pH敏感的氧化钽纳米材料的制备及其肿瘤靶向成像与治疗作用研究

Study on pH Sensitive Tantalum Oxide Nanomaterials for Tumor Targeted Imaging and Therapy

关键词:  氧化钽  pH敏感  分子靶向  联合治疗  多模态成像

Key words:  tantalum oxide  pH-sensitive  molecular target  combinational therapy  multimodal imaging

摘要:

目的 制备以西妥昔单抗(cetuximab，C225)作为靶分子的pH敏感的氧化钽纳米粒(TaO_x-C225 nanoparticles， TaO_x-C225 NPs)，用于肺癌的靶向诊疗。方法 以C225作为靶分子连接到TaO_x NPs表面，在其表面通过pH敏感的化学键连接功能性分子二氢卟吩e6、化疗药物盐酸阿霉素制得靶向表皮生长因子受体的pH敏感性纳米材料TaO_x-C225 NPs，并采用透射电镜、紫外光谱、HPLC对其进行表征和药物释放测试，通过体外细胞试验以及活体成像试验测试TaO_x-C225 NPs靶向肿瘤细胞的能力以及荧光成像能力，通过构建动物模型评价TaO_x-C225 NPs光动力和化疗联合杀伤肿瘤细胞的能力。结果 体外成像结果表明，TaO_x-C225 NPs能够被肿瘤细胞HCC827特异性摄取；在体内成像中，TaO_x-C225 NPs能够特异性地汇集在表皮生长因子受体高表达的HCC827肿瘤组织中，并具有较好的肿瘤与背景的对比度。体内肿瘤治疗研究表明，TaO_x-C225 NPs联合氙灯对肿瘤具有明显的抑制效果。此外，TaO_x-C225 NPs对健康组织无明显毒性。结论 利用靶向分子探针技术以及荧光成像技术实现了肿瘤的精准诊断，并通过光动力治疗与化疗的结合克服肿瘤耐药性，实现肺癌的精确杀伤。TaO_x-C225 NPs对未来肿瘤的诊断和局部治疗具有一定的借鉴意义。

Abstract:

OBJECTIVE To synthesize pH sensitive tantalum oxide nanoparticles with cetuximab(C225)(TaO_x-C225 NPs) as target molecule for targeted diagnosis and treatment of lung cancer.METHODS C225 was chose as EGFR ligand and connected to the surface of tantalum oxide nanoparticles(TaO_x NPs), which further modified with the photodynamic drug dihydroporphyhene e6 and chemotherapeutic drug doxorubicin hydrochloride through the amino-carboxyl reaction to produce the EGFR-targeted pH sensitive nanometer drug carriers TaO_x-C225 NPs. The morphology and spectra were characterized by transmission electron microscope(TEM) and UV-visible spectroscopy, respectively. Drug release rate of TaO_x-C225 NPs under different pH conditions was tested by HPLC. Subsequently, the targeting and imaging effects of TaOx-C225 NPs were evaluated through the in vitro cell and in vivo imaging experiments using confocal laser microscopy and fluorescence imaging. Finally, the model of subcutaneous tumor was constructed to evaluate the therapeutic effect of the combination of photodynamic therapy of TaOx-C225 NPs with chemotherap. RESULTS The in vitro imaging results showed that TaOx-C225 NPs were specific uptake by HCC827 cells. In vivo imaging, TaOx-C225 NPs also showed specific tumor accumulation with high tumor-to-background contrast on HCC827 subcutaneous tumor with high EGFR expression. Furthermore, the in vivo tumor treatment study revealed that the therapeutic effect of the TaOx-C225 NPs combined xenon lamp group was significantly better than that of other groups. Moreover, the TaOx-C225 NPs showed no significant toxicity to healthy tissues. CONCLUSION Targeted molecular probe technology and fluorescence imaging technology are used to achieve accurate diagnosis of tumors, the combination of photodynamic therapy and chemotherapy can overcome tumor drug resistance to achieve precise killing of lung cancer. The TaO_x-C225 NPs may have certain reference for future cancer diagnosis and treatment.