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 原发性卵巢癌，特别是腹水中生长的转移性细胞的化疗治疗的成功受到癌细胞的内在和获得性抗性以及化疗的不良副作用的限制。根据我们以前的研究结果和文献数据，我们假设，多药耐药卵巢肿瘤的有效治疗是可能的，只有通过同时抑制细胞耐药和细胞死亡诱导的几种抗癌药物具有不同的作用机制。如果在一个多功能系统中同时递送几种抗癌剂与其他活性成分，则可以实现这样的目标，所述其他活性成分执行不同的特定功能，用于增强细胞摄取和主要药物的效率，特别是在癌细胞中，限制不良副作用并防止现有耐药性的发展和/或抑制。在拟议的研究中，我们计划将纳米技术方法应用于这种多功能纳米治疗药物的开发和评估。该研究的长期目标是验证这一假设，并开发新型多功能纳米载体药物递送系统（NDDS），该系统将显着提高原发性卵巢癌和腹膜内转移化疗的疗效，同时最大限度地减少健康器官的副作用。一种新型的内部季铵化和表面乙酰化的聚酰胺-胺树枝状大分子（QPAMAM-NHAc）将被用作NDDS的纳米载体。NDDS将包含肿瘤特异性靶向部分、两种抗癌药物以及泵和非泵细胞抗性的抑制剂。紫杉醇、顺铂/卡铂及其组合将作为抗癌药物-细胞死亡诱导剂进行评价。将研究靶向MDR 1和CD 44 mRNA的siRNA作为泵抗性的抑制剂。靶向BCL 2 mRNA的siRNA将作为非泵抗性的抑制剂进行研究。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的细胞将用于在裸鼠中建立异位皮下和原位腹膜内模型。将比较实验性癌症的静脉内全身和腹膜内局部治疗。拟议工作的结果将用于设计用于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.