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

这项由约翰·霍普金斯大学材料研究部生物材料计划颁发的职业奖将支持开发新的战略，将抗癌药物的自组装引导成具有明确结构特征的超分子纳米结构，以提高药物载药量。目前癌症化疗药物的给药方法是使用纳米载体，将其包裹在脂质体或聚合物纳米粒内，或结合到亲水性聚合物上，从而改变药物的药代动力学特性和生物分布。此外，在实现每个载体的高和定量药物载量方面存在固有的困难。这个项目探索了药物分子可以为自组装成各种纳米结构提供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载荷的能力。所制备的纳米结构中的定量药物载量将由分子设计特征的本质来确保。值得注意的是，拟议的药物输送系统不需要任何额外的载体，缓解了与合成药物载体的长期毒性相关的潜在担忧。由于靶向给药和控制释放是开发有效的肿瘤化疗方法的基础，从拟议的研究活动中发展出来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K-12学生来说，提供药物递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，可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出能够以更高剂量将这些药物专门输送到肿瘤部位的方法。一个成功的交付战略有望通过减少副作用和更大的治疗效果而带来巨大的好处。因此，几十年来，用于将疏水性抗癌药物有效输送到肿瘤部位的纳米载体的创建在癌症化学研究中得到了合理的关注。然而，这一策略的一个根本限制是难以实现每个载体的高和定量的药物载量。此外，除了药物外，对合成纳米材料载体的短期和长期毒性的担忧往往导致详尽的临床前评估，这是药物转化为临床使用的困难障碍。拟议的工作旨在通过开发由抗癌药物本身制成的载体来应对这些挑战。这种药物纳米结构将含有特定的药物成分，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外展提供了充足的机会。拟议的教育计划预计将对参与计划的学生的兴趣和STEM职业生涯产生重大影响。该计划旨在教育和提供实践研究经验，旨在提高高中生和本科生对攻读高等教育和STEM博士学位的兴趣。这些经历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问题解决和团队合作的项目，如拟议的工程创新计划，增强他们对能力的信心。

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.