Europium Complexes-based Nanocomposite For Cancer Diagnosis And Therapy

Nanomedicine is the biomedical application of nanoscale materials for diagnosis and therapy of cancer. Recent advances in nanotechnology and biotechnology have contributed to the development of multifunctional nanoparticles as representative nanomedicine. They were initially developed to enable the target-specific delivery of imaging or therapeutic agents for biomedical applications. Due to their unique features including multifunctionality, large surface area, structural diversity, and long circulation time in blood compared to small molecules, nanoparticles have emerged as attractive preferences for optimized therapy through personalized medicine. Multimodal imaging and theragnosis are the cutting-edge technologies where the advantages of nanoparticles are maximized. Because each imaging modality has its pros and cons, the integration of several imaging agents with different properties into multifunctional nanoparticles allows precise and fast diagnosis of disease through synergetic multimodal imaging. The optical imaging is an important technique in biochemistry and molecular biology. It can be used to study a wide range of biological specimens, from cells to ex vivo tissue samples, and to in vivo imaging of live objects; it can also cover a broad range of length scale, from submicrometer-sized viruses and bacteria, to macroscopicsized live biological species. Thus, optical imaging provides a powerful noninvasive tool to visualize morphological details in tissue with subcellular resolution. However, the imperfect optical properties of conventional optical imaging agents and the challenge in incorporation of therapeutic functions onto them have severely limited their abilities for use in theranostics.Lanthanide complexes-doped nanocomposites are a promising new generation of imaging agents for bioimaging. Lanthanides possess intrinsic luminescence that originates from f-f electron transitions in the 4fn shell and offer unique properties for optical imaging contrast agents that address current limitations of their organic counterparts. First, due to shielding by the 5s and 5p orbitals, the 4f orbitals do not directly participate in chemical bonding. The emission wavelengths of lanthanides are thusminimally perturbed by the surrounding matrix and ligand field, resulting in sharp, line-like emission bands with the same fingerprint wavelengths and narrow peak widths of the corresponding free Ln(III) salts. Second, the f-f transitions are formally forbidden by the spin and Laporte rule and feature long excited-state lifetimes in the milli- to microsecond range. This property lends luminescent lanthanides to time-gated or time-resolved live-cell or in vivo imaging. Such an approach enhances signal-to-noise ratios through elimination of interferences from scattering and short-lived autofluorescence of biological constituents. Finally, because the differences in electronic properties between the different Ln(III) ions reside in the shielded 4f orbitals, varying the metal center imposes minor effects on the chemical properties of the Ln(III) complex, allowing for facile multiplexing for ratiometric or multimodal applications. Moreover lanthanides are typically chelated with multidentate ligands to attenuate the toxicity of free lanthanide ions. Considering the relatively poor stability of lanthanides complexes under moisture conditions, we designed multifunctional phenyl mesoporous silica NPs and constrained the lanthanides complexes by strong π-π interactions and the hydrophobic property to avoid fluorescence-quenching and leakage of the complexes. Thus, this nanocomposite have multiple attributes that make them well-suited for use in theranostics comprised of imaging, drug delivery, and therapy.The dissertation is mainly divided into following four chapters:Chapter 1: A brief review of a lanthanide complexes-based nanocomposite for cancer diagnosis and therapy.Chapter 2: Design of versatile europium complexes-based nanocomposite for ‘seeing’ drug release and action behaviour.Herein, for the first time, based on the coordination characteristics of the lanthanide ions including the exchangeable and extendable coordination sphere and susceptible photoluminescence(PL) intensity to the surrounding coordination environment, we propose a novel concept of drug coordination to real-time monitor drug release by PL emission of lanthanide complexes. We choose magnetic core coated phenyl mesoporous silica nanoparticles(phMSNs) as matrix and constraint the Eu(III) complex by strong π-π interaction and hydrophobic property. When the drug loaded into the channels of phMSNs shell by the coordination effect, the PL intensity of the Eu(III) complex can be enhanced drastically by inhibiting energy transfer(ET) from Eu(III) complex to phMSNs shell due to the coordination effect between the drug molecules and Eu(III) ions. And the real-time monitoring can be realized by the ET process recover with drug releasing. Most importantly, the Fe3O4 core endows the visualization function of the nanocomposite by the technique of atomic resolution TEM for finding the precise drug action sites and elucidating the anticancer action mechnism. Therefore, the design of the nanocomposite with integral composition can be used with existing clinical applications to determine online the drug concentrations in the tissue regions of interest and drug action behavior in real-time.Chapter 3: Europium complexes-based multifunctional nanocomposite for synergistic dualmode monitoring and therapy.Towards precision cancer medicine, attaining facilely operated synergistic tumor diagnosis and therapy based on one single platform with high performance remains extremely challenging. For the first time, by utilizing the luminescence resonance energy transfer(LRET) from a two-photonsensitized europium complex to gold nanotriangles, we successfully implemented multiple functions into one nanocomposite operated under single near infrared(NIR) light, including lightinduced drug release, temperature/luminescence dual-mode monitoring of drug release, and synergistic turning-on of photothermal chemotherapy. This ingenious and easily applied strategy can be used to design a new generation of theranostic nanocomposite enabling controllable synergistic therapy and real-time monitoring of drug release, which is highly desirable for applications in future precision medicine.Chapter 4: NIR/H2O2-triggered nanocomposites for highly efficient and selective synergistic photodynamic and photothermal therapy against hypoxic tumor cells.Photodynamic therapy(PDT) still faces a barrier of tumor selectivity, hypoxia-induced drug resistance, and common limitations of photosensitizers(PSs). In this work, smart near-infrared(NIR)/H2O2-triggered, cell-specific, and O2-evolving nanocomposites(NCs) were designed, constructed, and applied for an efficient synergistic PDT and photothermal therapy under a single NIR laser excitation. The obtained NCs can efficiently produce 1O2 by converting a deeply penetrating NIR light into a visible light to excite the PS molecule(methylene blue, MB); this process is realized by the luminescence resonance energy transfer from a two-photon-sensitized Eu(III) complex to MB. Moreover, once NCs are selectively taken up by αvβ3 integrin-rich tumor cells, the intracellular H2O2 can contact with the shell catalase of NCs and catalyze the generation of O2. Thus, NCs can achieve an unprecedented self-sufficiency of the O2 generation in the PDT process to overcome the hypoxia-induced drug resistance. Overall, this study provides a new insight into the design and fabrication of smart synergetic PDT/PTT systems toward more precise and effective therapy in the O2-deprived cancer cells.