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治疗药物 化疗治疗原发性卵巢癌的成功，特别是转移细胞的生长 在腹水中的应用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。 化疗根据我们先前的研究结果和文献数据，我们假设， 显著增强耐药卵巢癌的治疗和成像效果， 转移可以通过（1）通过至少两种不同的抗癌药物诱导癌细胞死亡， (2)通过靶向在这种抗性中起关键作用的蛋白质的siRNA抑制癌细胞抗性 和（3）特异性针对原发肿瘤中卵巢癌细胞的靶向药物、显像剂和siRNA， 转移只有当几种抗癌药物被递送到卵巢时，才能实现这样的目标。 肿瘤细胞与其他活性成分的组合，所述其他活性成分执行不同的特异性功能， 主要药物的细胞摄取和效率，特别是在癌细胞中，限制不良副作用，和 防止现有耐药性的发展和/或抑制。在这项研究中，我们 计划将纳米技术方法应用于开发和评估这种多组分 多功能纳米治疗。拟议研究的长期目标是验证这一假设 并开发一种新的多功能纳米技术为基础的药物输送系统的混合物（鸡尾酒） （NDDS），这将显着提高原发性卵巢癌化疗的疗效， 腹膜内转移，同时最小化对健康器官的副作用。羟基封端的PAMAM-OH 采用内部季铵化和表面乙酰化的聚酰胺胺树状大分子（QPAMAM-NHAc 作为纳米载体分别递送抗癌药物和siRNA。此外，每个NDDS将包含一个 肿瘤特异性靶向部分（肽）和一种活性组分（抗癌药物或siRNA或荧光 染料）。紫杉醇和顺铂/卡铂将作为抗癌药物-细胞死亡诱导剂进行评价。siRNA 将研究靶向MDR 1和CD 44 mRNA作为泵阻力的抑制剂。siRNA靶向 BCL 2 mRNA将作为非泵阻力的抑制因子进行研究。促黄体激素释放激素 （LHRH）肽将用作卵巢癌特异性靶向部分。已确立的人用多药 耐药卵巢癌细胞系以及从原发性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用于产生异位皮下和 裸鼠原位腹膜内模型。静脉全身和腹膜内局部给药 将对NDDS进行比较。研究结果将用于设计新型的多功能 纳米技术用于治疗不同的癌症。

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.