Multifunctional Nanotherapeutics for Cancer Treatment and Imaging

项目名称：用于癌症治疗和成像的多功能纳米疗法 原发卵巢癌化疗的成功，特别是转移细胞的生长 腹水中癌细胞的固有和获得性耐药以及 化疗。根据我们之前的研究结果和文献数据，我们假设 耐药卵巢癌的治疗和影像效果显著增强 转移可以通过(1)至少两种不同的抗癌药物诱导癌细胞死亡来实现， (2)靶向在癌细胞耐药中起关键作用的蛋白质的siRNA抑制癌细胞的耐药性 (3)靶向药物、显像剂和siRNA，特异性靶向原发肿瘤和 转移瘤。只有将几种抗癌药物输送到卵巢，才能实现这一目标 肿瘤细胞与其他执行不同特定功能的活性成分联合增强 主要药物在癌细胞中的细胞摄取和效率，限制副作用，以及 防止现有耐药性的发展和/或抑制。在建议的研究中，我们 计划将纳米技术方法应用于这种多组分的开发和评估 多功能纳米疗法。拟议研究的长期目标是验证这一假说 开发基于纳米技术的新型多功能药物递送系统的混合物(鸡尾酒) (NDDS)将显著提高原发性卵巢癌的化疗疗效和 腹膜内转移，同时最大限度地减少对健康器官的副作用。羟基封端的PAMAM-OH 将使用内部季胺化和表面乙酰化的聚(氨基胺)树枝状大分子(QPAMAM-NaAC 作为纳米载体，分别输送抗癌药物和siRNA。此外，每个NDDS将包含一个 肿瘤特异性靶向部分(肽)和一个活性成分(抗癌药物或siRNA或荧光 染料)。紫杉醇和顺铂/卡铂将被评估为抗癌药物-细胞死亡诱导剂。小干扰RNA 针对mdr1和CD44的mRNA将作为泵阻力的抑制因子进行研究。靶向siRNA BCL2mRNA将作为非泵阻力的抑制因子进行研究。促黄体生成素释放激素 促性腺激素释放激素(LHRH)肽将被用作卵巢癌特异性靶向部分。已确定的人类多药 耐药卵巢癌细胞系以及从原发肿瘤和恶性腹水中分离的细胞 晚期多药耐药卵巢癌患者将被用来创造异位皮下和 裸鼠原位腹膜腔内移植模型。静脉全身和腹膜局部给药 将对NDD进行比较。建议的研究结果将被用于设计新型多功能 用于治疗不同癌症的纳米技术方法。

Project Title: Multifunctional Nanotherapeutics for Cancer Treatment and Imaging The success of chemotherapeutic treatment of primary ovarian cancer, especially metastatic cells growing in ascitic fluid is limited by 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 hypothesized, that substantial enhancement in the effectiveness of treatment and imaging of drug resistant ovarian cancer and metastases can be achieved by the (1) induction of cancer cell death by at least two different anticancer drugs, (2) suppression of cancer cell resistance by siRNA targeted to proteins that play key roles in such resistance and (3) targeting drugs, imaging agents and siRNA specifically to ovarian cancer cells in primary tumor and metastases. Such an objective can only be achieved if several anticancer drugs are delivered to the ovarian tumor cells in combination with other active components that perform different specific functions for enhancing cellular uptake and efficiency of the main drugs specifically in cancer cells, limiting adverse side effects, and preventing the development and/or suppression of the existing drug resistance. In the proposed study, we plan to apply nanotechnology approaches to the development and evaluation of such multicomponent multifunctional nanotherapeutics. The long-term objective of the proposed research is to verify the hypothesis and develop a mixture (cocktail) of novel multifunctional Nanotechnology-based Drug Delivery Systems (NDDS) that will significantly increase the efficacy of the chemotherapy of primary ovarian cancer and intraperitoneal metastases while minimizing side effects on healthy organs. A hydroxyl terminated PAMAM-OH and internally quaternized and surface-acetylated Poly(amido amine) dendrimer (QPAMAM-NHAc) will be used as a nanocarrier to deliver anticancer drugs and siRNA, respectively. In addition, each NDDS will contain a tumor-specific targeting moiety (peptide) and one active component (anticancer drug or siRNA or fluorescent dye). Paclitaxel and cisplatin/carboplatin 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. Luteinizing Hormone-Releasing Hormone (LHRH) peptide will be used as ovarian cancer-specific targeting moiety. 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 administrations of NDDS will be compared. The results of the proposed research will be used to design novel multifunctional nanotechnology approaches for the treatment of different cancers.