Two combined photosensitizers: a goal for more effective photodynamic therapy of cancer

Abstract

Photodynamic therapy (PDT) is a clinically approved therapeutic modality for the treatment of diseases characterized by uncontrolled cell proliferation, mainly cancer. It involves the selective uptake of a photosensitizer (PS) by neoplastic tissue, which is able to produce reactive oxygen species upon irradiation with light, leading to tumor regression. Here a synergistic cell photoinactivation is reported based on the simultaneous administration of two PSs, zinc(II)-phthalocyanine (ZnPc) and the cationic porphyrin meso-tetrakis(4-N-methylpyridyl)porphine (TMPyP) in three cell lines (HeLa, HaCaT and MCF-7), using very low doses of PDT. We detected changes from predominant apoptosis (without cell detachment) to predominant necrosis, depending on the light dose used (2.4 and 3.6 J/cm2, respectively). Analysis of changes in cytoskeleton components (microtubules and F-actin), FAK protein, as well as time-lapse video microscopy evidenced that HeLa cells were induced to undergo apoptosis, without losing adhesion to the substrate. Moreover, 24 h after intravenous injection into tumor-bearing mice, ZnPc and TMPyP were preferentially accumulated in the tumor area. PDT with combined treatment produced significant retardation of tumor growth. We believe that this combined and highly efficient strategy (two PSs) may provide synergistic curative rates regarding conventional photodynamic treatments (with one PS alone).

Clinical use of photodynamic therapy in ocular tumors

“…173 Different photosensitizers create direct damage localized on the plasma membrane, lysosome, mitochondria, Golgi apparatus, endoplasmic reticulum, and nuclear membrane, and this localization appears to influence the type of cell death. 4,130 The extent of the effect of the tissue microenvironment and other cellular inputs, however, remains unclear. 36 Damage to tumor cells leads to the release of cell-death-associated molecular patterns (CDAMs) and damage-associated molecular patterns (DAMPs), which in turn attract leukocytes such as dendritic cells and neutrophils, thus producing an acute inflammatory response.…”

Porphyrin-based cationic amphiphilic photosensitisers as potential anticancer, antimicrobial and immunosuppressive agents

“…The use of combination strategies is also aimed at achieving higher impact at lower doses of each drug, thus avoiding the usual serious side effects, such as those linked with chemotherapy. A synergistic effect in killing cancer cells was found by combining two photosensitisers in PDT, zinc(II)-phthalocyanine and meso-tetrakis(4-Nmethylpyridyl)porphine (Acedo et al 2014).…”

Photodynamic therapy: Promotion of efficacy by a sequential protocol

“…A 1996 report showed that PDT sequentially directed against lysosomes and mitochondria could result in enhanced photokilling in a mouse sarcoma model [21]. Another report indicated a similar result when lysosomal and golgi were the PDT targets [22]. A potential mechanism for this result has been suggested: lysosomal photodamage can release calcium stores [23] which, in turn, activate the protease calpain leading to cleavage of ATG5 to a pro-apoptotic fragment [24].…”