Abstract
BackgroundApoptotic cascades may frequently be impaired in tumor cells; therefore, the approaches to circumvent these obstacles emerge as important therapeutic modalities.Methodology/Principal FindingsOur novel derivatives of chlorin e6, that is, its amide (compound 2) and boronated amide (compound 5) evoked no dark toxicity and demonstrated a significantly higher photosensitizing efficacy than chlorin e6 against transplanted aggressive tumors such as B16 melanoma and M-1 sarcoma. Compound 5 showed superior therapeutic potency. Illumination with red light of mammalian tumor cells loaded with 0.1 µM of 5 caused rapid (within the initial minutes) necrosis as determined by propidium iodide staining. The laser confocal microscopy-assisted analysis of cell death revealed the following order of events: prior to illumination, 5 accumulated in Golgi cysternae, endoplasmic reticulum and in some (but not all) lysosomes. In response to light, the reactive oxygen species burst was concomitant with the drop of mitochondrial transmembrane electric potential, the dramatic changes of mitochondrial shape and the loss of integrity of mitochondria and lysosomes. Within 3–4 min post illumination, the plasma membrane became permeable for propidium iodide. Compounds 2 and 5 were one order of magnitude more potent than chlorin e6 in photodamage of artificial liposomes monitored in a dye release assay. The latter effect depended on the content of non-saturated lipids; in liposomes consisting of saturated lipids no photodamage was detectable. The increased therapeutic efficacy of 5 compared with 2 was attributed to a striking difference in the ability of these photosensitizers to permeate through hydrophobic membrane interior as evidenced by measurements of voltage jump-induced relaxation of transmembrane current on planar lipid bilayers.Conclusions/SignificanceThe multimembrane photodestruction and cell necrosis induced by photoactivation of 2 and 5 are directly associated with membrane permeabilization caused by lipid photodamage.
Highlights
Photodynamic therapy (PDT), a modality that evokes cell damage after illumination in the presence of a photosensitizing agent, is gaining momentum in treatment of a variety of human diseases including cancer [1,2,3]
The synthesis proceeded via the formation of the amide derivative 2 obtained after the nucleophilic opening of the exocyclic ring in 1 with ethylenediamine
For biological studies the sodium salt, chlorin e6 13(1)-N-{2-[N-(1-carba-closo-dodecaboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester sodium 5 was obtained from cesium salt 4 (Figure S1)
Summary
Photodynamic therapy (PDT), a modality that evokes cell damage after illumination in the presence of a photosensitizing agent, is gaining momentum in treatment of a variety of human diseases including cancer [1,2,3]. Tetrapyrrole containing compounds whose macrocyclic moiety plays a key role in generating cytotoxic reactive oxygen species (ROS) upon light illumination (LI), are especially suitable for chemical modifications of the coordination sphere and at the periphery of the macrocycle. Conjugation of boron containing polyhedra (carboranes), a modification aimed primarily at compounds for boron neutron capture therapy, yielded agents more efficient in PDT than their boron-free counterparts. Vicente and colleagues [14] prepared a boronated chlorin based on the synthetic 5,10,15,20-tetrakis(pentafluorophenyl)chlorin derivative and 1-mercapto-o-carborane. These compounds demonstrated low-to-null dark toxicity, good intratumoral accumulation and an ability to kill cultured cells and tumor xenografts after photoactivation. Apoptotic cascades may frequently be impaired in tumor cells; the approaches to circumvent these obstacles emerge as important therapeutic modalities
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