Development of versatile platforms for constructing near-infrared photosensitizer based theragnosis system

Abstract

Theragnosis (therapy + diagnosis) is notable for early detection in the treatment of cancers, thereby increasing the survival rate of patients by enhancing the therapeutic effect. Currently, organic and inorganic materials have been studied with these theragnosis tools, and fluorescence, PET, CT, and PA have been used as methods for in vivo diagnosis of abnormal sites. Among these tools, organic systems can overcome the problems of toxicity and bioavailability of inorganic systems, and many studies have been conducted. In particular, an organic photosensitizer having a near-infrared light absorber has excellent resolution and contrast index compared to those of the conventional visible light region. The ability of these photosensitizers also includes a phototherapy property (such as for photodynamic therapy and photo-thermal therapy) by which is possible to deliver local therapy depending on irradiation by a particular laser. Therefore, I have developed an organic system with various properties, which enables diagnosis due to its high resolution and delivers laser phototherapy at the diagnosed position. In the work reported in this thesis, I constructed a near-infrared cyanine dye-based theragnosis system from two directions. First, a single-molecule photosensitizer capable of targeting cancer mitochondria was designed to detect the position of a substance from a fluorescent signal. In addition, a target-specific therapy was achieved through a photodynamic therapy effect (with or without a laser). Second, a nanoparticle composed of a near-infrared photosensitizer material was prepared and a tumor could then be detected using photoacoustic imaging. I also designed an experiment using local synergistic phototherapy based on the laser irradiation of loaded gemcitabine.

In Chapter 1, a noninvasive and selective therapy (photodynamic therapy: PDT) is reviewed from wide research in clinical fields. The lower efficiency of PDT can induce unexpected side effects. Mitochondria have been researched extensively as target sites to maximize PDT effects because they play crucial roles in metabolism and can be used as cancer markers due to their high transmembrane potential. Herein, is reported the development of a mitochondria-targeting photodynamic therapeutic agent (MitDt). This photosensitizer was synthesized from heptamethine cyanine dyes, which were conjugated or modified as follows. The heptamethine mesoposition was conjugated with a triphenylphosphonium derivative for mitochondrial targeting. The N-alkyl side chain was modified for regulation of charge balance and solubility, and the indolenine groups were brominated to enhance generation of reactive oxygen species (ROS) after laser irradiation. The synthesized MitDt increases the cancer uptake efficiency due to the lipo-cationic properties of the triphenylphosphonium. The PDT effects of MitDt are amplified after laser irradiation because mitochondria are susceptible to ROS, the response to which triggers an apoptotic anticancer effect. Consequently, related hypotheses were evaluated using in vitro and in vivo studies, and the results indicate strong potential for the use of MitDts as efficient single-molecule-based PDT agents for cancer treatment.

In Chapter 2, it is explained how image-guided therapy, combined with multimodal imaging and therapeutic action, forms an attractive system because it can induce outstanding effects at focused locations. However, conventional liposomes cannot figure in therapeutic or imaging roles themselves, thereby inducing the disadvantage of their biological unavailability as a bio-photonic theragnosis tool. Therefore, I propose a novel multimodality imaging-guided chemo-thermotherapy system composed of phosphocholine conjugated C11 heptamethine cyanine dye with PEG conjugated heptamethine cyanine dye (NEPC). It is possible to simultaneously obtain chemotherapy and photothermal therapy (PTT) effects at the diagnosis site using photoacoustic imaging by loading the target with gemcitabine (NEPCG). The results indicated that the nanoparticle had a bilayer structure with high thermal efficacy. Furthermore, NEPC showed remarkable therapeutic efficacy only after laser irradiation. NEPCG has greater anticancer efficacy than free gemcitabine (GEM) does and more than NEPC with or without laser irradiation, due to the synergistic effect of PTT and chemotherapy. These unique properties offer a new approach to realize the multimodal potential of fluorophore nanoparticles as accurate and effective tools in clinical fields