Enhancement of Antileukemic Activity by Gold Nanoparticles

金纳米粒子增强抗白血病活性

• 批准号: 7661247
• 负责人: Nicholas Alexander Kotov
• 金额: $ 15.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661247
• 关键词: 6-Mercaptopurine; Acute Lymphocytic Leukemia; Address; Adverse effects; Age; Animal Testing; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antineoplastic Agents; Area; Biological; Biological Availability; Blood; Blood Circulation; Cell Culture Techniques; Cell membrane; Cells; Charge; Child; Clinical; Collaborations; Communities; Data; Development; Diagnostic Imaging; Digestion; Disease; Drug Delivery Systems; Drug resistance; Drug usage; Engineering; Ethylene Glycols; Evaluation; Fluorescence; Funding; Goals; Gold; Grant; Human; In Vitro; Incubated; Inflammatory; Investigation; K-562; Knowledge; Life; Malignant Neoplasms; Metabolism; Methods; Michigan; Oral; Particle Size; Patients; Pharmaceutical Preparations; Phase; Preparation; Process; Prodrugs; Protocols documentation; Research; Research Personnel; Resistance; Schools; Seeds; Staging; Structure; Surface; System; Testing; Therapeutic; Time; Universities; Work; analog; anticancer activity; anticancer treatment; base; cancer imaging; chemotherapeutic agent; clinical practice; conventional therapy; dosage; ethylene glycol; improved; in vitro activity; intravenous administration; leukemia; macrophage; medical schools; nanocolloid; nanoparticle; nanoscale; novel; particle; public health relevance; stem; thiopurine; time use; tool

DESCRIPTION (provided by applicant): 6-mercaptopurine (6-MP) and other thiopurines, such as 6-mecaptopurine ribozide (6-MPR) are some of the most important and most widely utilized anitleukemic and anti-inflammatory drugs. Conventional therapy with 6-mercaptopurine and its analogues is based on oral or intravenous administration of the compounds however 6-MP is susceptible to enzymatic degradation and inactivation, which results in poor bioavailability and potential for the development of increased resistance. In this collaborative application between the School of Engineering and Medical School of the University of Michigan we put forward a concept of the delivery of 6-MP and related compounds by using small gold nanoparticles (Au NPs). We intend to show that 6-mercaptopurine-9-2-D-ribofuraniside (6-MPR, a pro- drug of 6-MP) adsorbed on the surface of Au NPs has significantly enhanced anti-leukemia activity. It stems both from the greater tendency to penetrate the cells and extended life-time in circulation. The structure of the particle can be further modified to improve blood clearance time and cancer targeting. The fundamental and novel aspects of the project include (1) the verification of particle size in nanoscale being one of the primary factors determining the particle retention by reticular endothelial system, and (2) elucidation of the intracellular metabolism of NPs and their stabilizer shell. This information is relevant for many potential applications of Au NP as a vehicle to a large number of drugs as well as cancer imaging. The Specific Aims (SAs) below will allow us to start validating the basic hypothesis and to obtain the proof-of-concept data allowing the scientific community to assess the potential of Au NPs as a delivery vehicle of mercaptopurines. SA1: Preparation of Au NP carrying 6-MPR and related drug delivery agents with cloaking and targeting functionalities. SA 2: In vitro evaluation of the clearance time using macrophages. SA3: Elucidation of the mechanism of 6-MPR delivery and release in leukemia cells. This project is based on the preliminary work done with the help of the seed grant from Children's Leukemia Research Association (investigator N. Kotov). The preliminary results give strong indications that 6- MPR-modified Au NPs have substantially increased anticancer activity as compared to free 6-MPR. We see the primary goal of this application in the accumulation of conceptually critical data and development of experimental tools for the transition into stages of more advanced testing of the drug delivery protocols with Au NPs. PUBLIC HEALTH RELEVANCE: Development of Au NPs for drug delivery of 6-MPR can substantially improve treatment of leukemia and reduce side-effects. The anticancer agent will also have longer span of activity and better efficacy.

描述（由申请人提供）：6-巯基嘌呤（6-MP）和其它硫代嘌呤，如6-巯基嘌呤核酰肼（6-MPR）是一些最重要和最广泛使用的抗白血病和抗炎药物。使用6-巯基嘌呤及其类似物的常规疗法是基于口服或静脉内施用化合物，然而6-MP易受酶降解和失活的影响，这导致生物利用度差和产生增加的抗性的可能性。在密歇根大学工程学院和医学院之间的这一合作应用中，我们提出了通过使用小的金纳米颗粒（Au NPs）递送6-MP和相关化合物的概念。我们打算证明吸附在Au NPs表面上的6-巯基嘌呤-9-2-D-呋喃核糖苷（6-MPR，6-MP的前药）具有显著增强的抗白血病活性。它源于更大的渗透细胞的趋势和延长的循环寿命。颗粒的结构可以进一步修饰以改善血液清除时间和癌症靶向。该项目的基本和新颖的方面包括：（1）验证纳米尺度的颗粒大小是决定网状内皮系统颗粒滞留的主要因素之一，以及（2）阐明纳米颗粒及其稳定剂壳的细胞内代谢。该信息与Au NP作为大量药物的载体以及癌症成像的许多潜在应用相关。下面的具体目标（SA）将使我们能够开始验证基本假设，并获得概念验证数据，使科学界能够评估Au NPs作为巯基嘌呤递送载体的潜力。SA 1：制备携带6-MPR的Au NP和具有掩蔽和靶向功能的相关药物递送剂。SA 2：使用巨噬细胞进行清除时间的体外评价。SA 3：阐明白血病细胞中6-MPR递送和释放的机制。本计画是在儿童白血病研究会种子基金的协助下所做的前期工作。Kotov）。初步结果强烈表明，与游离6-MPR相比，6-MPR修饰的Au NP具有显著增加的抗癌活性。我们看到这个应用程序的主要目标是积累概念上的关键数据和开发实验工具，以过渡到更先进的测试阶段的药物输送协议与Au纳米粒子。 公共卫生相关性：开发用于6-MPR药物递送的Au NPs可以显著改善白血病的治疗并减少副作用。抗癌剂还将具有更长的活性跨度和更好的功效。