权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Multifunctional Protein Nanocapsules for Targeted Delivery

用于靶向递送的多功能蛋白质纳米胶囊

基本信息

批准号：
8019564
负责人：
Szu-Wen Wang
金额：
$ 17.62万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8019564
关键词：
Address Adverse effects Affect Architecture Behavior Breast Cancer Cell Cardiotoxicity Cell physiology Cells Characteristics Chimeric Proteins Disease Dissociation Dose Doxorubicin Drug Carriers Drug Delivery Systems Effectiveness Encapsulated Endocytosis Engineering Environment Exhibits Genes Goals In Vitro Investigation Knowledge Learning Length Ligands Malignant Neoplasms Modeling Molecular Nature Patients Pharmaceutical Preparations Property Proteins Regenerative Medicine Structure System Technology Testing Therapeutic Time Work cancer cell cellular targeting cytotoxicity design improved late endosome malignant breast neoplasm nanometer nanoparticle nanoparticulate nanoscale novel novel therapeutics particle public health relevance pyruvate dehydrogenase receptor mediated endocytosis response scaffold targeted delivery trafficking

项目摘要

DESCRIPTION (provided by applicant): As a better understanding of cellular processes at the molecular level is gained, novel materials can be designed at the nanometer length scale which exploits this new knowledge to effectively deliver therapeutic compounds. However, limitations in synthesizing such small entities often preclude the ability to rationally incorporate multiple functions, which in turn restricts available delivery strategies. Significantly, our proposed delivery system can uniquely address some of these limitations of small nanoscale systems, thereby potentially extending the feasibility of nanoscale delivery systems. The goal of this proposed investigation is to incorporate multiple functionalities into 25-nm protein nanoparticles and test their potential for targeted drug delivery in cancer cells. This can potentially increase the effectiveness of a given drug by significantly decreasing the amount of drug needed, expanding its therapeutic capabilities, allowing greater control over targeting and release, and decreasing side effects. Our synthesis strategy involves genetically designing chimeras of protein nanoparticles, which enables the nanoscale architecture to be specifically tailored in a relatively straightforward manner. This proposed work will, for the first time, investigate the response of breast cancer cells to these protein nanoparticles and test the feasibility of using these multifunctional scaffolds for improving therapeutic delivery of doxorubicin. We hypothesize that cytotoxicity in cancer cells will be greatest when the multiple properties of cellular targeting, drug encapsulation, and pH-responsive dissociation and drug release are combined within each protein nanoparticle. To test this hypothesis, we propose the following specific aims: (1) Fabricate drug-loaded, pH-responsive protein nanoparticles that display cancer-targeting ligand, (2) Determine optimal conditions for cytotoxicity and in vitro dose-response profiles in breast cancer cells, and (3) Reconcile the mechanisms of endocytosis, compartmental trafficking, and drug release with nanoparticle characteristics and cytotoxicity. This proposed work not only will develop the technology of multifunctional protein nanoparticles in drug delivery, but will enable the use of the E2 scaffold as a model for determining general delivery principles. This includes identifying the structures and properties of targeted nanoparticles which affect cellular interaction and behavior. Furthermore, our target disease in this proposed work is breast cancer, which will be treated with protein-encapsulated doxorubicin. Although doxorubicin is a conventional line of treatment, it exhibits dose-dependent cardiotoxicity in patients. Information learned from this investigation could identify general strategies in nanoparticulate drug delivery that increase cytotoxicity in only cancer cells while decreasing overall doses and severe side-effects. PUBLIC HEALTH RELEVANCE: Multifunctional Protein Nanocapsules for Targeted Delivery In creating a new class of nanoscale drug carriers, the scope of novel therapeutic strategies in therapeutic delivery will be broadened. This has the potential to expand the efficacy of disease treatment and promote regenerative medicine.

描述（由申请人提供）：随着在分子水平上对细胞过程的更好理解，可以在纳米长度尺度上设计新材料，其利用这一新知识来有效地递送治疗化合物。然而，在综合这些小实体方面的局限性往往妨碍了合理整合多种功能的能力，这反过来又限制了可用的交付战略。值得注意的是，我们提出的递送系统可以独特地解决小纳米级系统的这些限制中的一些，从而潜在地扩展纳米级递送系统的可行性。这项研究的目标是将多种功能整合到25 nm蛋白质纳米颗粒中，并测试它们在癌细胞中靶向药物递送的潜力。这可以通过显着减少所需药物的量，扩大其治疗能力，允许更好地控制靶向和释放以及减少副作用来潜在地增加给定药物的有效性。我们的合成策略涉及基因设计蛋白质纳米颗粒的嵌合体，这使得纳米级架构能够以相对简单的方式进行专门定制。这项拟议的工作将首次研究乳腺癌细胞对这些蛋白质纳米颗粒的反应，并测试使用这些多功能支架改善多柔比星治疗递送的可行性。我们假设，当细胞靶向、药物包封、pH响应性解离和药物释放的多种特性在每个蛋白质纳米颗粒内组合时，癌细胞中的细胞毒性将最大。为了验证这一假设，我们提出了以下具体目标：（1）制造载药的pH响应性蛋白纳米颗粒，显示癌症靶向配体，（2）确定乳腺癌细胞中细胞毒性和体外剂量反应曲线的最佳条件，（3）阐明内吞作用，隔室运输和药物释放的机制与纳米颗粒特性和细胞毒性。这项拟议的工作不仅将开发多功能蛋白质纳米颗粒在药物递送中的技术，而且将使E2支架能够用作确定一般递送原则的模型。这包括识别影响细胞相互作用和行为的靶向纳米颗粒的结构和性质。此外，我们在这项工作中的目标疾病是乳腺癌，这将与蛋白质封装的阿霉素治疗。虽然阿霉素是一种常规治疗线，但它在患者中表现出剂量依赖性心脏毒性。从这项研究中了解到的信息可以确定纳米颗粒药物递送的一般策略，这些策略仅在癌细胞中增加细胞毒性，同时降低总剂量和严重的副作用。公共卫生关系：多功能蛋白质纳米胶囊的靶向递送在创建一类新的纳米级药物载体时，治疗递送中的新治疗策略的范围将被拓宽。这有可能扩大疾病治疗的疗效，促进再生医学。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protein nanocapsules containing doxorubicin as a pH-responsive delivery system.

DOI：
10.1002/smll.201002242
发表时间：
2011-04-18
期刊：
SMALL
影响因子：
13.3
作者：
Ren, Dongmei;Kratz, Felix;Wang, Szu-Wen
通讯作者：
Wang, Szu-Wen

Biomimetic Design of Protein Nanomaterials for Hydrophobic Molecular Transport.

DOI：
10.1002/adfm.201200052
发表时间：
2012-08-07
期刊：
ADVANCED FUNCTIONAL MATERIALS
影响因子：
19
作者：
Ren, Dongmei;Dalmau, Merce;Randall, Arlo;Shindel, Matthew M.;Baldi, Pierre;Wang, Szu-Wen
通讯作者：
Wang, Szu-Wen

Caged protein nanoparticles for drug delivery.