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Upconverting nanoparticles for integration in bioimaging and therapeutic applications.

Huang, Yue (2017). Upconverting nanoparticles for integration in bioimaging and therapeutic applications. Thèse. Québec, Université du Québec, Institut national de la recherche scientifique, Doctorat en sciences de l'énergie et des matériaux, 125 p.

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In recent years, lanthanide (Ln3+)-doped upconverting nanoparticles (UCNPs) have emerged as efficient and versatile bioimaging as well as therapeutic tools. In general, these nanoparticles can be excited with near-infrared (NIR) light and emit higher-energy photons spanning the ultraviolet (UV), visible and NIR ranges via a multiphoton process known as upconversion. The multiphoton excitation occurs through a plethora of 4f excited electronic energy states, which have long lifetimes (micro- to millisecond). Compared with conventional fluorophores, UCNPs possess several advantages including reduced autofluorescence background, remarkable tissue penetration, and low cytotoxicity. Driven by these factors, Ln3+-doped UCNPs could serve as excellent candidates for numerous biological applications. In this thesis, our work is mainly focused on the development of novel nanostructures combining UCNPs with other modalities for bioimaging and therapeutic applications. In the first part, we develop novel hybrid nanomaterials that exploit the interesting optical properties of both UCNPs and gold nanorods (GNRs), and bring them together onto a single nanoplatform. It is well known that GNRs are good candidates for photothermal therapy (PTT) where cancer cells are destroyed by optical heating. In order to generate a temperature increase in diseased cells, GNRs absorb light causing electrons to undergo transitions from the ground state to the excited state. The electronic excitation energy subsequently results in an increase in the kinetic energy, which leads to overheating of the local environment around the light absorbing species. Therefore, local cells or tissues could be destroyed by the heat produced. In addition, UCNPs can be applied as nanothermometers based on the temperature dependent luminescence where their luminescence intensity ratios (LIR) vary as a function of temperature. Thermal sensing with UCNPs could therefore be used for controlling the photothermal treatment, which would minimize collateral damage in healthy tissues surrounding the hyperthermia target. In detail, Part I is divided into two sections based on two different nanostructures (Section I and Section II). In Section I, we developed a novel core/shell nanostructure using a multistep strategy consisting of a GNR core with an upconverting shell of NaYF4:Er3+, Yb3+ (GNR@UCNPs). The absorption of GNR was tuned to ∼660 nm, which was resonant with the upconverted red Er3+ emission emanating from the 4F9/2 excited state. Upon laser irradiation, UCNPs converted NIR light to UV/visible photons via energy transfer, which could then be absorbed by GNRs and converted into heat. Meanwhile, the intensity ratio of the upconverted green emission showed remarkable thermal sensitivity, which was used to calculate the temperature change due to rapid heat conversion from the GNR core. Doxorubicin (DOX), a model anticancer drug, was selected to load into the GNR@UCNPs. In terms of the drug release profile, it was shown that the release of DOX was significantly enhanced at lower pH and higher temperature caused by photothermal effect. This multifunctional nanocomposite, which is well suited for bioimaging and local heating, shows strong potential for use in cancer therapy. In section II, we developed another novel multifunctional nanocomposite consisting of GNRs, silicon dioxide (SiO2), and NaGdF4:Er3+, Yb3+ UCNPs (GNR@SiO2@UCNPs), with highly integrated functionalities including luminescence imaging, PTT and photodynamic therapy (PDT) capabilities. PDT is a light-activated clinical treatment, which causes the controlled death of diseased cells, such as tumor cells. It is based on a process in which a light sensitive drug called a photosensitizer is introduced in the cells, and is subsequently excited with light at an appropriate wavelength. The absorbed energy is transferred to the molecular oxygen present in the surroundings, generating reactive oxygen species (ROS) whose presence can trigger the death of the cells. Regarding this novel nanostructure, the surface plasmon resonance (SPR) of GNRs was tuned to 980 nm, which overlapped with the Yb3+ absorption. Under exposure of laser irradiation, UCNPs and GNRs could be excited simultaneously resulting in the generation of heat by the GNR with the ability to detect the temperature increment from the NaGdF4:Er3+, Yb3+ UCNPs as above. In addition, it is worth noting that luminescence enhancement was observed when compared with bare UCNPs due to the localized field created by the GNRs. Finally, a photosensitizer, zinc phthalocyanine (ZnPc), was loaded into the mesoporous silica. Under laser irradiation, UCNPs absorbed NIR light and converted it to visible light, subsequently activating the photosensitizer to release singlet oxygen for future applications in PDT. Therefore, such multifunctional nanocomposites, which are well suited for bioimaging, photothermal and photodynamic effects and show strong potential in cancer therapy. Part II is focused on the hybrid nanocarrier consisting NaGdF4:Er3+, Yb3+ UCNPs that were encapsulated in the aqueous core of liposomes and the potential of the obtained nanocarriers for drug delivery was shown by co-loading DOX. Liposomes, which composed of a lamellar phase lipid bilayer, are considered as good candidates for drug delivery, since their structure is similar to that of cell membranes. They can be selectively trapped by tumor tissues due to the high permeability of tumor vasculature toward liposomes in combination with the lack of proper lymphatic drainage. Therefore, liposomes have been introduced as suitable nanocarriers for UCNPs. Under 980 nm excitation, a decrease of the green upconversion emission of the UCNPs was observed when DOX was co-loaded with the UCNPs in the liposome nanocarrier. This quenching effect was assigned to the energy transfer between the donor UCNP and the acceptor DOX, and most importantly, it allowed for the spectral monitoring of the DOX loading and release from the liposome nanocarriers. Thus, the drug loading, release, and spectral monitoring properties of the obtained liposome nanocarriers were thoroughly characterized allowing us to assess their potential as bioimaging and therapeutic nanocarriers.

Type de document: Thèse Thèse
Directeur de mémoire/thèse: Vetrone, Fiorenzo
Co-directeurs de mémoire/thèse: Rosei, Federico
Informations complémentaires: Résumé avec symboles
Mots-clés libres: upcoversion; nanoparticles; bioimaging; therapeutic applications; nanoparticules; imagerie médicale; applications thérapeutiques; UCNP
Centre: Centre Énergie Matériaux Télécommunications
Date de dépôt: 29 août 2017 19:06
Dernière modification: 29 août 2017 19:06
URI: http://espace.inrs.ca/id/eprint/5287

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