Nanomanufacturing of Hybrid Nanocarriers and Understanding their Physicochemical Properties for Targeted Drug Delivery

混合纳米载体的纳米制造并了解其用于靶向药物输送的理化特性

• 批准号: 2223689
• 负责人: Rizia Bardhan
• 金额: $ 65万
• 依托单位: Iowa State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2223689&HistoricalAwards=false
• 关键词: Nanomanufacturing; Hybrid; Nanocarriers; Understanding; their

Therapeutic nanocarriers have transformed the landscape of multiple diseases by enabling site-specific drug delivery. The localization of nanocarriers in biological cells is controlled by their physical and biochemical properties. The goal of this award is to design and manufacture hybrid liposomal nanocarriers, simultaneously tuning their mechanical and molecular properties to achieve high cellular uptake. This project demonstrates this goal in a brain model since nanocarrier transport through the blood brain barrier remains a critical challenge. Further, this work examines spatiotemporally controlled drug release from these nanocarriers using light to enable safe and targeted therapeutics. The research establishes mechanisms that show drug transport is controlled by novel physicochemical properties allowing the tailoring of a new class of nanocarriers targeted to study biological interactions. This class of nanocarriers advances drug delivery in difficult to treat disorders of the brain. The principles learnt can also be extended to achieve therapeutic response in other diseases, thus meeting national healthcare needs. This project seamlessly integrates research with education to transition this work through ‘lab-bench-to-classroom’ activities and by dissemination of ‘Fun with Color Capsules’ kits to K-12 students targeting underprivileged youths. By leveraging established and effective outreach programs, this work enables training of undergraduate and graduate students for the future workforce.The physicochemical behavior of therapeutic liposomal nanocarriers drives their interaction with biological interfaces and controls endocytosis in cells. Yet which properties should be tuned to enable efficient nanocarrier transport through biological barriers remains paradoxical. Therefore, approaches that leverage unexplored properties of nanocarriers are imperative to enable a paradigm shift in spatiotemporally controlled drug delivery. The goal of this project is to design and manufacture unconventional nanocarriers via bottom-up, directed self-assembly approaches. The research involves fabricating hybrid liposomal nanocarriers (LNCs) that synergize the properties of soft (liposome) core and hard (gold) shell nanoparticles in a single manufacturing platform enabling tunability of the elastic modulus and surface ligands. The research hypothesis is that these properties are mutually dependent, and when simultaneously tuned, achieve cell- and phenotype-specific targeting and therapeutic function demonstrated in an in vitro blood brain barrier (BBB) model. Further, LNCs are functionalized with antibody fragments that specifically target cells in the BBB. Another aim is to track LNCs in both cells and neurospheroids and pursue combinatorial optimization of the ligand density with elastic modulus to determine the stiffness-ligand regime that impacts cell-specific targeting. Finally, the project aims to demonstrate that these properties of LNCs enable effective photothermally actuated drug transport across the BBB.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

治疗性纳米载体通过实现特定部位的药物输送来改变多种疾病的景观。纳米载体在生物细胞中的定位受其物理和生化特性的控制。该奖项的目的是设计和制造混合脂质体纳米载体，只需调整其机械和分子特性即可获得高细胞摄取。该项目在大脑模型中展示了这一目标，因为纳米载体通过血脑屏障的运输仍然是一个至关重要的挑战。此外，该工作检查使用光线从这些纳米载体中释放了空间控制的药物，以实现安全和有针对性的治疗。该研究建立了表明药物运输的机制，该机制受到新颖的物理特性的控制，允许针对研究生物学相互作用的新型纳米载体量身定制。这类纳米载体以难以治疗大脑疾病的药物递送。还可以扩展原则以在其他疾病中实现治疗反应，从而满足国家医疗保健需求。该项目将研究与教育无缝整合，以通过“实验室基础到教室”的活动以及将“与​​彩色胶囊的乐趣”传播到针对针对弱势青年的K-12学生的活动。通过利用建立有效的外展计划，这项工作使本科生和研究生的培训可以培训未来的劳动力。热脂质体纳米载体的身体行为推动了与生物学接口的相互作用，并控制细胞中的内吞作用。然而，应调整哪些特性以实现通过生物屏障的有效纳米载体运输仍然是自相矛盾的。因此，必须利用纳米载体意外特性的方法是必须实现空间控制药物输送的范式转移。该项目的目的是通过自下而上的，定向的自组装方法来设计和制造非常规的纳米载体。该研究涉及在单个制造平台中制造杂化脂质体纳米载体（LNC），以协同软（脂质体）核心和硬壳（金）壳纳米颗粒的性质，从而实现弹性模量和表面配体的可密索性。研究假设是，这些特性是相互依赖的，并且在同时调整时，可以在体外血脑屏障（BBB）模型中表现出细胞和表型特异性靶向和治疗功能。此外，LNC通过特异性靶向BBB中细胞的抗体片段功能化。另一个目的是跟踪细胞和神经圈中的LNC，并使用弹性模量对配体密度进行组合优化，以确定影响细胞特异性靶向的刚度配体状态。最后，该项目旨在证明LNC的这些特性在BBB跨BBB启用了有效的光热激活药物运输。该奖项反映了NSF的法定任务，并通过使用基金会的智力优点和更广泛的影响评估标准，认为通过评估通过评估而被视为珍贵的支持。