基于纳米囊药物传输系统介导内照射直肠癌同步放化疗制剂的设计及机制研究

Rectal cancer poses a serious threat to human health all over the world, with an upward trend of incidence and mortality in our country. Currently, chemoradiotherapy is one of the most effective treatments for rectal cancer. Nanobiotechnology represents a promising opportunity for cancer theranostics, such as drug delivery, diagnosis, therapy and monitoring of drug efficiency. Based on our previous studies of the nano drug delivery system co-loaded with multi-drugs, which could induce the remarkably synergistic anticancer effect, we will fabricate functionalized nanocapsules, which load radionuclide of Na131I and chemotherapeutic agents of 5-fluorouracil and are modified with epidermal growth factor receptor (EGFR) monoclonal antibody (Cetuximab). And we will explore their application in new strategy of internal radiation chemoradiotherapy for rectal cancer in vitro and in vivo. Due to the specific recognition of EGFR on the rectal cancer cells, the functionalized nanocapsules could improve tumor targeting performance, precisely attack on tumor cells, avoid damage to normal tissues around the tumor, and reduce the systemic toxicity. The synergistic effect of internal radiation chemoradiotherapy could overcome the deficiency of single modality. We will further visualize the distribution of drugs and monitor the outcome of the synthetic therapy though single-photon emission computed tomography. The project will extend the practice and enrich the theory of internal radiation chemoradiotherapy for rectal cancer, and provide evidence for the clinical application.

直肠癌严重威胁人类健康，在我国其发病率和病死率呈上升趋势。同步放化疗是目前直肠癌最为有效的综合治疗策略。纳米生物技术在药物传输、诊断、治疗及疗效监测等肿瘤诊疗领域具有广阔的应用前景。我们前期制备了共载不同功能药物分子的纳米药物传输系统，具有协同增效作用，提高了肿瘤治疗效果。本项目将进一步丰富内涵、扩展外延，构建新型Cetuximab靶向修饰共载放射性核素Na131I及化疗药物5-Fu的纳米囊制剂，在体内外水平探索其介导内照射同步放化疗治疗直肠癌的新策略：靶向直肠癌组织、细胞，特异性地提高肿瘤区药物浓度、对肿瘤细胞施行“精准打击”，避免损伤周围的正常组织、降低全身毒副作用；克服单个治疗方法的不足，实现放疗、化疗协同增效，综合治疗；通过单光子发射计算机断层成像放射示踪的方法，可视化观察制剂在体内的分布及实时监测疗效；延伸同步放化疗的内涵与价值，丰富同步放化疗的技术与理论，为临床应用提供依据。

放射疗法和化学疗法一直以来都是治疗肿瘤的常用方法。单一的治疗方法在取得一定效果的同时也产生了严重的毒副作用。近年来，将不同疗法联合应用是癌症治疗的一个很有前途的选择。尤其是对于放疗不敏感或耐药的肿瘤来说，联合治疗是打开僵局的关键。基于此背景，本研究开发了一种肿瘤靶向的聚乙二醇-聚乳酸纳米粒，用于共同转运化疗药物5-氟尿嘧啶(5Fu)和放射性核素131I。为了提高纳米颗粒的靶向性同时提高药物的生物利用度，在聚乙二醇-聚乳酸纳米粒表面修饰西妥昔单抗，得到的纳米粒子(Cet-PEG-PLA-5Fu-131I)。该纳米颗粒呈球形，粒径约为110 nm，具有pH敏感性。荧光实验证实了Cet-PEG-PLA-5Fu-131I可以有效的进入表皮生长因子受体（EGF）高表达的结直肠癌细胞中。采用CCK-8和流式细胞仪检测Cet-PEG-PLA-5Fu-131I联合作用对大肠癌细胞存活率和细胞凋亡的影响。空白纳米粒(Cet-PEG-PLA)具有良好的生物相容性，与单独使用Cet-PEG-PLA-5Fu或Cet-PEG-PLA-131I相比，Cet-PEG-PLA-5Fu-131I纳米粒抑制细胞活力和诱导细胞凋亡效果最好。在小鼠异种移植模型中，与单独使用Cet-PEG-PLA-5Fu或Cet-PEG-PLA-131I相比，Cet-PEG-PLA-5Fu-131I纳米粒可以实现长效血液循环和肿瘤蓄积的作用，从而增强了抗肿瘤作用。此外，Cet-PEG-PLA-5Fu-131I纳米粒子联合放化疗比单纯放疗或化疗的肿瘤体积更小，组织学和免疫组织化学分析进一步证实了Cet-PEG-PLA-5Fu-131I纳米粒子优越的抗肿瘤作用。综上所述，Cet-PEG-PLA-5Fu-131I多功能纳米粒有望作为5Fu介导的化疗和131I介导的放疗联合给药的候选药物。