Biocompatible Metal (Core)-Layered Double Hydroxide (Shell) Nanoparticles for siRNA Delivery

用于 siRNA 递送的生物相容性金属（核）层状双氢氧化物（壳）纳米粒子

• 批准号: 0829128
• 负责人: Kaushal Rege
• 金额: $ 24万
• 依托单位: Arizona State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0829128&HistoricalAwards=false
• 关键词: Biocompatible; Metal; Core; Layered; Double

CBET-0829128K. Rege, Arizona State UniversityThe overall objective of this collaborative research is the engineering and mechanistic understanding of biocompatible core (gold nanorod)-shell (layered-double hydroxide or LDH) based nanoparticles for selective delivery of siRNA with an eye towards enhancing hyperthermia treatments. Specific segments in the proposed nanoparticle are dedicated to (1) hyperthermic ablation and (2) carrying siRNA for inhibiting heat shock protein response to hyperthermia. The proposed research, therefore, employs bottom-up nanoscale engineering for direct impact in biomedical problems.LDH structures are a class of inorganic ceramic materials with the general formula M2+1(1-x)M3+(OH)2.(An-)x/n.mH2O, where M2+ is a divalent cation, M3+ is a trivalent cation, and An- is the interlayer anion of valence n. The unique LDH structure readily allows the intercalation of anionic molecules (e.g. siRNA) via ion exchange; varying the ratios of metal ions results in the tunable loading of siRNA in these nanoparticles. Nanoscale LDH shells may be generated using physiologically necessary metals (e.g. iron and zinc), thus obviating toxicity-related concerns. Furthermore, the disintegration of the LDH shell at late endosomal / lysozomal (acidic) pH results in an environmentally-responsive platform. The primary objectives are: (1) synthesis and characterization of gold nanorod-LDH nanoparticles with narrow size distribution profiles, (2) generation of siRNA-loaded core-shell nanoparticles, and (3) in-vitro evaluation of siRNA delivery and combination treatment using core-shell nanostructures. Simultaneous siRNA delivery and hyperthermic ablation on a single nanoparticle are unique attributes of the proposed platform, and can significantly enhance therapeutic efficacies for the ablation of cancer cells. Successful completion of the proposed research will result in a platform that can be extended to diverse biomedical applications.The proposed research, at the interface of nanotechnology and biomedical sciences, synergistically combines principles from nanoparticle synthesis, hyperthermia, surface chemistry, biomolecular adsorption, and cell biology, and is intended to have a direct impact on biomedical sciences in the near future. Graduate students will be trained in the application of nanotechnology in the biomedical sciences resulting in well rounded, interdisciplinary training in engineering and biomedical sciences. The educational thrust is also on the recruitment of underrepresented populations and women in graduate studies in engineering as exemplified by the graduate students currently in our respective research groups. In addition, the PI has recently initiated collaboration with Down-to-Earth Science (DES), an NSF-funded GK-12 project at Arizona State University (http://gk12.asu.edu). The PI and Co-PI, and the graduate students will partner with the director, staff, and graduate students of the DES program in bringing the biomedical benefits of nanotechnology into K-12 classrooms through lectures and web-based education tools. The proposed research will also have a significant impact on undergraduate education with a particular emphasis on the biomedical benefits of nanotechnology. Six undergraduate students, including four from the Barrett Honors College, in the PI's laboratory and two undergraduate students in the co-PI's laboratory at ASU exemplify our commitment to encouraging talented students to pursue research opportunities and graduate studies in engineering. All undergraduate students in the PI?s laboratory are recipients of the Fulton Undergraduate Research Initiative (FURI) award from the Ira A. Fulton School of Engineering at ASU which is a unique program that encourages undergraduate research in engineering.

CBET-0829128K。Rege，亚利桑那州立大学这项合作研究的总体目标是对生物相容性核（金纳米棒）-壳（层状双氢氧化物或LDH）纳米颗粒的工程和机械理解，用于选择性递送siRNA，着眼于增强热疗治疗。所提出的纳米颗粒中的特定片段致力于（1）热消融和（2）携带siRNA以抑制热休克蛋白对热疗的反应。LDH结构是一类无机陶瓷材料，分子式为M2+1（1-x）M3+（OH）2。（An-）x/n·mH 2 O，其中M2+为二价阳离子，M3+为三价阳离子，An-为n价层间阴离子。独特的LDH结构容易允许阴离子分子（例如siRNA）通过离子交换嵌入;改变金属离子的比例导致siRNA在这些纳米颗粒中的可调负载。纳米级LDH壳可以使用生理上必需的金属（例如铁和锌）产生，从而避免毒性相关的问题。此外，LDH壳在晚期内体/溶酶体（酸性）pH下的崩解导致环境响应性平台。主要目标是：（1）具有窄尺寸分布特征的金纳米棒-LDH纳米颗粒的合成和表征，（2）负载siRNA的核-壳纳米颗粒的产生，和（3）使用核-壳纳米结构的siRNA递送和组合治疗的体外评价。在单个纳米颗粒上同时进行siRNA递送和热消融是所提出的平台的独特属性，并且可以显著增强消融癌细胞的治疗功效。成功完成拟议的研究将导致一个平台，可以扩展到不同的生物医学应用。拟议的研究，在纳米技术和生物医学科学的接口，协同结合纳米粒子合成，热疗，表面化学，生物分子吸附和细胞生物学的原则，并打算在不久的将来对生物医学科学产生直接影响。研究生将接受纳米技术在生物医学科学中的应用培训，从而在工程和生物医学科学方面进行全面的跨学科培训。教育重点也是招收代表性不足的人口和妇女参加工程学研究生学习，我们各自研究小组目前的研究生就是一个例子。此外，PI最近开始与“脚踏实地的科学”（DES）合作，这是美国国家科学基金会资助的亚利桑那州立大学的GK-12项目（http：gk12.asu.edu）。PI和Co-PI以及研究生将与DES计划的主任，工作人员和研究生合作，通过讲座和基于网络的教育工具将纳米技术的生物医学益处带入K-12教室。拟议的研究也将对本科教育产生重大影响，特别强调纳米技术的生物医学效益。六名本科生，包括四名来自巴雷特荣誉学院，在PI的实验室和两名本科生在共同PI的实验室在亚利桑那州立大学的承诺，鼓励有才华的学生追求研究机会和研究生学习工程。所有PI的本科生？的实验室是富尔顿大学本科生研究计划（FURI）奖的获得者。亚利桑那州立大学富尔顿工程学院，这是一个独特的项目，鼓励本科生在工程研究。