NIR Light-Activated Nanoparticles for Drug and Gene Delivery

用于药物和基因递送的近红外光激活纳米颗粒

基本信息

批准号：
8225217
负责人：
Joseph Anthony Zasadzinski
金额：
$ 32万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225217
关键词：
Address Antibodies Basic Science Benign Biocompatible Biological Biological Process Bypass Caenorhabditis elegans Caliber Cancer Biology Cell Culture Techniques Cell Line Cells Chemicals Chemistry Combination Drug Therapy Complex Cultured Cells Cytosol DNA Development Drug Controls Drug Delivery Systems Endosomes Epithelial Cells Exposure to Gene Delivery Gene Silencing Genes Genetic Materials Goals Gold Heating Hela Cells Image Label Life Ligands Light Link Lipids Lipofectamine Liposomes Malignant neoplasm of prostate Mammalian Cell Masks Methods MicroRNAs Microbubbles Molecular Mus Oligonucleotides Optics Organism Pattern Pharmaceutical Preparations Physiologic pulse Polymers Property Proteins RNA Interference Resolution Route Rupture Signal Transduction Pathway Silver Site Small Interfering RNA Source Structure Sulfhydryl Compounds Surface Suspension substance Suspensions Techniques Therapeutic Thick Time Tissues Toxic effect Transfection Water Work absorption base cell injury cell type chemical property chemotherapy controlled release design dithiol human embryonic stem cell human stem cells in vivo irradiation lithography millisecond nanomaterials nanoparticle nanorod nanoscale nanoshell novel physical property receptor research study small molecule stem cell differentiation targeted delivery vapor

项目摘要

DESCRIPTION (provided by applicant): Our goal is to develop robust siRNA and micro-RNA methods to regulate genes for basic research, permitting both temporal and spatial control of transfection with high efficiency in both cell culture and C. elegans by using the unique chemical and physical properties of hollow gold nanoshells (HGN). HGNs are 30 - 40 nm diameter, 3-5 nm thick, gold shells designed to strongly absorb physiologically friendly NIR light and convert this light energy into local heating. HGN can be easily conjugated to small molecules, targeting ligands, polymers, siRNA and DNA by simple thiol chemistry, or incorporated into or tethered to liposomes. Water, proteins, lipids, etc. do not absorb NIR light, so cells in culture are essentially transparent, which eliminates damage during exposure. Femtosecond NIR light pulses trigger release of thiol-conjugated siRNA or other molecules from the HGN by breaking thiol bonds without damaging the siRNA. Even more important to the development of efficient oligonucleotide and small molecule delivery, the well-known bottleneck of endosomal escape can be bypassed by converting the physiologically friendly NIR light energy absorbed by the HGN to heat, creating unstable microbubbles that mechanically rupture endosomes and release siRNA to the cytosol within seconds. This allows much lower concentrations of HGN-siRNA conjugates to be used, greatly increases transfection efficiency, and provides spatially and temporally controlled transfection that can be used to pattern cultured cells and address specific structures within C. elegans. HGN transfection is as efficient as Lipofectamine, but is non-toxic, and can be used in living organisms. In this proposal, we will use the HGN-siRNA platform to develop masking and unmasking techniques for activating or inactivating biological processes with remote control to devise simple and scalable methods of lithographic patterning of cultured cells in real time. We will investigate controlled release of small molecules from liposomes incorporating HGN using NIR light triggering to control release, thereby enabling basic cell biological studies, including human stem cell differentiation, cancer biology, and signal transduction pathways and routes to applications in chemotherapy and drug delivery. We will develop methods to multiplex the release from a single HGN using a combination of thiol and dithiol anchors that desorbs at different energies to release of multiple chemical species. New silver nanoshells and gold and silver nanorods will be synthesized to probe other regions of the NIR spectrum and provide simultaneous delivery and imaging opportunities. These new constructs could be addressed independently by using different wavelength NIR irradiation. This project takes full advantage of the unique HGN interactions with physiologically friendly NIR light to initiate and control biological processes with precise spatial control at millisecond rates in living cells and organisms.

描述（由申请人提供）：我们的目标是开发强大的 siRNA 和 micro-RNA 方法来调节基础研究的基因，通过使用独特的化学物质，可以在细胞培养物和秀丽隐杆线虫中高效地进行时间和空间上的转染控制空心金纳米壳（HGN）的物理性质。 HGN 是直径 30 - 40 nm、厚 3-5 nm 的金壳，旨在强烈吸收生理友好的近红外光并将这种光能转化为局部加热。 HGN 可以轻松地与小分子缀合，通过简单的硫醇化学作用靶向配体、聚合物、siRNA 和 DNA，或者掺入或束缚至脂质体。水、蛋白质、脂质等不吸收近红外光，因此培养物中的细胞基本上是透明的，这消除了暴露期间的损伤。飞秒 NIR 光脉冲通过破坏硫醇键，触发硫醇结合的 siRNA 或其他分子从 HGN 中释放，而不损坏 siRNA。对于开发有效的寡核苷酸和小分子递送来说更重要的是，通过将 HGN 吸收的生理友好的近红外光能转化为热量，产生不稳定的微泡，机械地破裂内涵体并释放 siRNA，可以绕过众所周知的内涵体逃逸瓶颈。在几秒钟内到达细胞质。这允许使用低得多的 HGN-siRNA 缀合物浓度，大大提高转染效率，并提供空间和时间控制的转染，可用于模式化培养细胞并解决秀丽隐杆线虫内的特定结构。 HGN 转染与 Lipofectamine 一样有效，但无毒，可用于活体生物体。在本提案中，我们将使用 HGN-siRNA 平台开发用于远程控制激活或失活生物过程的掩蔽和解除掩蔽技术，以设计简单且可扩展的实时培养细胞光刻图案化方法。我们将研究使用近红外光触发控制释放的小分子从掺入 HGN 的脂质体中的受控释放，从而实现基础细胞生物学研究，包括人类干细胞分化、癌症生物学、信号转导途径以及在化疗和药物输送中的应用途径。我们将开发使用硫醇和二硫醇锚的组合来多重释放单个 HGN 的方法，这些锚在不同的能量下解吸以释放多种化学物质。将合成新的银纳米壳以及金和银纳米棒，以探测近红外光谱的其他区域，并提供同时传输和成像的机会。这些新结构可以通过使用不同波长的近红外辐射来独立解决。该项目充分利用独特的 HGN 与生理友好型近红外光的相互作用，在活细胞和生物体中以毫秒速率精确空间控制来启动和控制生物过程。