Study On Gd₂O₃ Up-converting Hierarchical Nanoparticles For Tumor Treatment

Solid tumors are composed of tumor cells and tumor stroma,the latter containing cellular components?mesenchymal cells?and noncellular components.And cancer-associated fibroblasts?CAFs?are the overriding mesenchymal cells.Specific recognition of cancer cells is a premise of tumor ablation.The emerging of nanostructured substrates is of great importance for improving the ability of cancer cell recognition and capture.Obviously,killing malignant tumor cells and CAFs simultaneously provides an effective way to eradicate solid tumors.However,strategies effective to CAFs could also do harm to normal fibroblasts,so targeted killing of CAFs is still a great challenge.Photodynamic therapy?PDT?has virtues of minimal invasive injury,low cytotoxicity,fewer side effects and low cost,which makes it attract great interest.Upconverting nanoparticles?UCNPs?can convert near-infrared light into ultraviolet light or visible light absorbed by photosensitizers,and they are widely applied in deep tumor PDT.However,UCNPs possess low upconversion intensity,dispersity in aqueous and drug-loading rate,which limits efficient PDT.Thus,it is essential to develop a platform about targeting nano-drug for efficiently cancer treatment.And the platform can achieve simultaneous targeted killing of cancer cells and CAFs and fewer side effects.Based on the above purposes and inspired by the report that CAFs present a significantly higher response to PDT,hierarchical UCNPs were designed to mediate targeted PDT.And the upconversion luminescence performance,loading rate,the properties of cancer cell specific recognition and killing,PDT effect etc were studied.The concrete contents are as follows:1.Gd₂O₃:Yb,Tm,Zn UCNPs were prepared by co-doping Zn²⁺with Yb³⁺and Tm³⁺into Gd₂O₃ matrix.Upon 980 nm laser irradiation,Gd₂O₃:Yb,Tm,Zn UCNPs emitted blue upconverting fluorescence?460-500 nm?.And the upconversion intensity was enhanced 3.93 times than that of Zn²⁺-free UCNPs.The blue light emitting UCNPs was used to initiate the in-situ polymerization of PEGDA which formed a hierarchical coating layer on the UCNPs.The water dispersity and folic acid?FA?loading capacity of UCNPs were improved though the way.The UCNPs were fabricated via in-situ polymerization of PEGDA on the UCNPs surface.And FA was conjugated onto the PEDGA-coated UCNPs in order to fabricate hierarchical UCNPs-PEGDA-FA with upconversion fluorescent performance and targeting.2.In cell experiments,after 24 h incubation with UCNPs-PEGDA-FA,there was nearly nontoxic and no affinity of L929 cells.While UCNPs-PEGDA-FA exhibited a satisfactory cytotoxicity and the recognition of various cancer cells?HeLa,Bel-7402,MCF-7 and HepG2 cells?because of their morphology and composition.Especially as for HeLa cells with the overexpression of FA receptors,the results were more outstanding.Due to specific affinity between UCNPs-PEGDA-FA and HeLa cells,the formation of dense UCNPs shells on HeLa cell membranes caused cell death.The incubation experiments between UCNPs-PEGDA-FA and HeLa cells and L929 cells after mixed coculture indicated that the nanoparticles could kill simultaneously HeLa cells,while caused less damage to L929 cells.3.To further improve the efficiency of cancer therapy,the photosentisizer merocyanine 540?MC540?,as a PDT drug,was loaded to UCNPs-PEGDA-FA to gain UCNPs-PEGDA-FA-MC540.The results of ultrasound tests indicated that the MC540loading capacity of UCNPs-PEGDA-FA was stronger than that of UCNPs.In addition,higher efficient PDT on HeLa cells was performed under 980 nm laser irradiation with a power density of as low as 0.65 W/cm².Compared to uncoated UCNPs,the cancer killing efficiency was increased 2.37 times by UCNPs-PEGDA-FA mediated PDT.