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-丙氨酸（6-MP）和其他硫嘌呤，例如6-丙啉硫嘌呤核苷（6-MPR）是一些最重要，最广泛使用的厌食症和抗炎药。使用6-丙氨酸的常规治疗及其类似物是基于化合物的口服或静脉内给药，但是6-MP容易受到酶促降解和失活的影响，这会导致生物利用不良，并且潜力增加了抵抗力的增加。在密歇根大学工程学院与医学院之间的合作应用中，我们提出了通过使用小金纳米颗粒（AU NP）提供6-MP和相关化合物的概念。我们打算表明，吸附在Au NPs表面上的6-羟基托嘌呤-9-2-D-核呋喃酶（6-MPR，一种6-MP的药物）具有显着增强的抗白血病活性。它既源于穿透细胞的更大趋势并在循环中延长寿命。可以进一步修改粒子的结构，以改善血液清除时间和癌症的靶向。该项目的基本和新方面包括（1）纳米级粒度的验证是确定网状内皮系统颗粒保留率的主要因素之一，以及（2）阐明NPS的细胞内代谢及其稳定器壳。该信息与Au NP作为大量药物以及癌症成像的许多潜在应用有关。下面的具体目的（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 NP作为胃肽的输送工具的潜力。 SA1：携带6-MPR和相关药物输送剂的AU NP的制备，具有掩护和靶向功能。 SA 2：使用巨噬细胞在体外评估清除时间。 SA3：阐明白血病细胞中6-MPR递送和释放的机制。该项目基于儿童白血病研究协会（研究人员N. Kotov）的种子资助的初步工作。初步结果表明，与自由6-MPR相比，6-MPR修饰的Au NP具有显着增加的抗癌活性。我们看到了此应用的主要目标在概念上关键数据的积累和实验工具的开发中，以过渡到使用AU NP的药物输送方案进行更高级测试的阶段。 公共卫生相关性：开发用于服用6-MPR的药物的AU NP可以大大改善白血病的治疗方法并减少副作用。抗癌剂还将具有更长的活性和更好的功效。

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