Toward Dual and Targeted Cancer Therapy with Novel Phthalocyanine-based Photosensitizers

Phthalocyanines are versatile functional materials for a wide range of applications. This research work aims to explore their potential as activatable and efficient photosensitizers for targeted photodynamic therapy (PDT). This thesis describes the synthesis, spectroscopic characterization, photophysical properties, and in vitro photodynamic activities of several series of carefully designed phthalocyanine-based photosensitizers.;Chapter 1 presents an overview of PDT, including its historical development, photophysical and biological mechanisms, and current clinical applications. Various classes of photosensitizers are introduced with emphasis put on phthalocyanines, which have emerged as a promising class of second-generation photosensitizers for PDT. In order to enhance the therapeutic efficacy, considerable effort has been expended to functionalize the photosensitizers with a view to achieving dual and targeted therapy. The concept and recent development of this advanced modality is discussed and illustrated with relevant examples at the end of this chapter.;We have designed a novel phthalocyanine-platinum complex conjugate. Chapter 2 presents the synthesis and spectroscopic characterization of this conjugate, which comprises of a zinc(II) phthalocyanine and an oxaliplatin derivative that is known to have antitumor activity. The basic photophysical properties, aggregation behavior, and in vitro photodynamic activities of this conjugate have also been investigated and compared with those of some model compounds. This conjugate demonstrates a synergistic effect in which it shows a cytotoxic effect in the dark due to the oxaliplatin moiety and an enhanced cytotoxicity upon illumination due to the phthalocyanine unit toward the HT29 human colon adenocarcinoma cells. The high photodynamic activity can also be attributed to its higher cellular uptake and reactive oxygen species (ROS) generation efficiency. This conjugate shows preferential localization in the lysosomes and induces cell death mainly through apoptosis.;Chapter 3 describes the synthesis, spectroscopic characterization, and photophysical properties of a series of polyamine-substituted zinc(II) phthalocyanines. Their photodynamic activities toward B16 melanoma and Chinese hamster ovary (CHO) cells have been investigated. Their cellular uptake, subcellular localization, and cell death mechanism are also reported herein.;Chapter 4 reports the molecular design and development of a novel redox-responsive silicon(IV) phthalocyanine axially substituted with two ferrocenyl-chalcone derivatives via disulfide bonds, which are prone to rapid cleavage under a reducing environment. The basic photophysical properties of this compound and its cleavage kinetics upon exposure to a reductive stimulant have been studied by various spectroscopic methods. Its in vitro photodynamic activities including cytotoxicity, cellular uptake, and subcellular localization toward MCF-7 human breast cancer cells, both in the absence and presence of an external reducing agent, have also been examined.;Chapter 5 focuses on the exploration of a dual pH- and redox-responsive silicon(IV) phthalocyanine in which the ferrocenyl quenchers are axially coordinated to the macrocycle through an acid-labile hydrazone bond and a reducible disulfide bond. At physiological pH and low level of reducing agent, or under one of these conditions, the linker(s) remain(s) intact and hence the photosensitizer remains photodynamically "inactive" due to the quenching effect induced by the ferrocenyl unit(s). However, it becomes activated in an environment with low pH and high level of reducing agent, which is analogous to the conditions in tumor tissues. The effects of these external stimuli on the photophysical properties and in vitro photodynamic activities of this novel photosensitizer are examined in this chapter. (Abstract shortened by UMI.).