“…The sizes found through DLS are respective to the distribution of hydrodynamic nanoparticle diameter, unlike TEM/SEM images that yield the particle diameter. The sizes of drug-loaded nanoparticles compared to empty nanoparticles are typically larger, as also found in previous studies done in our laboratory using similar nanoparticle preparation using BPD nanoparticles [1]. The high encapsulation of both drugs may have caused the slight increase in size compared to the empty nanoparticles [2].…”

“…Glioblastoma multiforme (GBM) accounts for approximately 40% of all high-grade, type IV, intracranial tumors [1]. GBM, a subtype of glioma, or glial cell origin tumor, affects the brain or spinal cord and is characterized by aggressive metastatic potential with poor survival outcomes of 14 months with traditional treatments [1]. Five in 100,000 persons are diagnosed per year with this fatal cancer [2].…”

In silico tumor growth validation based on human brain cancer models

“…The data produced should be further analyzed in order to finalize the values. Bibliographic values for the spontaneous cell death in gliomas are 5-11% [262] and our preliminary results are in line to the reported ones.…”

“…The idea is that using simple rule-based models like this one that was inspired by Conway's "Game of Life", the fundamental GB hallmarks can be reproduced and form the typical morphology of small GB tumors. Assessing the pathophysiology of GB necrosis formation and evolution, as well as fostering the intrinsic glioma cell death is a current treatment target to several studies [262,265] and will further promote our GB ontogenesis understanding and the importance of necrosis as a GB diagnostic feature.…”

Reduction of Muscle-Invasive Tumors by Photodynamic Therapy with Tetrahydroporphyrin-Tetratosylat in an Orthotopic Rat Bladder Cancer Model

“…Reduced energy required for photoactivation minimizes tissue fibrosis following heat damage (14). Cytotoxic effects of THPTS-PDT have been described in different tumors (15)(16)(17), including human urothelial carcinoma cells in vitro. THPTS-PDT on human bladder carcinoma cells showed significant tumor cell toxicity while sparing normal human detrusor myocytes.…”