CAREER: Self-Assembly of Anti-Cancer Drugs into Well-Defined Supramolecular Nanostructures

职业：抗癌药物自组装成明确的超分子纳米结构

• 批准号: 1255281
• 负责人: Honggang Cui
• 金额: $ 49.97万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1255281&HistoricalAwards=false
• 关键词: CAREER; Self; Assembly; Anti; Cancer

This Career Award by the Biomaterials Program in the Division of Materials Research to Johns Hopkins University will support the development of new strategies to direct the self-assembly of anticancer drugs into supramolecular nanostructures with well-defined structural features for increased drug loading capacities. Current approaches for the delivery of cancer chemotherapeutics in using nanoscale carriers through encapsulation within liposomes or polymeric nanoparticles, or by conjugation to hydrophilic polymers tend to modify the drug's pharmacokinetic properties and biodistribution. Additionally, there are inherent difficulties in achieving a high and quantitative drug loading per carrier. This project explores the potential molecular interactions that drug molecules can offer for self-assembly into a variety of nanostructures, and seeks to understand how these supramolecular nanostructures affect the ability of the system to release their therapeutic payloads. The quantitative drug loading in the prepared nanostructures would be ensured by the very nature of themolecular design features. Notably, the proposed drug delivery system does not require any additional carriers, easing potential concerns associated with the long term toxicity of synthetic drug carriers. Since targeted drug delivery and controlled release are the foundations in the development of effective chemotherapies for tumor treatments, the fundamental knowledge developed from the proposed research activities will open new avenues for cancer chemotherapies. The proposed education plan aims to promote training, learning, and teaching of students at all levels, and broadening the participation of students from underrepresented groups in the Baltimore City Public School system. For K-12 students in particular, the provision of an experiential learning opportunity in drug delivery research would spark their interest in science, and helps in creating the next generation of young scientists.Chemotherapy is currently the most effective method available for the treatment of metastatic cancers, producing the highest survival and cure rates. The toxicity of anticancer drugs to healthy cells, however, requires the development of methodologies that can deliver these drugs exclusively to the tumor sites at higher doses. A successful delivery strategy promises immense benefits through both the reduction of side-effects and a greater treatment efficacy. Accordingly, the creation of nano-sized vehicles for the effective delivery of hydrophobic anticancer drugs to tumor sites has garnered justifiable attention in cancer chemotherapy research for several decades. A fundamental limitation of this strategy, however, is the difficulty in achieving a high and quantitative drug loading content per carrier. Also, concerns regarding the short-term and long-term toxicities of the synthetic nanomaterial carriers other than the drugs to be delivered often lead to exhaustive preclinical evaluation, representing a difficult hurdle for the drug's translation into clinical use.The proposed work aims to address these challenges though the development of delivery vehicles made of anticancer drugs themselves. Such drug nanostructures would contain a specific drug content, and do not require the use of additional drug carriers.The multidisciplinary nature of drug delivery research provides ample opportunities for education and outreach.The proposed educational plan is expected to have a significant impact on the interests and STEM careers of participating students. With programs designed to educate and provide hands-on research experience, the plan aims to increase interest in the pursuit of higher education and doctoral studies of STEM for high school and undergraduate students respectively. These experiences will reinforce their interests in the various science related disciplines and boost confidence in their abilities through programs that focus on creative problem solving and teamwork, such as the proposed Engineering Innovation initiative.

约翰·霍普金斯大学材料研究部生物材料项目颁发的这一职业奖将支持开发新策略，将抗癌药物自组装成具有明确结构特征的超分子纳米结构，以提高载药能力。目前使用纳米级载体通过脂质体或聚合物纳米粒子封装或通过与亲水性聚合物缀合来递送癌症化疗药物的方法往往会改变药物的药代动力学特性和生物分布。此外，实现每个载体的高定量载药量存在固有的困难。该项目探索了药物分子可自组装成各种纳米结构的潜在分子相互作用，并试图了解这些超分子纳米结构如何影响系统释放其治疗有效负载的能力。分子设计特征的本质将确保所制备的纳米结构中的定量载药量。值得注意的是，所提出的药物输送系统不需要任何额外的载体，减轻了与合成药物载体的长期毒性相关的潜在担忧。由于靶向药物递送和控释是开发有效肿瘤治疗化疗的基础，因此从拟议的研究活动中开发的基础知识将为癌症化疗开辟新的途径。拟议的教育计划旨在促进各级学生的培训、学习和教学，并扩大巴尔的摩市公立学校系统中代表性不足群体的学生的参与。特别是对于 K-12 学生来说，提供药物输送研究的体验式学习机会将激发他们对科学的兴趣，并有助于培养下一代年轻科学家。化疗是目前治疗转移性癌症最有效的方法癌症，产生最高的存活率和治愈率。然而，抗癌药物对健康细胞的毒性需要开发能够以更高剂量将这些药物专门递送到肿瘤部位的方法。成功的给药策略可以通过减少副作用和提高治疗效果带来巨大的好处。因此，几十年来，用于将疏水性抗癌药物有效递送至肿瘤部位的纳米尺寸载体的创建在癌症化疗研究中引起了合理的关注。然而，该策略的一个根本限制是难以实现每个载体的高定量载药量。此外，对合成纳米材料载体（而不是要输送的药物）的短期和长期毒性的担忧常常导致详尽的临床前评估，这为药物转化为临床应用带来了困难。拟议的工作旨在解决这些挑战是通过开发由抗癌药物本身制成的运载工具来实现的。这种药物纳米结构将包含特定的药物含量，并且不需要使用额外的药物载体。药物输送研究的多学科性质为教育和推广提供了充足的机会。所提出的教育计划预计将对利益产生重大影响以及参与学生的 STEM 职业。该计划旨在通过旨在教育和提供实践研究经验的项目，旨在提高高中生和本科生分别接受 STEM 高等教育和博士研究的兴趣。这些经验将增强他们对各种科学相关学科的兴趣，并通过专注于创造性解决问题和团队合作的项目（例如拟议的工程创新计划）增强对自己能力的信心。

项目成果

Utilizing the Hofmeister Effect to Induce Hydrogelation of Nonionic Supramolecular Polymers into a Therapeutic Depot

利用霍夫迈斯特效应诱导非离子超分子聚合物水凝胶化形成治疗库

• DOI: 10.1002/anie.202306652
• 发表时间: 2023-09
• 期刊: Angewandte Chemie International Edition
• 作者: Wang, Han;Su, Hao;Xu, Tian;Cui, Honggang
• 通讯作者: Cui, Honggang