Microfluidic Synthesis of Nanoparticles for Oligonucleotide Delivery

用于寡核苷酸递送的纳米颗粒的微流体合成

• 批准号: 7363104
• 负责人: Robert J Lee
• 金额: $ 15.94万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-20 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7363104
• 关键词: Acute Myelocytic Leukemia; Antineoplastic Agents; Base Pairing; Binding; Biodistribution; Blood Circulation; Cell membrane; Cells; Class; Clinical; Clinical Trials; DNA delivery; Development; Devices; Down-Regulation; Drug Delivery Systems; Drug Kinetics; Environment; Enzymes; Evaluation; Gene Expression; Government; Human; In Vitro; Lead; Lipids; Liquid substance; Malignant - descriptor; Malignant Neoplasms; Messenger RNA; Methods; MicroRNAs; Microfluidics; Modality; Molecular Weight; Oblimersen; Ohio; Oligodeoxyribonucleotides; Oligonucleotides; Oncogenes; Particulate; Permeability; Persons; Pharmaceutical Preparations; Polymers; Problem Solving; Process; Production; Proteins; Purpose; RNA; RNA Sequences; Rate; Reagent; Reporting; Resistance; Single-Stranded DNA; Solutions; Structure; System; Technology; Therapeutic; Tissues; Toxic effect; Translational Repression; Translations; Treatment Efficacy; Tumor Suppressor Genes; Universities; Validation; Vertebral column; base; biomaterial compatibility; cancer cell; cancer therapy; clinical application; concept; design; hydrophilicity; in vivo; innovation; leukemia; melanoma; nanodevice; nanoparticle; nanoscale; novel strategies; particle; pre-clinical; preclinical study; size; success; tumor

DESCRIPTION (provided by applicant): Therapeutic oligonucleotides, in particular, micro RNA (miR), hold great promise to become effective anticancer agents. Their clinical usage is, however, limited by the lack of efficient methods for parenteral administration. Delivery via multi-functional nanoparticles is a potential solution to this problem. However, current nanoparticle manufacturing methods, which are based on bulk mixing of multiple reagents, have had only limited success in pre-clinical and clinical trials. Since bulk mixing is heterogeneous at local environment and consequently leads to the nanoparticles with poorly defined and non-uniform structures and compositions, we hypothesize that efficient and safe delivery can be achieved by tightly controlling the size, structure, and compositions of the synthetic nanoparticles. We therefore propose to employ microfluidic technology, which is capable of precisely controlling the mixing process at the micrometer scale, to the synthesis of multi-functional nanoparticles with uniform and well-defined structures and compositions for the delivery of therapeutic oligonucleotides to cancer cells. Our specific aims are (1) to optimize and validate microfluidic systems for the synthesis of multi-functional polymer and lipid-based nanoparticles containing synthetic miR (e.g., miR29b) and oligodeoxyribonucleotide (e.g., G3139) compounds targeting specific antiapoptotic proteins e.g., Bcl-2 and Mcl- 1, respectively, in melanoma and acute myeloid leukemia cells; and (2) to conduct in vitro and in vivo preclinical studies to characterize delivery efficiency, toxicity, biocompatibility, pharmacokinetics, biodistribution, and therapeutic efficacy of the microfluidic-based nanoparticles. If successful, this could lead to development of a new treatment modality for cancers such as melanoma and leukemia. Project Narrative: Oligonucleotides (especially micro RNA) hold great potential to become a new class of anticancer drugs, but their clinical applications are limited by a lack of efficient delivery methods. We seek to solve this problem by developing nanoscale, multi-functional, particle-like devices capable of delivering oligonucleotide drugs to cancer cells efficiently. The nanodevices will be assembled through a novel approach based on the precise manipulation of liquid flows at micrometer scale.

描述（由申请人提供）：治疗性寡核苷酸，特别是微小RNA（miR），很有希望成为有效的抗癌剂。然而，它们的临床应用受到缺乏有效的胃肠外给药方法的限制。通过多功能纳米颗粒递送是解决这个问题的潜在方案。然而，目前的纳米颗粒制造方法，其基于多种试剂的大量混合，在临床前和临床试验中仅取得有限的成功。由于本体混合在局部环境下是不均匀的，因此导致纳米颗粒具有不明确和不均匀的结构和组成，我们假设可以通过严格控制合成纳米颗粒的尺寸，结构和组成来实现有效和安全的递送。因此，我们建议采用微流控技术，这是能够精确地控制在微米级的混合过程，以合成具有均匀和明确的结构和组合物的多功能纳米粒子的治疗性寡核苷酸递送到癌细胞。我们的具体目标是（1）优化和验证用于合成多功能聚合物和含有合成miR的基于脂质的纳米颗粒（例如，miR 29 b）和寡脱氧核糖核苷酸（例如，G3139）靶向特异性抗凋亡蛋白的化合物，Bcl-2和Mcl- 1分别在黑色素瘤和急性髓性白血病细胞中的作用;以及（2）进行体外和体内临床前研究以表征基于微流体的纳米颗粒的递送效率、毒性、生物相容性、药代动力学、生物分布和治疗功效。如果成功的话，这可能会导致开发一种新的癌症治疗方法，如黑色素瘤和白血病。 项目叙述：寡核苷酸（特别是微小RNA）具有成为一类新型抗癌药物的巨大潜力，但由于缺乏有效的递送方法，其临床应用受到限制。我们试图通过开发能够有效地将寡核苷酸药物递送到癌细胞的纳米级、多功能、颗粒状装置来解决这个问题。纳米器件将通过一种基于在微米尺度上精确操纵液体流动的新方法组装。