Development of Novel Multifunctional Photosensitizing Systems for Cancer Treatment


Student thesis: Doctoral Thesis

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Award date7 Sep 2020


Photodynamic therapy (PDT) is a promising therapeutic modality for the treatment of cancer. This thesis describes the design, synthesis, characterization, and photophysical properties of a series of multifunctional photosensitizing systems, as well as their in vitro and in vivo biological evaluation.

Chapter 1 gives a brief overview of PDT, including its development, mechanisms and limitations. It focuses on the introduction of different approaches to increase the tumor selectivity and therapeutic efficiency of photosensitizers. The contents include the common principle of targeted PDT, examples of photosensitizers with targeting moieties, and their biological evaluation in targeted therapy. Moreover, the recent progress on PDT combined with other therapeutic modalities, including chemo-therapy and starvation therapy, is also reviewed.

Targeted PDT has received considerable attention as a promising way for cancer treatment due to the high selectivity of photosensitizers between normal and tumor tissues. Bioorthogonal ligation is an emerging strategy for targeted therapy with high specificity, efficiency and biocompatibility. In Chapter 2, two highly efficient bioorthogonal ligation methods, namely inverse electron-demand Diels-Alder reaction and copper-catalysed alkyne-azide cycloaddition, were employed to perform site-specific delivery of a distyryl boron dipyrromethene (DSBDP)-based photosensitizer which is substituted with 1,2,4,5-tetrazine and alkyne moieties. Having both tetrazine and alkyne moieties, the DSBDP could specifically bind to the cancer cells through bioorthogonal reaction with either one of these functional tags, confining the photocytotoxic effect and potentially minimizing the side effects to the normal tissues. The synthesis, characterization, photophysical properties, in vitro site-specific bioorthogonal ligation studies and in vivo biodistribution are reported herein.

Considering the complex tumor microenvironment, it is unsatisfying to rely on single treatment, combination therapy usually exhibits enhanced therapeutic efficacy. Chapter 3 describes the preparation and characterization of a series of multifunctional polymeric micelles encapsulating activatable photosensitizer-anticancer conjugate, zinc(II) phthalocyanine-doxorubicin (ZnPc-Dox), and hypoxia-activated prodrug tirapazamine (TPZ) through the self-assembly of amphiphilic copolymers. In this system, ZnPc is conjugated to the Dox through an acid-labile hydrazone linker. It is expected that the Dox and ZnPc can be separated in the acidic subcellular compartments of the cancer cells and exhibit chemo-therapeutic effect and photocytoxicity upon laser irradiation. In the meantime, the hypoxia microenvironment due to continuous oxygen consumption during PDT can trigger the activity of prodrug TPZ to achieve hypoxia-activated chemotherapy for enhanced cell killing, thus contributing the synergistic anticancer effect.

Dox is one of the major chemotherapeutic drugs against hepatocellular carcinoma, however, it suffers from drug efflux mediated by various drug transporter proteins. Chapter 4 presents the preparation, characterization, and photodynamic activities of a series of polymeric micelles consisting of mitochondria-targeted photosensitizer, Dox, and glucose oxidase (GOD), to overcome the Dox resistance on Dox-resistant hepatocellular carcinoma (R-HepG2) cells and achieve the combined therapeutic effect of PDT, chemotherapy and starvation therapy. The photosensitizer contains triphenylphosphonium (TPP) mitochondrial targeting group and dichloroacetate (DCA), which is a metabolic modulator to weaken drug resistance mechanisms. While the glucose oxidase is designed for glucose consumption, which can induce the starvation therapy. All the in vitro studies against R-HepG2 cells are described in this chapter.

The thesis is concluded with a brief summary of all mentioned studies in Chapter 5 along with a future prospective.

1H- and 13C-NMR spectra and ESI mass analysis of all new compounds are included in Appendix.