Synthesis Of Organic And Inorganic Hybrid Photothermal Nanomaterials For Tumor Therapy

Photothermal therapy?PTT?,as a minimally invasive therapeutic methodology,employs photothermal agents to absorb the laser light and then covert it into thermal energy,leading to thermal ablation of cancer cells and the subsequent cell death.The near-infrared?NIR,?=700-1400 nm?laser induced PTT?NIR-PTT?has attracted increasing attention due to their superior tissue penetration abilities,and the typical penetration depth of the NIR light can reach several centimeters in biological tissues.However,the therapy effects are strongly influenced by the laser's irradiation time and densities.To improve the therapeutic effects,it is necessary to develop the efficient multifunctional hybrid nanomaterials which integrate various technologies for multi-model imaging and comprehensive treatment of tumors,overcoming the side effects of single ways.In this thesis,we first explore the CuS-based smart nanocapsules for the photothermal-/chemo therapy of tumor,then further explore the hydrophilic CuS-based and Fe-based multifunctional hybrid nanoparticles for the multi-mode imaging guided therapy,specifically as follows.?1?CuS-based smart nanocapsules from design,preparation to the photothermal-/chemo therapy of tumor.Photothermal ablation therapy possesses great potential in cancer treatment,but the therapy effects would be shut without near-infrared?NIR?laser irradiation.Chemotherapy has been widely applied,however the in vivo dose of anticancer drugs in tumor cannot be well controlled.To solve these problems,Herein,we have designed and fabricated the smart MEO2MA@MEO2MA-coOEGMA-CuS-DOX?abbreviated as G-CuS-DOX?hybrid nanocapsule that can be switched off/on and adjusted by NIR laser.The hybrid nanocapsule consist of three components,where the thermosensitive MEO2MA@MEO2MA-co-OEGMA nanogels?abbreviated as G?as the nanocarriers were prepared by emulsion polymerization with low-critical-solution-temperature?LCST?of 42 °C;CuS nanoparticles as the photothermal component were synthesized by in situ growth and Doxorubicin?DOX?was served as the anticancer drug.Under the irradiation of NIR laser?intensity: 2.0 W/cm2?,the solution of G-CuS-DOX hybrid nanocapsules?Cu concentration: 10-120 ppm?exhibits a rapid temperature elevation from room-temperature to 34-57 °C.When temperature exceeds their LCST,G-CuS-DOX hybrid nanocapsules simultaneously exhibit both photothermal effects and the controllable DOX-release ability,which can be switched off/on by NIR laser.On the contrary,if NIR laser is switched off,the solution temperature goes down,leading to the interruption of above both performances.Subsequently,the hybrid nanocapsules were injected into the tumor and close to cancer cells.Under the irradiation of 915 nm laser,the cancer cells can be efficiently destroyed,both the tumor growth and metastasis lesions in liver suffer a significant inhibition.Therefore,the present G-CuS-DOX hybrid nanocapsules possess great superiority as novel smart in vivo agents for the synergic tumor therapy.?2?The preparation of multifunctional nanomaterial platforms: Cu@PDA-Gd-FA for cancer targeting theranosticsThe CuS-based semiconductor nanoagents have been developed for multimodal imaging and NIR-PTT of tumor.However,these nanoagents always have a unpleasant stability in physiological solution due to their weakly chemical bonding with the organics or targeting ligands,leading to the poor theranostics effects.Herein,we report the novel multifunctional nanomaterial platforms CuS@PDA-Gd-FA hybrid nanoparticles for combining MRI and targeting NIR-PTT of tumors.The hybrid nanoparticles were consisted of three parts,where the CuS was coated by polydopamine?PDA?in water as the photothermal agents,FA was connected by Schiff base or Michael addition reactions as the targeting ligands,Gd was served as the contrast imaging agent.The solution of CuS@PDA-Gd-FA?Cu concentration: 20-170 ppm?exhibits a rapid temperature elevation from room-temperature to 31.3-50.3 °C,conferring their high NIR photothermal effect.Furthermore,this hybrid nanoparticle remains excellent magnetic property for T1-weighted MRI imaging.Subsequently,CuS@PDA-Gd-FA physiological saline?PBS?dispersion was i.v.injected into the HeLa tumor-bearing mice.The nanoparticles can able to target to tumor tissue through FA-mediated targeting pathway,enabling effective MR and fluorescence imaging of tumors.Then under the irradiation of 915 nm laser,the tumor growth can be effectively inhibited.Therefore,multifunctional nanomaterial platforms: Cu@PDA-Gd-FA have great potential to be used as theranostic nanoagents for MR,florescence and near-infrared multimode imaging guided NIR-PTT of tumor.?3?Design and synthesis of PEGylated FeS₂ multifunctional hybrid nanoparticles for imaging guided photothermal therapy of tumorIdeal theranostic nanoplatform for tumor should be one nanoparticle that has single semiconductor or metal structural component but contains all multi-model imaging and therapy abilities.The design and preparation of such nanoparticle remains the serious challenge.Herein,we reported the controllable synthesis of PEGylated FeS₂ hybrid nanoparticles with high carrier concentrations by a one-step solvothermal route.FeS₂ nanoparticles with size of <50 nm?FeS₂-30?have the decreased photoabsorption intensity from visible to NIR region,due to low S vacancy concentration.By tuning their sharp/size and then enhancing S vacancy concentration,the photoabsorption intensity of PEGylated FeS₂ hybrid nanoparticles with size of >300 nm?FeS₂-350?goes up with the increase of the wavelength,conferring their high NIR photothermal effect for thermal imaging.Furthermore,PEGylated FeS₂ remains can be served as the excellent photothermal agents for the simultaneous NIR imaging and NIR-PTT of in vivo tumor cells.Furthermore,they remained excellent magnetic property for T2-weighted MRI,which can be used as the effective T2-weighted MR imaging contrast agents for tumors in vivo,leading to the guide of the therapies.More importantly,these PEGylated FeS₂ hybrid nanoparticles can be excreted from the mice body.Therefore,PEGylated FeS₂ hybrid nanoparticles has great potential to be used as novel “all-in-one” multifunctional theranostic nanoagents for MRI and near-infrared dual-modal imaging guided NIRPTT of tumor.