A potent nonporphyrin class of photodynamic therapeutic agent: cellular localisation, cytotoxic potential and influence of hypoxia

Abstract

We have developed a totally new class of nonporphyrin photodynamic therapeutic agents with a specific focus on two lead candidates azadipyrromethene (ADPM)01 and ADPM06. Confocal laser scanning microscopy imaging showed that these compounds are exclusively localised to the cytosolic compartment, with specific accumulation in the endoplasmic reticulum and to a lesser extent in the mitochondria. Light-induced toxicity assays, carried out over a broad range of human tumour cell lines, displayed EC 50 values in the micro-molar range for ADPM01 and nano-molar range for ADPM06, with no discernable activity bias for a specific cell type. Strikingly, the more active agent, ADPM06, even retained significant activity under hypoxic conditions. Both photosensitisers showed low to nondeterminable dark toxicity. Flow cytometric analysis revealed that ADPM01 and ADPM06 were highly effective at inducing apoptosis as a mode of cell death. The photophysical and biological characteristics of these PDT agents suggest that they have potential for the development of new anticancer therapeutics.

Synthesis, spectroscopic, and in vitro investigations of 2,6-diiodo-BODIPYs with PDT and bioimaging applications

“…It is possible that the mono-styryl-diiodo-BODIPYs bind preferentially to anti-apoptotic Bcl-2 proteins compared with their di-styryl analogs, causing cell apoptosis and/or autophagy [53], leading to rapid cell death. Previous studies have also shown that phototoxic BODIPYs tend to localize preferentially in the ER or mitochondria [24–29]. …”

“…Their remarkable photophysical properties, including high extinction coefficients, easily tunable absorption and emission profiles, high stability and solubility, as well as their known ability to permeate cells, make them suitable for exploration as PDT agents [21,22]. It has been shown that some BODIPYs bearing heavy atoms, such as iodine or bromine, display cytotoxic properties when exposed to light while others remain non-toxic [23–29]. The effects of the “spin-orbit couplings” of heavy atoms favor intersystem crossing from the excited singlet to the triplet state needed for singlet oxygen generation [30–32].…”

Vascular-targeted photodynamic therapy with BF2-chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment

“…Our previous studies have shown the ADPM family of photosensitisers to be an exciting new class of agents having significant potential for preclinical development (Gorman et al, 2004;Gallagher et al, 2005). Unlike many other PDT photosensitisers, ADPM agents are synthetic and can be readily modified about the core periphery to affect drug properties (McDonnell et al, 2005).…”

“…We have previously reported the discovery of a novel class of non-porphyrin-based modifiable PDT agents, termed the BF 2 -chelated tetraaryl-azadipyrromethenes (ADPMs), and have shown in vitro that their photophysical and biological characteristics have significant potential for the development as new anti-cancer therapeutics (Gorman et al, 2004;Gallagher et al, 2005). We have shown that this new class of PDT agent possesses excellent photophysical properties and as having EC 50 values in the low nano-molar range for lead compound ADPM06, with no discernable activity bias for a specific tumour cell type.…”

Boron dipyrromethene (BODIPY)-based photosensitizers for photodynamic therapy

“…Further development of the aza-BODIPYs as effective anticancer therapeutics required comprehensive studies on ADPM06. 132 The lead compound displayed localization in the cytoplasmic compartment with a large accumulation in the endoplasmic reticulum with minor localization to the mitochondria. ADPM06 induced apoptosis as a mechanism for cell death.…”