Functionalized Nano-graphene In Biomedical Applications

In recent years, owing to their unique physical and chemical properties,nano-graphene has attracted tremendous interest in many different fields includingbiomedicine. In this dissertation, we have systematically studied the biomedicalapplications of functionalized nano-graphene, particularly for cancer diagnosis andtreatment, and explored the biological effect and potential toxicity of nano-graphene inanimals. PEGylated nano-graphene with excellent water-soluble and biocompatibility issynthesized and used for tumor imaging and photothermal therapy. How sizes andsurface chemistry affect the in vivo behaviors and photothermal therapeutic efficacy ofnano-graphene is then carefully investigated, realizing highly efficient in vivo tumorablation under an ultra-low laser power density using our optimized nano-grapheneformulation. Graphene-based magnetic nanocomposite is further developed and appliedfor tumor multimodal imaging and imaging guided cancer therapy. Moreover, the invivo biodistribution, excretion and the potential toxicity of nano-graphene with differentsizes and surface coatings are systematically investigated, suggesting thatnano-graphene with small sizes and well-designed surface coatings is not noticeablytoxic in vivo to animals. The main results of this dissertation are summarized asfollowing:Chapter1: This chapter is an introductive overview that summarizes thefunctionalization, biomedical applications, and toxicology of nano-graphene.Chapter2: We studied the in vivo behaviors of polyethylene glycol (PEG)functionalized nano-graphene oxide (nGO-PEG) by a near-infrared (NIR) fluorescentdye. In vivo fluorescence imaging revealed high tumor uptake of nGO-PEG in severalxenograft tumor mouse models and relatively low retention in reticuloendothelialsystems (RES). We then utilized the strong optical absorbance of nGO-PEG in the NIRregion for in vivo photothermal therapy, achieving100%tumor ablation in a mousetumor model.Chapter3: We synthesized a number of graphene oxide (GO) derivatives with different sizes and surface coatings, and then studied how sizes and surface chemistrywould affect the in vivo behaviors of nano-graphene. It was found that ultra-small nanoreduced GO (nRGO) with covalent PEG coating showed greatly enhanced NIRabsorbance, prolonged blood circulation half-life, as well as increased tumor uptake.Using this optimized nGO-PEG, we realized highly efficient in vivo tumor ablation byusing an ultra-low laser power density in our mouse experiments.Chapter4: We prepared reduced graphene oxide (RGO)-iron oxide (IONP)nanocomposite, which was noncovalently functionalized with PEG to render highstability in physiological solutions. Utilizing the intrinsic high NIR optical absorbanceand strong magnetic property of the obtained RGO–IONP–PEG, as well as externallabels, we realized in vivo multimodal photoacoustic tomography (PAT), magneticresonance (MR) and fluorescence imaging, based on which photothermal therapy wasdesigned and carried out. This work demonstrated the great promise of usinggraphene-based multifunctional nano-composites for cancer theranostic applications.Chapter5: We for the first time studied the long-term biodistribution and potentialtoxicity of PEGylated nano-GO (nGO-PEG) labeled with125I. It was found thatnGO-PEG mainly accumulated in the reticuloendothelial system (RES) including liverand spleen after intravenous administration and could be gradually cleared out, likely byboth renal and fecal excretion. Moreover, nGO-PEG did not cause appreciable toxicityat our tested dose (20mg/kg) to the treated mice by hematology analysis andhistological examinations.Chapter6: We systematically investigated the in vivo biodistribution and potentialtoxicity of nano-graphene and its derivatives via oral and intraperitoneal (i.p.)administration. We found that nGO-PEG labeled with125I showed no obvious tissueuptake via oral administration. In contrast, high accumulation of nGO-PEG，RGO-PEGand nRGO-PEG, but not as-made GO, in the reticuloendothelial (RES) system includingliver and spleen was observed after i.p. injection. Although GO and PEGylated GOderivatives would retain in the mouse body over a long period of time after i.p. injection,their toxicity to the treated animals was insignificant.In summary, this dissertation, we have systematically studied the biomedicalapplications of nano-graphene, particularly for imaging and photothermal therapy ofcancer, and carefully investigated the toxicology of functionalized nano-graphene in vivo to animals. Our results greatly promote graphene-based biomedical research, andprovide helpful guidelines for the future explorations of other functional nanomaterialsin cancer theranostics.