Self-assembled Amino Acid- and Short Peptide-based Photosensitizing Nanomaterials for Antitumor Photoynamic and Photothermal Therapy

基於氨基酸和短肽的自組裝光敏納米材料在光動力和光熱抗腫瘤治療中的應用

Student thesis: Doctoral Thesis

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Award date18 Sep 2020

Abstract

Phototherapies, including photodynamic therapy (PDT) and photothermal therapy (PTT), are attractive and non-invasive techniques for precision cancer treatment. The photosensitizing agents that accumulate in the tumor site convert absorbed near-infrared (NIR) light energy to generate reactive oxygen species (ROS) or heat, causing the ablation of tumor cells. However, the photosensitizing materials face several serious problems, including poor tumor targeting, long-term toxicity, hypoxic tumor microenvironment and limited absorbance in biological window, which compromise the clinical application of phototherapy. Tremendous interest in self-assembly of amino acids and short peptide towards functional nanomaterials has been inspired by naturally evolving self-assembly in biological construction of multiple and sophisticated protein architectures in organism. However, the utilization of the small biomolecule combinations and their cooperative interactions to design and create rationally desired phototherapeutic nanomaterials for addressing the aforementioned issues still remains a formidable challenge. In this thesis, we have employed small biological molecules, such as amino acids, oligopeptides or essential trace elements, including iron and copper ions, as building blocks to fabricate several photosensitizing materials via a molecular self-assembly strategy, either self-assembly of oligopeptides-based photosensitizers, or co-assembly from amino acids, metal ions and photosensitizers. The design, preparation, characterization, mechanism exploration, spectroscopic and physicochemical properties of these systems, as well as in vitro and in vivo therapeutic behaviors are reported.

Chapter 1 primarily introduces the research actuality of phototherapies including PDT and PTT in cancer therapy, as well as the historical development and current problems of nanomedicine applied to these modalities. The self-assembly of simple biomolecules, as a novel and innovative strategy, the origin, mechanism and application of which were also reviewed.

Chapter 2 reports the supramolecular nanophotosensitizing systems self-assembled by Zinc (II) Phthalocyanine (ZnPc) conjugated with a short peptide (Gly-Gly-Lys) and a biotin moiety based on non-covalent interactions, which encapsulating the hydrophobic ZnPc into the core and exposing the biotin moieties on the outermost surface. The resulted self-assembled nanoparticles achieve the efficient selectivity to cancer cell. Moreover, the amphipathic targeting ZnPc-peptide conjugate could co-assemble with doxorubicin (DOX) to form the co-assembled nanoparticles, which demonstrated the synergistic photodynamic therapy and chemotherapy in in vitro studies and in vivo studies.

Chapter 3 presents catalase-like supramolecular nanozyme with O2 self-supplying based on iron coordination-driven self-assembly of amino acid to address the hypoxic tumor microenvironment during PDT. The organization of amphiphilic amino acids are precisely manipulated by iron coordination to induce the formation of nanovesicle-like hollow nanozyme. The hollow nanozyme could highly accumulating both hydrophobic photosensitizer ZnPc and hydrophilic hypoxia induced factor-1α (HIF-1α) inhibitor acriflavine (ACF) to form the multifunctional nanozyme. The co-loaded nanozyme could selectively release ZnPc and ACF within the tumor region and give rise to simultaneously Fenton reaction triggered tumor oxygenation and residual HIF-1 functional inhibition. These favorable therapeutic features result in highly efficient PDT without adverse effects in vitro and in vivo.

As an extension of the study in Chapter 3, Chapter 4 describes the catalase-like nanozyme based on copper coordination self-assembly of amino acid for co-loading glucose oxidase (GOD) and reactive oxygen species activated prodrug (ZnPc-TK-DOX) to achieve cooperative therapy combining starving therapy, PDT and chemotherapy. The co-loaded self-assembled nanoparticles demonstrated the uniform and spherical size, stimuli-release properties, oxygen self-supplying ability, as well as the combined therapeutic effect in cellular studies. 

Chapter 5 describes a dual targeting ZnPc-peptide conjugates (ZnPc-RGDK), which achieved firstly fabrication of supramolecular photothermal materials with a super-large absorption redshift of 155 nm (from 675 nm to 830 nm) by a kinetically controlled self-assembly strategy. The sufficient rearrangement of intermolecular aggregates to an ordered structure (nanofibers, fusiform-like sheet nanostructures and bundled fusiform-like sheet nanostructures) rather than nanoparticles, probably result from the aprotic solvent THF overcoming the energy barriers in this kinetically controlled self-assembly process. The super-large redshift in the absorbance was further revealed to originate from the orderly stacked phthalocyanine chromophores, which enable a charge transfer state between peptide and metal zinc. Importantly, the nanofibers demonstrated the excellent photothermal conversion efficiency and stability, resulting the efficient PTT effect for tumor ablation in in vivo studies, highlighting the opportunities to develop next generation photothermal agents.

The thesis is concluded with a brief summary of the aforementioned studies in Chapter 6, as well as a future prospective for further development of amino acid- and peptide-based nanomaterials in the area of phototherapies.