Novel Functionalized Magnetic Nanosystems For Tumor Imaging And Combination Therapy

Magnetic nanomaterials,especially magnetic iron oxide nanoparticles(IONPs),have received increasing attention from researchers in the field of biomedical research in recent years.It is mainly owing to the following reasons:first of all,IONPs are non-toxic materials with good biocompatibility and biodegradability;secondly,thanks to the surface chemistry of IONPs,which allows for ligand-exchange and further modifications,thus enabling the conjugation of functional molecules,such as antibodies,aptamers,therapeutic drugs and genes,and fluorescent tags as well;third,the magnetic property of IONPs shifts from paramagnetic to superparamagnetic and finally to ferromagnetic as the particles grow,which is controllable via fine-tuning the synthesis route;and lastly,depending on the magnetic properties,IONPs can act as T₁ or T₂ contrast agents in magnetic resonance imaging(MRI)applications,and induce intracellular hyperthermia under alternating magnetic field(AMF),so as to achieve controlled drug release and magnetothermal therapy.Therefore,IONPs-based theranostic nanoplatforms are widely considered to have great clinical translational potential in the field of cancer diagnostics and therapeutics.In this dissertation,we focused on a series of fundamental and critical issues about the synthesis conditions,surface modification,and functional modification of IONPs,and the construction of superparamagnetic IONPs based gene and drug delivery nano-vehicles,in order to achieve molecular-imaging based recognition of tumor cells from normal cells,and perform dual-modality imaging as well as gene silencing sensitized magnetothermal-chemotherapy treatment in animal tumor model.In Chapter 1,we traced the development of modern cancer therapeutics and nanotechnology,addressed the findings on synthesis,surface modification and functional modification of IONPs in recent decades,and reviewed the state-of-the-art applications of IONPs in the field of tumor imaging,diagnostics and therapeutics.Finally,we provided an outlook for the tumor theranostic applications of IONPs-based full-suite nanoplatform.In Chapter 2,we built a programmable linear temperature control system from scratch,for the thermal decomposition synthesis of IONPs,and obtained a series of superparamagnetic nanoparticles with highly crystalline,regular morphology,monodispersity,and high saturation magnetization.Subsequently,we transferred hydrophobic IONPs into aqueous phase by performing surface ligand-exchange reactions.In Chapter 3,we first designed a hairpin-structured molecular beacon that recognizes HSP90?mRNA(HSP90?-MB);and based on the 11 nm superparamagnetic iron oxide nanocubes(IONCs)synthesized in Chapter 2,we fabricated a new kind of nanobeacons,which were built with IONCs,generation 4 poly(amidoamine)dendrimer(G4 PAMAM),Pluronic P123(P123),and HSP90?-MB.The nanobeacons were able to perform real-time detection and depletion of tumor-associated HSP90?mRNA in living cells,thus allowed us to distinguish cancer cells from normal cells and down-regulate the overexpression of HSP90?in malignant cells.Finally,we explored the MRI T₂ contrast ability of the nanobeacons in a tumor model.In Chapter 4,we constructed ZIPP-Apt:DOX/siHSPs,an active targeting theranostic nanosystem loaded with chemotherapeutic drugs and siRNAs,using 15 nm superparamagnetic zinc-doped iron oxide nano-octahedrons(ZIONOs)synthesized in Chapter 2 as the magnetic core.Near-infrared fluorescence(NIR)dye Cy5.5 was introduced,and the NIR/MRI dual-modality imaging properties of the theranostic nanosystem were explored in vivo.Last,the tumor suppression efficacy of ZIPP-Apt:DOX/siHSPs-mediated Hsp70 and Hsp90 silencing sensitized magnetothermia-chemo combination therapy was investigated in vitro and in vivo.Our results demonstrate the cellular uptake and the tumor-specific accumulation of ZIPP-Apt:DOX/siHSPs were significantly increased due to the AS1411-nucleolin affinity,and further confirmed that the simultaneous depletion of Hsp70 and Hsp90 sensitized magnetic hyperthermia and chemotherapy-induced cell death,thus exhibited promising combination therapeutic efficacy,with negligible acute systemic toxicity.In summary,multifunctional theranostic nanosystems were constructed based on superparamagnetic iron oxide nanoparticles,which allowed in situ detection and down-regulation of tumor-related mRNAs,as well as dual-modality imaging and siRNA sensitized magnetothermia-chemo combination therapy in vivo,thus opened up a new avenue toward clinical applications of versatile magnetic nanosystems.