Abstract
Photodynamic therapy (PDT) is an attractive and non-invasive therapeutic modality for precision cancer treatment. It involves the interactions of a photosensitive drug, light of an appropriate wavelength, and oxygen. Upon light irradiation, the photosensitizing agents can convert molecular oxygen into reactive oxygen species (ROS) to ablate tumor cells. This thesis describes the design, synthesis, characterization, photophysical properties, in vitro and in vivo biological evaluation of a series of advanced photosensitizing systems for targeted PDT.Chapter 1 presents a brief overview of PDT, which includes the basic principle of photodynamic reaction, biological mechanisms of PDT for tumor ablation, and limitations of PDT. Recent research on different approaches to enhance PDT efficacy are also mentioned, such as increasing the tumor selectivity and therapeutic efficiency of photosensitizers, and relieving the tumor hypoxic environment to promote PDT. Moreover, the progress of combination of PDT with other therapeutic modalities, including chemotherapy, photothermal therapy (PTT) and immunotherapy is also reviewed.
Considering the complex tumor microenvironment, combination therapy usually exhibits enhanced therapeutic efficacy when compared with single treatment due to the different therapeutic mechanisms. Chapter 2 describes the synthesis, photophysical properties, and in vitro photodynamic activities of a series of silicon (IV) phthalocyanines (SiPcs) substituted with one or two naturally occurring microtubule polymerization inhibitor combretastatin A-4 (CA4). The SiPc substituted with one CA4 and three tetra-ethylene glycol chains preferentially localized in the endoplasmic reticulum and showed dark cytotoxicity solely due to the CA4 and enhanced cytotoxicity upon light irradiation.
In Chapter 3, a switchable bifunctional zinc(II) phthalocyanine containing 4-nitrobenzyl group (ZnPc-NO2) is reported, and its phototherapeutic mode can be regulated by nitroreductase (NTR) overexpressed in hypoxic tumor cells. This ZnPc-NO2 conjugate could eliminate aerobic tumor cells by generating ROS upon illumination. In the presence of NTR in hypoxic cancer cells, the 4-nitrobenzyl groups of ZnPc-NO2 was removed via reduction and subsequent self-immolation reaction, hence converting PDT to photothermal therapy. This conjugate could generate ROS under normoxia and heat under hypoxia to kill cancer cells upon light irradiation. The design, synthesis, characterization, and in vitro photodynamic and photothermal properties of ZnPc-NO2 is presented herein.
Hypoxia is one of the hallmarks of solid tumor, which heavily restricts the clinical translation of PDT. Chapter 4 reports catalase-like supramolecular nanophotosensitizers with O2 self-supplying based on cupric-ion-promoted self-assembly. This chapter describes the synthesis and characterization of a glutathione (GSH)-activatable photosensitizer with triazole carboxyl group (ZnPc*), which could assemble with copper(II) ions and chemotherapeutic agent 7-ethyl-10-hydroxycamptothecin (SN38) to form nanodrugs. The nanophotosensitizers could disassemble and release ZnPc*, SN38 and copper(II) ion due to the acidic cellular environment. The photosensitizing properties of ZnPc* was restored due to the high GSH concentration in the tumor cells. The released copper(II) ions could catalyze the conversion of hydrogen peroxide (H2O2) to O2 through catalase-like reaction and relieved tumor hypoxia. In vitro and in vivo results demonstrated that these self-assembled nanophotosensitizers significantly improved antitumor efficacy and overcame the hypoxia, exhibited synergistic photodynamic and chemotherapeutic effect.
As an extension of the study in Chapter 4, Chapter 5 presents a biomineralization of manganese doped calcium phosphate nanoparticles encapsulating carboxy ZnPc to relieve tumor hypoxia. Once the nanoparticles internalized into tumor cells, the nanoparticles released the payloads, including carboxy ZnPc, Ca2+ and Mn2+ ions. The elevated intracellular Ca2+ ions could induce severe mitochondrial dysfunction and respiratory depression to spare endogenous O2. Meanwhile, the Mn2+ ions could convert H2O2 to O2 in acidic environment via a catalase-like reaction, providing more O2 for PDT. Systematic in vitro and in vivo experiments demonstrated that this nanoparticle could suppress O2-consumption of cellular respiration and generate O2 via catalase-like reaction induced by Mn2+, boosting ROS generation to eradicate the hypoxic tumor.
Chapter 6 describes the supramolecular nanophotosensitizing systems consisting of ZnPc conjugated with a short peptide (Asp-Gly-Glu-Ala), namely ZnPc-DGEA. This short peptide DGEA could act as a targeting ligand to bind with integrin α2β1 overexpressed in cancer cells. Moreover, the amphipathic ZnPc-DGEA conjugate could co-assemble with poly ADP-ribose polymerase inhibitor (PARP), Olaparib to form the nanoparticles. These nanoparticles could inhibit DNA repair and enhance antitumor effect, as demonstrated by a series of in vitro and in vivo experiments.
The thesis is concluded with a brief summary of all studies in Chapter 7, along with a future prospective.
1H NMR spectra and ESI mass analysis of all new compounds are included in Appendix.
| Date of Award | 14 Mar 2023 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Pui Chi LO (Supervisor) |