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Integrated multifunctional nanoplatforms with bioimaging and therapeutic modalities in the biological window.

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Yang, Fan (2019). Integrated multifunctional nanoplatforms with bioimaging and therapeutic modalities in the biological window. Thèse. Québec, Université du Québec, Institut national de la recherche scientifique, Doctorat en sciences de l'énergie et des matériaux, 168 p.

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Nowadays, with the rapid development of nanotechnology towards personalized and nano-medicine, engineering multifunctional nanoplatforms for the purpose of concurrent therapeutic and diagnostic (theranostic) modalities is critical for addressing challenging issues associated with cancers. Multifunctional nanoparticles (NPs), which integrate superparamagnetic and photoluminescent nanocomponents into a single particle, as an emerging class of nanomaterials, are extremely important for realizing this ultimate goal. Owing to their unique superparamagnetism, superparamagnetic NPs can be used to magnetically confine various biological species (DNAs, proteins, bacteria, cancer cells, etc.), thus allowing for ultra-sensitive biological detection. They can also serve as: i) magnetic resonance (MR) imaging contrast agents for the diagnosis of malignant tissues, ii) vehicles for carrying therapeutic payloads (anticancer drugs, small inhibitory RNA) to desired tumor sites in a target-specific manner, and iii) hyperthermia agents for cancer therapy under an alternating magnetic field. On the other hand, photoluminescent nanomaterials as contrast agents are widely used for the purposed of photoluminescence bioimaging, mainly for cells and tissues, thus allowing to acquire information of biological species and events. Therefore, multifunctional (superparamagnetic and photoluminescent) NPs which simultaneously possess both diagnostic and therapeutic functions, are expected to lead to a combined range of potential applications, such as bimodal imaging, photoluminescence monitored magnetic-driven drug delivery and simultaneous in vivo imaging and targeted hyperthermia therapy. However, the photoluminescent component in most studies regarding multifunctional NPs has so far been based on visible-emitting organic dyes, quantum dots (QDs) and upconverting nanoparticles (UCNPs). These multifunctional NPs exhibit low tissue penetration of excitation and emission light as a result of the considerable tissue absorption and low signal-to-noise ratio due to strong background autofluorescence from biological tissues, which restrict their use as contrast agents for in vivo imaging. To overcome this issue, the alternative contrast agents, whose absorption and emission wavelength are both in the so-called biological windows situated in the near-infrared (NIR) range (denoted as NIR-I: 700–950 nm; NIR-II: 1000–1350 nm) in which tissues are optically transparent, should be used. In this thesis, our work is mainly focused on the development of multifunctional magnetic and photoluminescent nanoplatforms in the NIR-I/II range with modalities for bioimaging and therapeutics. In the first part, we developed a multifunctional core/shell/shell nanoplatform (Fe3O4@SiO2@NaYF4:Nd3+), which consists of a superparamagnetic Fe3O4 core surrounded by an intermediate SiO2 shell and further coated by an outer photoluminescent shell of NaYF4:Nd3+. Recently, Nd3+-doped NPs became one of the most rapidly growing research areas because of their high absorption cross section and low phototoxicity compared with commonly used Yb3+-doped UCNPs. Most importantly, Nd3+-doped NPs can be efficiently excited by laser at ca. 800 nm (NIR-I) and present three emission peaks at 900 (NIR-I), 1060 (NIR-II), and 1340 nm (NIR-II), respectively. Both excitation and emission wavelengths of Nd3+-doped NPs are located within the optically transparent biological windows in the NIR. Owing to this unique NIR-to-NIR photoluminescence feature, the prepared Fe3O4@SiO2@NaYF4:Nd3+ NPs exhibit deep-tissue penetrated optical properties with a high signal-to-noise ratio. Our NIR imaging experiment has demonstrated that the NIR photoluminescence signal of Fe3O4@SiO2@NaYF4:Nd3+ NPs can be transmitted across a tissue as thick as 13 mm, about three times thicker than that can be achieved by similar core/shell/shell NPs containing the upconverting shell of Fe3O4@SiO2@NaYF4:Er3+,Yb3+ NPs. Meanwhile, these multifunctional NPs possess excellent superparamagnetic properties due to Fe3O4 core inside, which result in rapid magnetic response to an external magnetic field, making them suitable for magnetic-driven biological applications. Another important bio-medical application of Fe3O4@SiO2@NaYF4:Nd3+ NPs, arising from superparamagnetic propriety, is their exploitation as T2 contrast agents for MR imaging. In vivo MR imaging exhibits the significant darkening effect in T2-weighted images with the use of Fe3O4@SiO2@NaYF4:Nd3+ NPs as contrast agents. Moreover, by designing this nanoplatform, the potential toxicity of highly photoluminescent optical probes, such as QDs that usually contain Pb and/or Cd can be largely avoided, as demonstrated through cytotoxicity assay using HeLa cancer cells and human embryonic kidney (HEK 293T) cells. Therefore, this multifunctional nanoplatform is a promising candidate for high-resolution and deep-tissue bimodal (optical and MR) imaging in vivo. The multifunctional nanoplatform in Part I shows low magnetization due to their single magnetic core feature, which is not suitable for magnetic-driven bioapplications and magnetothermal therapy. Engineering multifunctional nanoplatform containing multiple magnetic NPs is beneficial for realizing fast confinement bioapplications and achieving more effective magnetothermal therapy. Part