Shape Specific, Enzyme-Responsive, Nano-Imprinted Particles for Drug Delivery

用于药物输送的形状特定、酶响应、纳米压印颗粒

基本信息

批准号：
7644354
负责人：
KRISHNENDU ROY
金额：
$ 22万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7644354
关键词：
Abraxane Advanced Development Affect Animal Model Animals Apoptosis Area Behavior Blood Circulation Blood Vessels Blood specimen Body Image Bystander Effect Caring Cathepsins Cathepsins B Cell Culture Techniques Cell physiology Cells Characteristics Chemistry Clinical Clinical Treatment Complex Contrast Media Cysteine Protease DNA Development Diagnostic Dimensions Disease Dose Doxorubicin Hydrochloride Liposome Drug Delivery Systems Drug Formulations Drug Kinetics Elements Emulsions Encapsulated Endocytosis Ensure Enzymes Epidermal Growth Factor Epidermal Growth Factor Receptor Extravasation Fibroblasts Future Genetic Transcription Goals Harvest Image In Vitro Injection of therapeutic agent Kinetics Length Ligands Lipids Liposomes Literature Luciferases Luminescent Proteins Malignant Neoplasms Malignant neoplasm of lung Methods Modeling Mono-S Morbidity - disease rate Mus Nanomanufacturing Nanotechnology Non-Small-Cell Lung Carcinoma Normal Cell Oligonucleotides Organ Harvestings Particle Size Pathway interactions Pentas Peptides Performance Pharmaceutical Preparations Play Polyethylene Glycols Polymers Production Property Proteins Quantum Dots Reporting Research Role Series Shapes Signal Transduction Small Interfering RNA Specificity Stimulus Structure Surface System Tail Techniques Technology Therapeutic Time Transfection Translations Up-Regulation Veins aptamer base cancer cell cancer therapy crosslink cytotoxic density design flexibility imprint improved in vivo lithography manufacturing process mortality nanocarrier nanofabrication nanoimprint lithography nanoimprinting nanometer nanoparticle nanoscale nanosized neoplastic cell particle research study response scale up self assembly success therapeutic protein transcription factor tumor tumor specificity uptake

项目摘要

DESCRIPTION (provided by applicant): Nanotechnology is one of the most promising avenues for the development of advanced drug delivery vehicles. Classically, the field has focused on synthesizing nanocarriers based on self assembly or emulsion based concepts. Although significant progress has been made in polymeric or liposomal drug delivery systems, there remain some key fundamental limitations. These include inability to (a) precisely control shape, aspect ratios, size and polydispersity of the nanocarriers and (b) integrate a variety of disease-specific triggered release mechanisms into the nanoparticle design. Our objective is to use top-down, high throughput nanofabrication technology, specifically a modified step and flash imprint lithography (S-FIL) method, to synthesize highly monodisperse polymer nanocarriers of various shapes, sizes and aspect ratios. By incorporating disease-responsive elements (e.g. peptides) directly into the particle matrix we propose to impart enzyme-responsive release properties into these nanocarriers such that drugs or contrast agents are released primarily in response to tumor-associated signals. The specific aims for this two year period are: Aim 1: To develop a high throughput, top-down nano manufacturing process for fabrication of tumor-targeted, enzyme responsive nanocarriers of precise size and geometry (shape or aspect ratio). In this aim, a modified Step and Flash Imprint Lithography (S-FIL) technique will be employed to produce nanometer size particles of various sizes, cross-sectional shapes, and aspect ratios. The basic material for particle synthesis will be polyethylene glycol diacrylates (PEGDA) and the acrylated penta peptide GFLGK (peptide-DA), which is sensitive to lysosomal cysteine proteases (e.g. Cathepsin B). Cathepsin B is highly over expressed in a variety of cancers including non-small cell lung cancer (NSCLC). Aim 2: To evaluate the effects of size, shape, aspect ratios and macromer concentration on (a) in-vitro cellular uptake of imprinted nanocarriers and (b) intracellular release and transfection of model drugs and contrast agents from enzyme-responsive nanoparticles. We hypothesize that particle shapes, aspect ratio as well as nanoscale dimensions should significantly influence the efficiency of particle internalization. In addition, intracellular delivery of the encapsulated drugs as well as transfection efficacy of a model SiRNA drug will be studied using both fibroblast and lung cancer cells. Aim 3: To study bio- distribution of nanoimprinted particles of various size, shapes and aspect ratios in naove as well as tumor bearing animals. A major hypothesis in studying nanoparticles of various cross sectional shapes and aspect ratios is that these geometric parameters might have strong influence on particle transport properties in blood vessels and therefore should have significant impact on particle bio-distribution as well as tumor accumulation efficacy. Collectively these results should provide a strong basis for future studies on the delivery of therapeutic and diagnostic agents in animal models of various cancers. The goal of this two year exploratory project is to develop a nanoimprint lithography method for fabrication of smart drug delivery nanoparticles. This is a unique top down nanofabrication method for particle synthesis. These nanoparticles are designed to have specific size and shape that can influence their bio distribution. In addition the particles would be able to target tumor cells and deliver the cargo (drugs or imaging agents) to the tumor primarily in response to a disease-specific signal, e.g. enzyme up regulation.

