Assembly Of Copper Sulfide Based Composite Nanocapsules For Synergistic Chemo-photothermal Cancer Therapy

Due to high morbidity and mortality,cancer has been one of the most serious threats to human life.Although the traditional therapy can alleviate the cancer condition to a certain extent,but it often causes some adverse effects to patients such as toxic side effects,large area trauma,multidrug resistance and so on which can’t get a satisfactory therapeutic effect.So,looking for safe and effective therapy is still a very serious challenge.The study found that the heat resistance of tumor tissue is worse than the normal tissue because of poor heat dissipation capacity,for this feature,the emerging nanoparticle-assisted photothermal therapy（PTT）which employs the photothermal agents to convert photon energy into heat for local thermal ablation of cancer cells has become one of the most promising cancer therapies.Compared with the conventional therapy,PTT exhibits unique advantages in cancer therapy including minimal invasiveness,precise spatial-temporal selectivity,low side effects,simple to operate,etc.In order to improve the therapeutic effect,especially at the stage of cancer metastasis,PTT can be combined with chemotherapy which maintain their high photothermal conversion efficiency and the local heating would enhance the permeability of anticancer drug to cell membrane to promote the chemo-photothermal therapeutic effect synergistically at same time.In this paper,hydrophobic photothermal agent copper sulfide（CuS）nanodisks which synthesized by high-temperature organic-phase method and anticancer drug paclitaxel（PTX）have been co-encapsulated into hybrid silica nanocapsules（CuS-PTX/SiO₂）by triblock copolymer Pluronic?F127(PEO₁₀₀-PPO₆₅-PEO₁₀₀)micelles based soft-template method.On the basis of exploring the self-assembly process,photothermal properties,stability in biological environment and drug delivery of composite nanocapsules were studied.After that,the designed nanocapsules were applied in vitro and vivo experiments of combining the photothermal therapy and chemotherapy of liver cancer cell（HepG2）,details are as follows:（1）Synthesis and optical properties of CuS nanoparticles.Hydrophobic copper sulfide nanodisks was synthesized by the heat-up method and the influences of size,dielectric environment,copper/sulfur ratio and other parameters on optical properties of CuS nanodisks were investigated.The results indicated that these CuS nanodisks have strong optical absorption in the near infrared（NIR）region which are attributed to the localized surface plasmon resonance（LSPR）arised from the coupling between optical field and collective oscillation of the free holes generated by Cu defects.What’s more,the hole concentration in the CuS nanodisk was calculated to be 5.5×10²¹/cm³ by the Drude model,and the properties of LSPR are more sensitive by copper/sulfur ratio than morphology and environment.（2）Assembly and properties of CuS composite nanocapsules.F127 block copolymer self-assembled micelles were utilized as a soft template,during the micellization process,Oleylamine（OLAM）decorated CuS nanodisks,the hydrophobic TMOS molecules which used as SiO₂ precursor,and PTX were loaded into the core of F127 micelle for biomimetic preparing of multifunctional hybrid CuS-PTX@SiO₂ nanocapsules under room temperature.It was found that there have a strong hydrophobic-hydrophobic interaction between the C-H chains of OLAM and PPO core of F127 micelle,which made the nanodisks to form as face to face assemblies inside the nanocapules.In addition,the size of composite nanocapsules can be less than 100 nm by adjusting the concentration of CuS nanodisks.These CuS nanodisk assemblies based composite nanocapsules exhibit enhanced photothermal conversion efficiency（PCE）up to 31.2%under 980 nm laser irradiation and also high thermal stability and high biocompatibility.Moreover,the loaded PTX can be sustained released and controlled by NIR laser radiation.（3）Evaluation of the effect of combined photothermal therapy and chemotherapy on CuS-PTX/SiO₂ composite nanocapsules.In vitro and vivo experiments of HepG2 indicat adequate cytocompatibility of CuS/SiO₂ nanocapsules.CuS-PTX/SiO₂ composite nanocapsules can be effective in the local photothermal ablation of tumor cells under 980 nm laser irradiation,and the combined chemo-photothermal therapy can significantly improve the therapeutic efficacy compared with chemotherapy or photothermal therapy（PTT）alone which could inhibit 97%of tumor proliferation,most of the tumor-bearing nude mice were cured.H&E staining of the main organs in different groups was also carried out after the various treatments.As expected,no obvious pathological changes occurred in the main organs of mice,indicating that the biocompatibility of composite nanocapsules could satisfy the requirement of being a highly active therapeutic nanoplatform for the anticancer therapy.