Combination Nanotherapeutic Strategies to Overcome Tumor Drug Resistance

项目名称：克服肿瘤耐药性的联合纳米治疗策略 原发卵巢癌，尤其是腹水中生长的转移细胞的化疗成功受到癌细胞固有的和获得性耐药以及化疗的副作用的限制。根据我们以往的研究结果和文献资料，我们推测，只有通过多种不同作用机制的抗癌药物同时抑制细胞耐药和诱导细胞死亡，才有可能有效地治疗多药耐药卵巢肿瘤。如果在一个多功能系统中同时给予几种抗癌药物，并结合发挥不同特定功能的其他活性成分，以增强细胞对主要药物的摄取和效率，特别是在癌细胞中，限制不良副作用和防止发展和/或抑制现有的耐药性，就可以实现这些目标。在拟议的研究中，我们计划将纳米技术方法应用于此类多功能纳米疗法的开发和评估。这项研究的长期目标是验证这一假说，开发新型多功能纳米载体给药系统(S)，该系统将显著提高原发性卵巢癌和腹膜转移癌的化疗效率，同时将健康器官的副作用降至最低。一种新型的内部季胺化和表面乙酰化的聚酰胺胺树枝状大分子(QPAMAM-NAAC)将被用作NDDS的纳米载体。NDDS将包含一个肿瘤特异性靶向部分，两种抗癌药物，以及泵和非泵细胞耐药的抑制物。紫杉醇、顺铂/卡铂及其组合将被评为抗癌药物--细胞死亡诱导剂。针对MDR1和CD44 mRNA的siRNA将作为泵阻力的抑制因子进行研究。靶向bcl2mRNA的siRNA将作为非泵阻力的抑制因子进行研究。已建立的人多药耐药卵巢癌细胞系以及从晚期多药耐药卵巢癌患者的原发肿瘤和恶性腹水中分离出的细胞将被用于建立裸鼠异位皮下和原位腹膜内模型。对实验性癌症的静脉全身治疗和腹膜内局部治疗进行比较。这项拟议工作的结果将用于设计治疗不同癌症的新型多功能纳米技术方法。

Project Title: Combination Nanotherapeutic Strategies to Overcome Tumor Drug Resistance The success of chemotherapeutic treatment of primary ovarian cancer and especially metastatic cells growing in ascitic fluid is limited by the intrinsic and acquired resistance of cancer cells and adverse side effects of chemotherapy. Based on the results of our previous study and literature data, we hypothesize, that the effective treatment of multidrug resistant ovarian tumors is possible only by the simultaneous suppression of cellular resistance and cell death induction by several anticancer agents with different mechanisms of action. Such goals can be achieved if several anticancer agents are simultaneously delivered in one multifunctional system in combination with other active ingredients that perform different specific functions for enhancing cellular uptake and efficiency of the main drug specifically in cancer cells, limiting adverse side effects and preventing the development and/or suppression of the existent drug resistance. In the proposed study, we plan to apply nanotechnology approaches to the development and evaluation of such multifunctional nanotherapeutics. The long-term objective of the proposed research is to verify the hypothesis and develop novel multifunctional Nanocarrier-based Drug Delivery System(s) (NDDS) that will significantly increase the efficacy of the chemotherapy of primary ovarian cancer and intraperitoneal metastases while minimizing side effects in healthy organs. A novel internally quaternized and surfaceacetylated poly(amidoamine) dendrimer (QPAMAM-NHAc) will be used as a nanocarrier for NDDS. The NDDS will contain a tumor-specific targeting moiety, two anticancer drugs, and suppressors of pump and nonpump cellular resistance. Paclitaxel, cisplatin/carboplatin and their combination will be evaluated as anticancer drugs - cell death inducers. siRNA targeted to MDR1 and CD44 mRNA will be investigated as suppressors of pump resistance. siRNA targeted to BCL2 mRNA will be studied as a suppressor of nonpump resistance. Established human multidrug resistant ovarian cancer cell lines as well as cells isolated from primary tumor and malignant ascites from patients with advanced multidrug resistant ovarian carcinoma will be used to create ectopic subcutaneous and orthotopic intraperitoneal models in nude mice. Intravenous systemic and intraperitoneal local treatments of experimental cancers will be compared. The results of the proposed work will be used to design novel multifunctional nanotechnology approaches for the treatment of different cancers.