描述（由申请人提供）：纳米技术是开发先进药物输送载体最有前途的途径之一。传统上，该领域专注于基于自组装或基于乳液的概念合成纳米载体。尽管聚合物或脂质体药物递送系统已取得重大进展，但仍然存在一些关键的基本限制。这些问题包括无法（a）精确控制纳米载体的形状、长宽比、尺寸和多分散性以及（b）将各种疾病特异性触发释放机制整合到纳米颗粒设计中。我们的目标是使用自上而下的高通量纳米制造技术，特别是改进的步骤和闪速压印光刻（S-FIL）方法，来合成各种形状、尺寸和长宽比的高度单分散聚合物纳米载体。通过将疾病反应元件（例如肽）直接掺入颗粒基质中，我们建议将酶反应释放特性赋予这些纳米载体，以便药物或造影剂主要响应肿瘤相关信号而释放。这两年的具体目标是：目标 1：开发高通量、自上而下的纳米制造工艺，用于制造具有精确尺寸和几何形状（形状或长宽比）的肿瘤靶向、酶响应纳米载体。为此，将采用改进的步进和闪存压印光刻 (S-FIL) 技术来生产各种尺寸、横截面形状和纵横比的纳米尺寸颗粒。颗粒合成的基本材料是聚乙二醇二丙烯酸酯（PEGDA）和丙烯酸酯五肽 GFLGK（肽-DA），它对溶酶体半胱氨酸蛋白酶（例如组织蛋白酶 B）敏感。组织蛋白酶 B 在包括非小细胞肺癌 (NSCLC) 在内的多种癌症中高度过度表达。目标 2：评估尺寸、形状、长宽比和大分子单体浓度对 (a) 印记纳米载体的体外细胞摄取和 (b) 酶响应纳米粒子中模型药物和造影剂的细胞内释放和转染的影响。我们假设颗粒形状、长宽比以及纳米级尺寸应该显着影响颗粒内化的效率。此外，还将使用成纤维细胞和肺癌细胞来研究封装药物的细胞内递送以及模型 SiRNA 药物的转染功效。目标 3：研究不同尺寸、形状和长宽比的纳米压印颗粒在幼稚动物和荷瘤动物体内的生物分布。研究各种横截面形状和长宽比的纳米颗粒的一个主要假设是，这些几何参数可能对血管中的颗粒传输特性有很大影响，因此应该对颗粒生物分布以及肿瘤积累功效产生重大影响。总的来说，这些结果应该为未来在各种癌症动物模型中递送治疗和诊断药物的研究提供坚实的基础。这个为期两年的探索性项目的目标是开发一种用于制造智能药物输送纳米粒子的纳米压印光刻方法。这是一种独特的自上而下的粒子合成纳米加工方法。这些纳米粒子被设计成具有特定的尺寸和形状，可以影响它们的生物分布。此外，这些颗粒将能够靶向肿瘤细胞并将货物（药物或显像剂）递送到肿瘤，主要是响应疾病特异性信号，例如，酶上调。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of shape, size, and aspect ratio on nanoparticle penetration and distribution inside solid tissues using 3D spheroid models.

DOI：
10.1002/adhm.201500441
发表时间：
2015-10-28
期刊：
ADVANCED HEALTHCARE MATERIALS
影响因子：
10
作者：
Agarwal, Rachit;Jurney, Patrick;Raythatha, Mansi;Singh, Vikramjit;Sreenivasan, Sidlgata. V.;Shi, Li;Roy, Krishnendu
通讯作者：
Roy, Krishnendu

Scalable imprinting of shape-specific polymeric nanocarriers using a release layer of switchable water solubility.