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位点特异性药物递送改变了多种疾病的面貌。纳米载体在生物细胞中的定位受其物理和生物化学性质控制。该奖项的目标是设计和制造混合脂质体纳米载体，同时调整其机械和分子特性，以实现高细胞摄取。该项目在大脑模型中证明了这一目标，因为纳米载体通过血脑屏障的运输仍然是一个关键的挑战。此外，这项工作研究了时空控制的药物释放从这些纳米载体使用光，使安全和有针对性的治疗。该研究建立了一种机制，表明药物转运是由新的物理化学性质控制的，允许定制一类新的纳米载体，以研究生物相互作用。这类纳米载体推进了难以治疗的脑部疾病的药物输送。所学到的原则也可以扩展到其他疾病的治疗反应，从而满足国家的医疗保健需求。该项目无缝地将研究与教育结合起来，通过“实验室到教室”的活动，并通过向针对贫困青年的K-12学生分发“彩色胶囊的乐趣”工具包，将这项工作过渡。通过利用已建立和有效的推广计划，这项工作能够为未来的劳动力培养本科生和研究生。治疗性脂质体纳米载体的物理化学行为驱动它们与生物界面的相互作用，并控制细胞内吞作用。然而，应该调整哪些特性以使纳米载体能够有效地通过生物屏障运输仍然是矛盾的。因此，利用纳米载体的未开发性质的方法对于实现时空控制药物递送的范式转变至关重要。该项目的目标是通过自下而上的定向自组装方法设计和制造非常规纳米载体。该研究涉及制造混合脂质体纳米载体（LNC），其在单个制造平台中协同软（脂质体）核和硬（金）壳纳米颗粒的性质，从而实现弹性模量和表面配体的可调节性。研究假设这些特性是相互依赖的，并且当同时调整时，实现细胞和表型特异性靶向和治疗功能，这些功能在体外血脑屏障（BBB）模型中得到证实。此外，LNC用特异性靶向BBB中的细胞的抗体片段功能化。另一个目的是跟踪细胞和神经球中的LNC，并追求配体密度与弹性模量的组合优化，以确定影响细胞特异性靶向的刚度-配体方案。最后，该项目旨在证明LNC的这些特性使有效的光热驱动药物运输通过BBB。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。