Systemic Nanocurcumin for Pancreatic Cancer Therapy

用于胰腺癌治疗的全身纳米姜黄素

基本信息

批准号：
7984046
负责人：
ANIRBAN MAITRA
金额：
$ 21.52万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2010-08-25 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7984046
关键词：
Adenocarcinoma Cell Affect Alleles Animal Model Antibodies Antineoplastic Agents Artificial nanoparticles Biological Availability Biological Markers Bypass CCNE1 gene Cell Line Cells Clinical Clinical Trials Collaborations Conduct Clinical Trials Correlative Study Curcuma longa Curcumin DNA Data Dendritic Cells Disease Progression Dose Drug Formulations Drug Kinetics Encapsulated Engineering Funding Genetic Genetically Engineered Mouse Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Histopathology Human Immune response Immunocompetent In Vitro Infiltration Laboratories Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of pancreas Measures Modeling Mus Nanotechnology Natural History Neoplasm Metastasis Pancreatic Adenocarcinoma Patients Pharmaceutical Preparations Pharmacodynamics Plasma Preparation Resistance Resources Serum Spices Surface Surface Antigens T-Lymphocyte TP53 gene Testing Therapeutic Time Tissues Toxic effect Toxicology Treatment Efficacy Tumeric United States Food and Drug Administration Vaccines Validation Visceral Work Xenograft Model Xenograft procedure base cancer therapy compliance behavior dosage gemcitabine human disease in vivo iron oxide mouse model mutant nanoparticle neoplastic cell next generation novel polyphenol preclinical study subcutaneous targeted delivery trafficking tumor tumor immunology vaccine efficacy

项目摘要

Curcumin, a yellow polyphenol compound found in the Indian spice turmeric (Curcuma longa) demonstrates potent anti-cancer effects against a wide variety of human tumor models in preclinical studies. A major pitfall forthe application of curcumin to human cancer therapy has been its limited systemic bioavailability, such that the few clinical trials conducted so far had administered "mega" doses (8-10 grams) of free curcumin daily to pafients in order to yield detectable levels. These high dosages significanfiy affect patient compliance and have stymied the application of this promising, and relafively non-toxic, agent to most visceral malignancies that would mandate high plasma levels of the active therapeutic. A novel nanoparticle encapsulated formulation of curcumin (nanocurcumin) has been engineered which bypasses the bioavailability pitfall of this compound, and enables strikingly higher circulafing and tissue levels upon parenteral administrafion. Nanocurcumin causes significant growth reduction of subcutaneous and orthotopic pancreatic cancer xenografts, and abrogates systemic metastases when co-administered with gemcitabine in a spontaneously metastatic animal model. The studies proposed herein have the overarching goal of performing the efficacy, pharmacokinetics, and toxicity data required for filing an invesfigafional new drug (IND) application with the USFDA. To this effect, nanocurcumin (as single agent or in combination with gemcitabine) will be tested in a panel of low-passage gemcitabine-resistant patientderived orthotopic xenografts (Aim 1) and in a uniformly lethal genetically engineered mouse model (Aim 2), and will undergo "regulatory grade" in vitro and in vivo toxicology testing by the federally-funded Nanotechnology Characterization Laboratory (NCL) (Aim 3), in preparation for a pre-IND application. Two hypothesis-driven aims that integrate unique CCNE resources will also be pursued, including the effects of nanocurcumin on vaccine efficacy and quantifiable measures of cellular immune response (Aim 4; in collaboration with Project 3) and engineering the next generafion of active-targeted anfibody-conjugated nanocurcumin (Aim 6; in collaboration with the Nanoparticle Engineering and the Validafion Cores).

姜黄素是印度香料姜黄（Curcuma longa）中发现的一种黄色多酚化合物，在临床前研究中表现出有效的抗癌作用，对各种人类肿瘤模型。将姜黄素应用于人类癌症治疗的主要陷阱是其系统性的生物利用度有限，因此到目前为止进行的少数临床试验每天对“大型”剂量（8-10克）的胃姜黄素进行给药，以便产生可检测到的水平。这些高剂量显着影响患者的依从性，并在大多数内脏恶性肿瘤中的这种有希望的且无毒的药物的应用中，这将使高血浆高血浆的活性治疗水平。已经设计了一种新型的纳米颗粒（纳米纯蛋白）的制剂，该制剂已经绕开了该化合物的生物利用度陷阱，并在肠胃外行政管理时可以使循环和组织水平更高。纳米毒素会导致皮下和原位胰腺癌异种移植物的显着增长，并在自发转移动物模型中与吉西他滨共同管理时，消除了全身转移。本文提出的研究的总体目标是执行向USFDA提出Invesfigafional新药（IND）所需的功效，药代动力学和毒性数据。 To this effect, nanocurcumin (as single agent or in combination with gemcitabine) will be tested in a panel of low-passage gemcitabine-resistant patientderived orthotopic xenografts (Aim 1) and in a uniformly lethal genetically engineered mouse model (Aim 2), and will undergo "regulatory grade" in vitro and in vivo toxicology testing by the federally-funded纳米技术表征实验室（NCL）（AIM 3），为预先应用做准备。还将追求两个假设驱动的目标，这些驱动的目的还将被追求，包括纳米果蛋白对疫苗功效的影响和细胞免疫反应的可量化措施（AIM 4；与项目3合作）以及与现有的抗抗体抗体的nanocurcumin and nanocurcumin和NINAN（AIL AIM）进行工程（与项目3合作）（内核）。