Stimuli-responsive Nanoparticles For Cancer Imaging And Therapy

With the rapid development of smart nanocarriers in cancer diagnosis and therapy, the tailor-made design of new functionalized nanocarriers has been considered as emerging theranostic strategy and gained much attention from researchers. On the one hand, the efficient theranostic system through the coassembly of smart nanocarriers can achieve precise identification of tumor and simultaneously hold great potentials as drug vehicles for cancer therapy. On the other hand, smart nanocarriers are able to trigger signal activation or smart drug release in response to tumor microenvironments and further improve precise spatiotemporal control in drug release to achieve biological specificity in diagnosis and therapy. Owing to these remarkable physicochemical properties, they have offered potential solutions for many of the current challenges in cancer therapy.Stimuli-responsive nanocarriers can release payloads in response to intrinsic biological stimuli or external stimuli. Various stimuli, mainly including lysosomal pH, cytoplasmic glutathione(GSH), reactive oxygen species(ROS), enzyme, temperature, ultrasound, light and ray, can be adopted purposefully and in control. Herein, in this study we focus on the design of smart stimuli-responsive copolymers, and then use them as vehicles to load near-infrared(NIRF) cyanine dye indocyanine green(ICG) and chemotherapeutic compound doxorubicin(DOX), which applies NIRF imaging of ICG for tumor detection and synergized cancer therapy combining photothermal therapy(PTT) of ICG and chemotherapy of DOX for enhanced anti-cancer efficiency.Charpter 1: Recent research progresses in tumor diagnosis and therapy(especially in combined treatment) are briefly introduced and reviewed. Further various types of stimuli-responsive nanoparticles(NPs) designed recently are reviewed in detail and systematically, which can be the theory foundation for our research.Charpter 2: We successfully fabricated dually pH/reduction-responsive terpolymeric vesicles with monodispersive size distribution, which are constructed by assembling acetal- and disulfide-functionalized star terpolymer(PEG45-PCL60-PNIPAM33) with ICG and DOX. The vesicular nanostructure exhibits multiple theranostic features including on-demand drug releases responding to pH/reduction stimuli, enhanced photothermal conversion efficiency of cyanine dye, and efficient drug translocation from lysosomes to cytoplasm, as well as preferable cellular uptakes and biodistribution. These multiple theranostic features result in ultrahigh-contrast fluorescence imaging and thermo-chemotherapy-synergized tumor ablation. The dually stimuli-responsive vesicles represent a versatile theranostic approach for enhanced cancer imaging and therapy.Charpter 3: We successfully obtained ultrafast NIR light-responsive micelles(Se-NPs) by loading ICG and DOX with selenide-containing polymer(PEG-PUSe-PEG). The average particle size of Se-NPs is 109 nm. TEM morphology showed the particles are uniform and round. Moreover, Se-NPs were found to possess enhanced photostability and chemical stability in vitro as compared with free ICG/DOX. In addition, more amounts of singlet oxygen could be produced by ICG at NIR irradiation, which contributed to triggering the oxidation-responsiveness of Se-NPs and furthermore releasing more DOX. Singlet oxygen can cause lysosomal membrane disruption and then result in efficient drug translocation from lysosomes to cytoplasm. In conclusion, Se-NPs exhibit on-demand intracellular drug release and enhanced intracellular drug translocation, which subsequently result in thermo-chemotherapy-synergized tumor ablation.