Multifunctional Nanotherapeutics for Cancer Treatment and Imaging

用于癌症治疗和成像的多功能纳米疗法

• 批准号: 8100432
• 负责人: Tamara Minko
• 金额: $ 30.77万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100432
• 关键词: ABCB1 gene; Address; Adverse effects; Amidone; Amines; Antineoplastic Agents; BCL-2 Protein; BCL2 gene; Blood; Blood Circulation; CD44 gene; Cancer cell line; Carboplatin; Cell Death; Cell Death Induction; Cell membrane; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Complex; Data; Dendrimers; Development; Disadvantaged; Disseminated Malignant Neoplasm; Drug Delivery Systems; Drug Efflux; Drug resistance; Evaluation; Fluorescent Dyes; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Analog; Human; Hydroxyl Radical; Image; Individual; Intravenous; Investigation; Literature; Malignant Neoplasms; Malignant neoplasm of ovary; Messenger RNA; Metastatic Malignant Neoplasm to the Ovary; Methodology; Methods; Modeling; Modification; Molecular Target; Multi-Drug Resistance; Nanotechnology; Neoplasm Metastasis; Nude Mice; Organ; Ovarian Ablation; Ovarian Carcinoma; Paclitaxel; Patients; Penetration; Peptides; Peritoneal Fluid; Pharmaceutical Preparations; Play; Primary Neoplasm; Proteins; Pump; Research; Resistance; Signal Pathway; Small Interfering RNA; Solid; Solid Neoplasm; Stream; Surface; System; Testing; Therapeutic; Tissues; Toxic effect; Treatment Effectiveness; Treatment Failure; Tumor Tissue; Work; base; cancer cell; cancer imaging; cancer therapy; chemotherapy; design; effective therapy; efflux pump; effusion; innovation; intraperitoneal; malignant ascites; nanocarrier; nanoparticle; nanotherapeutic; neoplastic cell; novel; ovarian neoplasm; overexpression; prevent; public health relevance; receptor; research study; subcutaneous; success; targeted delivery; traditional therapy; tumor; uptake

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We are proposing a novel nanotechnology-based approach for the effective treatment of ovarian cancer by simultaneous suppression of cellular resistance by siRNA targeted to MDR1, CD44 and BCL2 mRNA and cell death induction by two anticancer drugs (paclitaxel and cisplatin) with different mechanisms of action. The objective of the proposed research is to develop a novel mixture ("cocktail") of multifunctional nanocarrier- based drug delivery systems that will significantly increase the efficacy of the chemotherapy of primary ovarian cancer and intraperitoneal metastases while minimizing side effects of treatment on healthy organs.

描述（由申请人提供）： 原发性卵巢癌，特别是腹水中生长的转移细胞的化疗治疗的成功受到癌细胞的固有和获得性耐药性以及化疗的不良副作用的限制。根据我们之前的研究结果和文献数据，我们假设，耐药性卵巢癌和转移瘤的治疗和成像效果的显着增强可以通过以下方式实现：（1）通过至少两种不同的方法诱导癌细胞死亡。抗癌药物，(2) 通过针对在耐药性中起关键作用的蛋白质的 siRNA 抑制癌细胞耐药性，以及 (3) 将药物、显像剂和 siRNA 特异性地靶向原发性肿瘤和转移灶中的卵巢癌细胞。只有将多种抗癌药物与其他具有不同特定功能的活性成分联合递送至卵巢肿瘤细胞，才能实现这一目标，以增强主要药物在癌细胞中的细胞摄取和效率，限制不良副作用，以及防止现有耐药性的发展和/或抑制。在拟议的研究中，我们计划应用纳米技术方法来开发和评估此类多组分多功能纳米疗法。拟议研究的长期目标是验证这一假设并开发一种基于纳米技术的新型多功能药物输送系统（NDDS）的混合物（鸡尾酒），该混合物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对健康器官的副作用。羟基封端的 PAMAM-OH 和内部季铵化和表面乙酰化的聚（酰胺胺）树枝状聚合物 (QPAMAM-NHAc) 将用作纳米载体，分别递送抗癌药物和 siRNA。此外，每个NDDS将包含肿瘤特异性靶向部分（肽）和一种活性成分（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估。将研究针对 MDR1 和 CD44 mRNA 的 siRNA 作为泵阻力的抑制剂。将研究针对 BCL2 mRNA 的 siRNA 作为非泵阻力的抑制剂。黄体生成素释放激素（LHRH）肽将用作卵巢癌特异性靶向部分。已建立的人多重耐药卵巢癌细胞系以及从原发肿瘤和晚期多重耐药卵巢癌患者的恶性腹水中分离的细胞将用于在裸鼠中创建异位皮下和原位腹膜内模型。将比较 NDDS 的静脉全身给药和腹膜内局部给药。拟议研究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。 公共卫生相关性： 我们提出了一种基于纳米技术的新型方法，通过针对 MDR1、CD44 和 BCL2 mRNA 的 siRNA 抑制细胞耐药性，并通过具有不同作用机制的两种抗癌药物（紫杉醇和顺铂）诱导细胞死亡，从而有效治疗卵巢癌。拟议研究的目的是开发一种基于多功能纳米载体的药物递送系统的新型混合物（“鸡尾酒”），该混合物将显着提高原发性卵巢癌和腹膜内转移瘤的化疗疗效，同时最大限度地减少治疗对健康器官的副作用。