Multifunctional Nanotherapeutics for Cancer Treatment and Imaging

用于癌症治疗和成像的多功能纳米疗法

基本信息

批准号：
8676693
负责人：
Tamara Minko
金额：
$ 30.09万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676693
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 Targeting 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 receptor research study subcutaneous success targeted delivery traditional therapy tumor uptake

项目摘要

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.

项目名称：用于癌症治疗和成像的多功能纳米治疗剂原发性卵巢癌的化学治疗的成功，尤其是转移细胞的生长在腹水中受到癌细胞的内在耐药性和获得性的限制，以及化学疗法。根据我们先前的研究和文献数据的结果，我们假设耐药性卵巢癌的治疗和成像的有效性和成像的大幅增强（1）至少两种不同的抗癌药物（1）诱导癌细胞死亡，可以实现转移酶（2）靶向蛋白质的siRNA抑制癌细胞耐药性，这些蛋白质在这种抗性中起关键作用（3）针对药物，成像剂和siRNA专门针对原发性肿瘤和转移。只有在将几种抗癌药物输送到卵巢时才能实现这样的目标肿瘤细胞与执行不同特定功能的其他活性组件结合起来主要药物专门在癌细胞中的细胞摄取和效率，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此类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假设并开发新型多功能纳米技术的药物输送系统的混合物（鸡尾酒）（NDD）将显着提高原发性卵巢癌和腹膜内转移，同时最大程度地减少对健康器官的副作用。羟基终止PAMAM-OH 并将使用内部和表面乙酰化的聚（amido胺）树状胺（QPAMAM-NHAC）作为纳米载体分别提供抗癌药物和siRNA。此外，每个NDD都将包含一个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/卡铂将被评估为抗癌药物 - 细胞死亡诱导剂。 sirna 针对MDR1和CD44 mRNA的靶向将作为泵抗性的抑制剂进行研究。 siRNA针对 Bcl2 mRNA将作为非泵电阻的抑制剂进行研究。黄体生成激素释放激素（LHRH）肽将用作卵巢癌特异性靶向部分。建立的人类多饮抗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患有晚期多药抗卵巢癌的患者将用于创建异位皮下和裸鼠的原位腹膜腹膜腹膜模型。静脉注射系统和腹膜内部管理将比较NDD的。拟议研究的结果将用于设计新型的多功能纳米技术方法用于治疗不同的癌症。