Development of Multifunctional Nanomedicine Platforms for Advanced Cancer Treatment

多功能納米載體的構建及其在癌症治療中的應用

Student thesis: Doctoral Thesis

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Award date30 Aug 2018

Abstract

Nanomedicine has emerged as an innovative and promising approach to overcome the disadvantages of conventional cancer therapies, such as poor solubility in aqueous solution, fast metabolism of anti-cancer drugs, low tumor targeting property, derived multidrug-resistance problem, and so on. In addition, nanomedicine can provide a platform for the combination of multiple therapeutic modalities to enhance the treatment efficacy. This thesis describes a series of multifunctional nanomedicine platforms for advanced cancer therapy. The design, preparation, characterization, spectroscopic and photophysical properties of these systems, as well as their in vitro and in vivo behaviors are reported.

Chapter 1 describes a landscape of cancer nanomedicine, in regard to its historical development, properties and categories. It focuses on introducing two kinds of photo-based therapeutic modalities involved in my work, photodynamic therapy (PDT) and photothermal therapy (PTT), which hold great potential for cancer treatment in recent years. The contents include the basic principles of each therapy, examples of phototherapeutic agents, and their application in combination therapy. Moreover, the recent progress on nanomedicine for combined phototherapy and chemotherapy is reviewed.

Combined chemo-PDT has received considerable attention as a promising way to treat cancer. Chapter 2 focuses on a series of polymeric micelles encapsulating different ratios of doxorubicin (DOX) and zinc(II) phthalocyanine (ZnPc) for dual chemo-PDT. The amphiphilic block copolymers consist of methoxypolyethylene glycol (PEG) and poly(β-benzyl-L-aspartate) (PBLA), in which DOX and ZnPc were conjugated to the aspartate side chain through an acid-labile hydrazone linker and a redox-responsive disulfide linker, respectively. Upon cleavage of the sensitive linkers and the release of drugs at tumor sites, the therapeutic effect of the drugs could be restored. The synthesis, characterization, photophysical properties, and cleavage kinetics of these polymeric prodrug micelles are reported. The cellular uptake, intracellular ROS generation, dark- and photo-cytotoxicity of these prodrug micelles are examined on human hepatocellular carcinoma HepG2 cells. The cell death pathway and in vivo biodistribution of the most promising micelles are also reported therein.

DOX resistance is a major challenge for the chemotherapy against hepatocellular carcinoma. Chemo-PDT has been recognized as a promising strategy to conquer the drug resistance based on different mechanisms. As an extension of the study in Chapter 2, Chapter 3 applies the pH- and redox-responsive prodrug micelles, which have the similar chemical structure and function as the micelles described above, for combating DOX-resistant human hepatocellular carcinoma (R-HepG2) cells. The synergistic therapeutic effect on R-HepG2 cells induced by chemo-PDT has been investigated and discussed in this chapter.

PTT of cancer has attracted much attention because of its high inherent specificity and low invasive burden. One of the prerequisites for successful PTT is the targeting property of the PTT agents to the cancer tissues. Meanwhile, the PTT agents should exhibit good biodegradability, long-term safety, and photothermal stability. Chapter 4 reports a kind of biodegradable tumor-targeting hybrid poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating ZnPc as PTT agents for targeted treatment of cancers overexpressing cluster determinant 44 (CD44) receptors. The aggregation of ZnPc in the PLGA core resulted in a large red-shift of Q-band absorbance to 832 nm, leading to the significant PTT effect upon irradiation by a 808 nm NIR laser. The photothermal conversion is evaluated in solution study and the PTT-induced cell death has also been investigated on human colorectal adenocarcinoma HT29 cells and human lung carcinoma A549 cells.

To further integrate multiple cancer therapeutic modalities, a triple-collaborative theranostic nanosystem based on mesoporous silica-coated gold nanorod (GNRs@mSiO2) has been designed and prepared. Gold nanorods are used as PTT agents and mesoporous silica shell is used to incorporate photosensitizers (ZnPc) and epidermal-growth-factor receptors inhibitors (Erlotinib). The mesoporous silica shell is further modified with hyaluronic acid (HA) to enhance the targeting effect to the cancer cells overexpressing CD44 receptors. Due to the co-localization of therapeutic agents in a single nanoplatform, the synergy induced by PTT, PDT and erlotinib can be achieved. The results of this work are reported in Chapter 5.

The thesis is concluded with a brief summary of the aforementioned studies in Chapter 6 along with a future prospective of the multifunctional nanomedicine.

1H and 13C {1H} nuclear magnetic resonance (NMR) spectra and electrospray ionization (ESI) mass spectra of all the new compounds and polymers are included in the Appendix.