Water Soluble Systems of Tetrapyrazinoporphyrazine Derivatives for Photodynamic Therapy

Abstract

In this Ph.D. thesis, incorporation of tetrapyrazinoporphyrazines (TPP) into various types of glucose groups were attempted in order to improve the solubility of photosensitizers in aqueous media but also give the targeting ability against the tumor cells. At first, two types of TPP complexes, conjugated with D-glucose groups linked by polyethylene glycol (PEG) chains were synthesized in order to improve solubility in aqueous media. One introduced Zinc atom and the other does Silicon atom on their central metal positions. The peripheral positions of both TPP complexes were substituted with bornane groups for preventing the molecules from aggregation as giving the steric hindrance with bulkiness. Next, monomers containing acetyl-glucose and azide groups were prepared by defined synthetic method, respectively. Statistical copolymers were synthesized through RAFT polymerization, and were introduced TPPs though the reaction with azide groups by click chemistry. The acetyl-glucose moieties on copolymers were deprotected through hydrolysis with NaOMe. These statistical copolymer structures showed enhanced not only solubility, but also tumor selectivity through the multivalent effect of glycopolymers. At last, three kinds of amphiphilic block copolymers were synthesized by RAFT polymerization, which composed of polystyrene, polyglucosyl ethyl methacrylate and PEG. TPPs, which were substituted with trihexylsiloxy groups on central silicon atom in their axial directions, were synthesized. Furthermore, micelles were prepared with the block copolymers and photosensitizer in the aqueous solvent for encapsulation of the hydrophobic photosensitizers. Characterizations of the structures were proceeded by using NMR, IR, MALDI-TOF, GPC, DLS, and TEM. Their photochemical and photophysical properties were measured including UV-vis absorption, fluorescence emission, singlet oxygen generation, and photo-degradation both in organic and aqueous media through the appropriate methods. Prepared compounds exhibited outstanding selectivity and photo-toxicity against the tumor cells (MDA-MB-231) compared to normal cells (NIH3T3). This research has a special meaning as the hydrophobic photosensitizers incorporation into biocompatible glucose through several methods, which achieved increase of solubility and providing the selectivity against tumors.