新型pH敏感靶向纳米载药体系与逆转恶性淋巴瘤多药耐药的机制研究

项目名称： 新型pH敏感靶向纳米载药体系与逆转恶性淋巴瘤多药耐药的机制研究

项目编号： No.81201704

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 王筠

作者单位： 南京医科大学

项目金额： 23万元

中文摘要： 恶性淋巴瘤易复发并对化疗药物产生多药耐药（MDR）。绝大多数起源于B淋巴细胞系的恶性淋巴瘤细胞表面表达CD22抗原，与CD20不同，CD22 抗原与抗体结合后能迅速内化，使 CD22 抗体偶联毒素成为治疗 B淋巴细胞系肿瘤很有前景的方法。本课题选择最常用于淋巴瘤治疗的化疗药物阿霉素（DOX）为药物模型，拟制备偶联抗CD22单克隆抗体Fab'片段、pH敏感的磁性纳米氧化铁（MNPs）载药体系，探讨其逆转肿瘤MDR的作用及潜在的机制。通过对MNPs进行表面修饰，优化与DOX、CD22(Fab')的反应条件，制备新型pH敏感靶向纳米载药体系CD22(Fab')-DOX-MNPs，比较该体系对非霍奇金淋巴瘤（NHL）敏感株Raji细胞和耐药株Raji/DOX细胞的细胞毒作用，以及在耐药荷瘤裸鼠的体内抗肿瘤作用，评估其逆转MDR效果，为临床应用提供实验研究基础。

中文关键词： 恶性淋巴瘤；多药耐药；抗CD22单克隆抗体；阿霉素；纳米载药体系

英文摘要： Most malignant lymphomas are initially responsive to chemotherapy. However, the efficacy of chemotherapy is often limited by selection of drug-resistant cells expressing the multidrug resistance (MDR) phenotype and relapse is common. Most malignant lymphoma cells which are of B-lymphocyte origin express CD22 antigen. In contrast to CD20, CD22 undergoes constitutive endocytosis and is well suited for efficient delivery of the toxin into the cell. To overcome MDR and decrease toxicity, we will develop an elegant alternative approach to deliver selectively chemotherapeutic drugs to malignant lymphoma cells by employing doxorubicin-loaded magnetic iron oxide nanoparticles modified by a ligand for the B cell-specific cell-surface protein CD22 also known as anti-CD22 Fab' fragments. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy, will be covalently bound to iron oxide nanoparticle via a pH sensitive hydrazone linkage. The preparation of the novel doxorubicin-loaded CD22 targeting and pH sensitive nanoparticles will be optimized. Nanoparticles uptake, retention, and dose-dependent cytotoxicity will be compared in wild-type and DOX-resistant human Non-Hodgkin's lymphoma (NHL) Raji cells. The anti-tumor efficacy will be examined in a Raji/DOX lymphoma mice model.The MDR efficiency wil

英文关键词： malignant lymphomas；multidrug resistance；anti–CD22 antibodies；doxorubicin；nanoparticledrug delivery systems