Preparation Of UCNP@PDA@lenvatinib Nanocomposites For Chemo-photothermal Therapy Of Anaplastic Thyroid Cancer

Background and object:Thyroid cancer is the most common endocrine malignancy.The incidence of thyroid cancer has been increasing rapidly worldwide.By the year2020,in the wordwide the incidence of thyroid cancer was 3%in all malignant tumors,ranking ninth,while the incidence rate of thyroid cancer was fifth among the global female population.Thyroid cancer can be divided into papillary thyroid cancer(PTC),follicular thyroid cancer(FTC),medullary thyroid cancer(MTC)and anaplastic thyroid cancer(ATC).The incidence of anaplastic thyroid cancer is only 1-5%of all thyroid cancer,but the differentiation degree and the malignancy degree is worst.The one year survival-rate of anaplastic thyroid cancer is less than 20%.Moreover,anaplastic thyroid cancer is highly invasive and metastatic,and often accompanied by cervical lymph node metastasis,invasion of surrounding tissues and organs and systemic metastasis.Because the anaplastic thyroid cancer has a certain resistance to surgery,endocrine therapy,radiotherapy and chemotherapy and other traditional treatment methods,it is essential to explore a new treatment method for anaplastic thyroid cancer to improve the condition and the quality of life of patients.Photothermal therapy is a new treatment method,which can irradiate the tumor site with near-infrared light,so that the photothermal agent in the tumor site can absorb near-infrared light and convert the light energy into heat energy,causing the temperature of the tumor site to rise rapidly to kill the tumor cells,and will not cause obvious damage to the surrounding normal tissues.Due to the advantages of non-invasive,controllable and less side effects,photothermal therapy has great potential in tumor treatment.Moreover,for thyroid cancer,which is a superficial tumor,the interference of tissue to light source is less,light can achieve better tissue penetration effect,and photothermal therapy can play a better therapeutic effect.In this study,we coated the surface of upconversion nanoparticles(UCNP)with a layer of polymer poly(dopamine)(PDA)which has near-infrared light absorption properties,and the obtained core-shell UCNP@PDA nanoparticles were loaded with targeted chemotherapeutic drug lenvatinib on the surface.Finally,we obtained the UCNP@PDA@lenvatinib composites.The nanocomposite can increase the temperature of the tumor site and further release chemotherapy drugs under the irradiation of 808nm near-infrared laser,and achieve the purpose to kill tumor cell.The UCNP@PDA@lenvatinib nanocomposites provide a new possibility for the treatment of anaplastic thyroid cancer.Methods:1.Synthesis and characterization of UCNP、UCNP@PDA、UCNP@PDA@lenvatinib.We observed the morphology and distribution of nanoparticles by transmission electron microscope and measured the particle size and zeta potential.2.Under the 1.8 W/cm~2,808 nm NIR-laser,we evaluated the photothermal properties and photothermal stability of UCNP@PDA nanoparticles and calculated the photothermal conversion efficiency of nanoparticles.3.MTT method was used to evaluate the cytotoxicity of UCNP@PDA@lenvatinib under 808 nm NIR-laser and the living and dead cells were stained by Calcein-Am and PI.4.The C643 anaplastic thyroid tumor-bearing mice were injected UCNP@PDA@lenvatinib nanoparticles through tail vein and then we observed the distribution of the nanoparticles in the tumor sites.The temperature change of the tumor sites was observed and recorded.5.The C643 anaplastic thyroid tumor-bearing mice were injected UCNP@PDA@lenvatinib nanoparticles through tail vein.Then we observed the tumor growth curve.6.We evaluated the biosafety of the UCNP@PDA@lenvatinib nanoparticles in vivo.Results:1.The prepared UCNP、UCNP@PDA、UCNP@PDA@lenvatinib nanoparticles have spherical structure,uniform size and uniform distribution.The size of UCNP is 78±1 nm and the zeta potential is-16.5 m V.The size of UCNP@PDA is 124±1 nm and the zeta potential is-1.38 m V.And the UV-vis absorption spectrum confirmed the successful loading of PDA and lenvatinib on the surface of UCNP@PDA@lenvatinib nanocomposites.2.The photothermal conversion efficiency of UCNP@PDA is 30.7%and the nanoparticles have good photothermal properties and photothermal stability.3.After irradiation by the 1.8 W/cm~2,808 nm NIR-laser,the UCNP@PDA@lenvatinib nanoparticles have strong cytotoxicity in cells.4.After exposed to 808 nm NIR-laser for 8 h,the nanoparticles lead to the most ditributition in the tumor sites of the C643 tumor-bearing mice.And the the temperature of the tumor sites increases rapidly after exposed to the 808 nm NIR-laser.5.After irradiation by the 1.8 W/cm~2,808 nm NIR-laser,the UCNP@PDA@lenvatinib nanoparticles can significantly inhibit the tumor growth of the C643 tumor-bearing mice.6.The UCNP@PDA@lenvatinib nanoparticles have good biological safety in vivo.Conclusion:In this study,we successfully prepared the UCNP@PDA@lenvatinib nanocomposites.After irradiated by the 1.8 W/cm~2,808 nm NIR-laser,the nanocomposites can rapidly increase the temperature in tumor sites and lead to tumor cell apoptosis and necrosis.In vivo,the nanocomposites can significantly inhibit the growth of tumor,and have good biological safety.