Enhancement of Antileukemic Activity by Gold Nanoparticles

金纳米粒子增强抗白血病活性

• 批准号: 7867890
• 负责人: Nicholas Alexander Kotov
• 金额: $ 15.26万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867890
• 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）和其他硫嘌呤，如6-巯基嘌呤核苷（6-MPR）是一些最重要和最广泛使用的抗白血病和抗炎药物。6-巯基嘌呤及其类似物的传统治疗是基于口服或静脉给药的化合物，但6-巯基嘌呤容易被酶降解和失活，这导致生物利用度差，并有可能增加耐药性。在这项密歇根大学工程学院和医学院的合作应用中，我们提出了使用小金纳米颗粒（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表面的6-巯基嘌呤-9-2- d -核糖呋喃苷（6-MPR， 6-MP的前体药物）显著增强了抗白血病活性。它既源于更大的渗透细胞的倾向，也源于循环寿命的延长。该颗粒的结构可以进一步修改，以提高血液清除时间和癌症靶向性。该项目的基本和新颖方面包括：(1)验证纳米尺度的颗粒大小是决定网状内皮系统颗粒保留的主要因素之一；(2)阐明NPs及其稳定剂壳的细胞内代谢。这一信息与Au NP作为大量药物和癌症成像载体的许多潜在应用有关。下面的具体目标（SAs）将使我们能够开始验证基本假设，并获得概念验证数据，从而使科学界能够评估Au NPs作为巯基嘌呤递送载体的潜力。SA1：携带6-MPR的Au NP及具有隐蔽性和靶向性的相关药物递送剂的制备。SA 2：利用巨噬细胞体外评估清除时间。SA3：阐明6-MPR在白血病细胞中的传递和释放机制。这个项目是在儿童白血病研究协会（研究者N. Kotov）种子基金的帮助下完成的初步工作。初步结果表明，与游离6- mpr相比，6- mpr修饰的Au NPs具有显著提高的抗癌活性。我们认为这一应用的主要目标是积累概念上关键的数据和开发实验工具，以过渡到Au NPs给药方案的更高级测试阶段。

项目成果

Detection and monitoring of the multiple inflammatory responses by photoacoustic molecular imaging using selectively targeted gold nanorods.

• DOI: 10.1364/boe.2.000645
• 发表时间: 2011-02-23
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Ha S;Carson A;Agarwal A;Kotov NA;Kim K
• 通讯作者: Kim K

Nanocomposite microcontainers.

• DOI: 10.1002/adma.201201378
• 发表时间: 2012-09-04
• 期刊: ADVANCED MATERIALS
• 影响因子: 29.4
• 作者: Andres, Christine M.;Larraza, Inigo;Corrales, Teresa;Kotov, Nicholas A.
• 通讯作者: Kotov, Nicholas A.

Direct-write maskless lithography of LBL nanocomposite films and its prospects for MEMS technologies.

• DOI: 10.1039/c2nr30197k
• 发表时间: 2012-08-07
• 期刊: Nanoscale
• 影响因子: 6.7
• 作者: Bai Y;Ho S;Kotov NA
• 通讯作者: Kotov NA

Subcellular neural probes from single-crystal gold nanowires.

• DOI: 10.1021/nn5024522
• 发表时间: 2014-08-26
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Kang M;Jung S;Zhang H;Kang T;Kang H;Yoo Y;Hong JP;Ahn JP;Kwak J;Jeon D;Kotov NA;Kim B
• 通讯作者: Kim B

"Cloud" assemblies: quantum dots form electrostatically bound dynamic nebulae around large gold nanoparticles.

• DOI: 10.1039/c0cp00186d
• 发表时间: 2010-09
• 期刊: Physical chemistry chemical physics : PCCP
• 作者: G. Lilly;Jaebeom Lee;N. Kotov