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Title: Zn-porphyrin-based Photosensitizers –Investigation of Structure-activity Relationship
Authors: ملاك مصطفى شرارة 
Supervisor: د. ليدميل بينوف
Keywords: Zn-porphyrin-based Photosensitizers
Issue Date: 2015
Publisher:  Kuwait university - college of graduate studies
Abstract: In photodynamic therapy (PDT), short lived reactive species are photogenerated upon the illumination of photosensitizers (PSs). The location of the damage as well as its extent determines the mode of cell death, and consequently the outcome of PDT. Available PSs lack some of the characteristics of an ideal PS, so new and more efficient photosensitizing candidates are needed. The aim of this study was to investigate the photodynamic activity, dark toxicity and subcellular localization of novel water soluble porphyrin-based cationic PSs. This study showed that low concentrations (0.5 μM) of Zn porphyrins did not cause dark toxicity. Limited cytotoxicity was observed immediately post illumination; but metabolic activity and cellular proliferation of PII cells were blocked when incubated in the dark for 24 h post illumination. Although the photochemistry of tested porphyrins was similar in terms of generating singlet oxygen, they demonstrated different photocytotoxic efficiency. The subcellular localization and efficiency of these metalloporphyrins were influenced by their physical properties. Although photocytotoxic Zn porphyrins localized to mitochondria and endoplasmic reticulum and caused DNA fragmentation, none induced external exposure of phosphatidylserine which represents a key apoptotic marker. Assessment of the plasma membrane integrity of treated cells showed that prevention of the execution of apoptosis was not due to plasma membrane damage. SDS-PAGE and immunoblot analysis indicated that photo-treatment with low concentrations of ZnPs initiates light-independent reactions which continue after illumination, resulting in extensive protein cross-links and profound cellular damage. Such processes in turn switched the balance of cell death pathways towards necrosis. Cationic amphiphilic Zn porphyrins, particularly ZnTnHex-3-PyP and ZnTnHexOE-3-PyP, show mitochondrial targeting in cultured cancer cells. However, at low photosensitizer concentrations, post-illumination light independent reactions suppress execution of apoptotic pathways and favor necrotic cell death.
Appears in Programs:0540 Medical Biochemistry (M.Sc.)

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