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）和其他硫代嘌呤，例如6-巯基嘌呤核结合物（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常规治疗基于口服或静脉内施用化合物，但6-MP易于酶促降解和失活，这导致生物利用度差并有可能产生耐药性增加。在密歇根大学工程学院和医学院之间的合作应用中，我们提出了利用小型金纳米粒子（Au NP）递送6-MP和相关化合物的概念。我们的目的是证明吸附在Au NPs表面的6-mercaptopurine-9-2-D-ribofuraniside（6-MPR，6-MP的前药）可以显着增强抗白血病活性。它源于穿透细胞的更大趋势和循环寿命的延长。可以进一步修饰颗粒的结构，以改善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）验证纳米级颗粒尺寸是决定网状内皮系统颗粒保留的主要因素之一，以及（2）阐明纳米颗粒及其稳定剂外壳的细胞内代谢。该信息与 Au NP 作为大量药物以及癌症成像载体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，从而使科学界能够评估 Au NP 作为巯基嘌呤递送工具的潜力。 SA1：携带6-MPR的Au NP和具有隐身和靶向功能的相关药物递送剂的制备。 SA 2：使用巨噬细胞体外评估清除时间。 SA3：阐明白血病细胞中 6-MPR 递送和释放的机制。该项目是在儿童白血病研究协会（研究员 N. Kotov）种子资助的帮助下完成的初步工作的基础上进行的。初步结果有力地表明，与游离 6-MPR 相比，6-MPR 修饰的 Au NP 显着提高了抗癌活性。我们认为该应用的主要目标是积累概念上的关键数据和开发实验工具，以过渡到金纳米粒子药物输送方案的更高级测试阶段。 公共健康相关性：开发用于 6-MPR 药物输送的 Au NP 可以显着改善白血病的治疗并减少副作用。该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