II is thus focused on the development of novel multifunctional theranostic NPs that exploit multiple superparamagnetic Fe3O4 NPs and interesting NIR-emitting PbS/CdS QDs, and their integration into a single nanoplatform. Self-assembly, as a powerful tool to design and fabricate functional nanomaterials for the purpose of rational control of the optical, electronic and magnetic pairing between distinct NPs, has attracted increasing research attention for their applications in biomedical diagnosis, plasmonics, and energy conversion. Self-assembled supernanoparticles (SPs) involving different types of NPs can possess not only the intrinsic physical and chemical characteristics of their individual NPs but also the collective properties of these NPs due to the coupling effect. In this part, the nanoplatform was specifically prepared by the self-assembling of superparamagnetic Fe3O4 NPs and photoluminescent PbS/CdS QDs with their emission in NIR-II and its self-assembly formation mechanism was systematically studied. Due to their unique NIR photoluminescence feature, the self-assembled Fe3O4 and PbS/CdS (NIR-II) supernanoparticles [SASNs (NIR-II)] exhibit outstanding deep-tissue penetration property as an optical imaging probe, allowing the NIR photoluminescence signal to be detected through a tissue as thick as 14 mm, about three times thicker than that can be achieved by their counterpart operating within the first biological window [SASNs (NIR-I)]. At the same time, clustered Fe3O4 NPs constituting SASNs (NIR-II) largely increase the magnetic field inhomogeneity by the synergistic effect, resulting in a significantly enhanced T2 relaxivity (282 mM-1s-1, ca. 4 times higher than that of free Fe3O4 NPs), as demonstrated by the remarkable darkening effect on in vivo MR imaging. Regarding the potential nanomedicine-related therapeutic modalities, magnetothermal therapy suffers from the low heat conversion efficiency of currently studied magnetic NPs, while photothermal therapy is not suitable for deep-lying subcutaneous cancer cells due to the limitation of light penetration. More interestingly, the prepared SASNs (NIR-II) in our work possess the dual capacity to act as both magnetothermal and photothermal agents, overcoming the main drawbacks of each type of heating separately. When SASNs (NIR-II) were exposed to the dual-mode (magnetothermal and photothermal) heating set-up, the thermal energy transfer efficiency (specific loss power, SLP) was amplified 7-fold compared with magnetic heating alone. These results, in hand with the excellent photo and colloidal stability, and negligible cytotoxicity, demonstrate the potential use of SASNs (NIR-II) for deep-tissue bimodal (optical and MR) imaging in vivo, while simultaneously enabling SASNs (NIR-II) mediated dual-mode heating treatment for cancer therapy. Although SASNs (NIR-II) possess excellent dual-mode heating therapeutic modality, polyvinylpyrrolidone (PVP) coating served as NPs surface stabilizer shows fair biocompatibility and difficulty of further versatile functionalization. In addition, we propose to explore drug delivery modality with our multifunctional nanoplatform. Previously published work has indicated mesoporous materials are extremely suitable for drug delivery. With this consideration, mesoporous silica (mSiO2) appears as a promising drug carrier because it generally possesses a rigid mesostructured framework with high stability and ease of surface functionalization for linking drug molecules. In the third part, we specifically designed another type of multifunctional theranostic nanoplatform based on the large-pore mSiO2. To date, the work regarding the preparation of uniform mSiO2 with large pore size (> 5 nm) is very limited. In this part, relatively-large-pore (>10 nm) mSiO2 as matrix was deliberately synthesized by a biphase stratification continuous growth approach, followed by a simple silane coupling reaction to form thiol-modified mSiO2. Owing to its unique relatively-large-pore structure with high loading capacity, the nanoplatform (mSiO2@PbS/CdS-Fe3O4) was then fabricated by coordination-driven embedding of superparamagnetic Fe3O4 NPs and PbS/CdS QDs of suitable size into the mesoporous channels of mSiO2. In particular, the QDs were selected in such a way that they could be excited by the light in NIR-I as well as emit in NIR-II. The excellent NIR deep-tissue optical and superparamagnetic behavior of mSiO2@PbS/CdS-Fe3O4 particles enables their use as bimodal imaging (optical and MR) contrast agents, thus increasing the reliability and accuracy of diagnosis. On the other hand, when the mSiO2@PbS/CdS-Fe3O4 nanoplatform was exposed to external physical stimuli of magnetic field (MF) and/or a NIR laser, this nanoplatform produced strong local heating as a highly efficient magnetic hyperthermia therapy (MHT)/photothermal therapy (PTT) agent. At last, this nanoplatform also demonstrate great potential as a drug delivery carrier due to large-pore characteristics. Doxorubicin (DOX), a widely used clinical anticancer drug, was chosen as a model to study their drug release behavior. After being loaded with DOX, the release rate of DOX under multi-stimuli (pH/MF/NIR) was significantly enhanced at lower pH and higher temperatures, caused by magnethermal/photothermal effects. This nanoplatform thus yielded a synergistic effect from the integrated heating mode and multi-stimuli responsive drug release to achieve a high therapeutic efficacy.

Type de document: Thèse Thèse
Directeur de mémoire/thèse: Ma, Dongling
Co-directeurs de mémoire/thèse: Vetrone, Fiorenzo; Liu, Xinyu
Mots-clés libres: énergie et matériaux
Centre: Centre Énergie Matériaux Télécommunications
Date de dépôt: 08 nov. 2019 17:46
Dernière modification: 08 nov. 2019 17:46
URI: http://espace.inrs.ca/id/eprint/9066

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