Rational design of soft nanoparticles for non-invasive drug delivery

用于非侵入性药物输送的软纳米颗粒的合理设计

• 批准号: RGPIN-2014-06706
• 负责人: Foldvari, Marianna
• 金额: $ 1.82万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=612374
• 关键词: Rational; design; soft; nanoparticles; non

Gene therapy, the targeted insertion of DNA coding for a therapeutic gene into the nuclei of diseased cells or tissues followed by its expression, is one of the most promising new therapies for a host of diseases and conditions. The first gene therapy product, Gendicine (adenoviral vector-based) was approved in China in 2003 for head and neck cancer. On July 24, 2012 the European Medicines Agency approved the adeno-associated viral (AAV) gene therapy, Glybera by uniQure, for lipoprotein lipase deficiency, an orphan disease. uniQure is also developing the use of a GDNF (glial cell derived neurotrophic factor) gene in their AAV-2 delivery vector for the treatment of Parkinson’s disease. Currently >1300 gene therapy clinical trials are in progress (www.clinicaltrials.gov). In spite of the tremendous progress, a number of challenges remain in realizing the full benefit of this treatment mode. In particular, to achieve the full benefit of gene therapy, it is necessary to develop gene delivery vectors with targeting ability, high transfection efficiency and improved safety. Currently, viruses are the most efficient vectors for DNA delivery, but their use has many disadvantages: high immunogenicity and toxicity, limitations in the size of DNA sequences that can be encapsulated, and potential for mutagenesis. Novel non-viral delivery systems do not present these disadvantages and offer tremendous promise for gene therapy. However, non-viral systems are not yet effective and specific enough for clinical applications. Improvements in both the structure and function of these systems are required. Moreover, in applications where the target site is an externally accessible organ/tissue, such as the eye, skin, nasal/vaginal/oral mucosa, a non-invasive approach to gene therapy, such as topical and oral administration, is highly desirable but not presently feasible due to the lack of effective delivery systems. The research program will focus on both the fundamental and applied aspects of delivery system design for nucleic acids, with specific focus on plasmid DNA and siRNA. In the process of developing new, more advanced non-viral technologies to deliver and target genes and siRNA in the body, the cellular and subcellular pathways of interaction must be fully understood. Induction of the correct and specific therapeutic responses is dependent upon the ‘intelligence’ of the delivery system to arrive to the intended target sites and be activated there. During the design of these systems, visualization of the interaction process and the quantification of the delivery efficiency are required. Nucleic acid-based therapeutic agents are especially difficult molecules to deliver successfully. This is one of the reasons why there is currently only one way administer these compounds: by injection. Development of non-invasive delivery systems that can transport drugs through the skin, cornea, nasal and vaginal mucosa after topical administration could provide an approach to target gene therapies locally and painlessly. In addition, the localized approach could overcome problems related to drug stability during oral and parenteral dosing and absorption, local toxicity and irritation from injection, and multiple dosing because of short drug half-lives. Nanotechnological approaches provide significant potential in the design and development of topical non-invasive delivery and targeting systems for nucleic acids. We propose developing non-invasive drug delivery systems based on composite nanoparticles using self-assembling and targetable biomaterials, including phospholipids, gemini surfactants, acylated amino acids and carbon nanotubes.

基因治疗是将编码治疗性基因的DNA定向插入疾病细胞或组织的细胞核中，然后进行表达，是治疗一系列疾病和疾病的最有前途的新疗法之一。第一个基因治疗产品Gendicine(以腺病毒载体为基础)于2003年在中国获得批准，用于治疗头颈癌。2012年7月24日，欧洲药品管理局批准了腺相关病毒(AAV)基因疗法Glybera by uniQure，用于治疗脂蛋白脂肪酶缺乏症，这是一种孤儿疾病。UnQure还在开发在他们的AAV-2递送载体中使用GDNF(胶质细胞衍生神经营养因子)基因来治疗帕金森氏症。目前，&gt；1300项基因治疗临床试验正在进行中(www.Clinicaltrials.gov)。 尽管取得了巨大的进步，但在实现这种治疗模式的全部好处方面仍然存在一些挑战。尤其是为了实现基因治疗的全部效益，有必要开发具有靶向性、高转染率和更高安全性的基因递送载体。目前，病毒是最有效的DNA载体，但它们的使用有许多缺点：高免疫原性和毒性，可被包裹的DNA序列大小的限制，以及潜在的突变。新的非病毒递送系统不存在这些缺点，并为基因治疗提供了巨大的希望。然而，非病毒系统还不够有效和足够具体的临床应用。这些系统的结构和功能都需要改进。此外，在靶点是外部可接触的器官/组织的应用中，如眼睛、皮肤、鼻/阴道/口腔粘膜，非侵入性的基因治疗方法，如局部和口服给药，是非常可取的，但由于缺乏有效的递送系统，目前还不可行。 该研究计划将重点放在核酸递送系统设计的基本和应用方面，特别是质粒DNA和siRNA。在开发新的、更先进的非病毒技术来传递和靶向体内的基因和siRNA的过程中，必须充分了解细胞和亚细胞相互作用的途径。正确和特定的治疗反应的诱导依赖于传递系统到达预定靶点并在那里被激活的“智能”。 在这些系统的设计过程中，需要可视化的交互过程和交付效率的量化。以核酸为基础的治疗剂是特别难成功输送的分子。这就是为什么目前只有一种方法给这些化合物的原因之一：注射。开发非侵入性的给药系统，可以在局部给药后通过皮肤、角膜、鼻腔和阴道粘膜输送药物，可以为局部和无痛的靶向基因治疗提供一种方法。此外，这种局部给药方法可以克服口服和静脉给药和吸收过程中的药物稳定性、注射的局部毒性和刺激性以及由于药物半衰期短而多次给药的问题。纳米技术方法在设计和开发局部非侵入性核酸递送和靶向系统方面提供了巨大的潜力。我们建议利用自组装和靶向生物材料，包括磷脂、双子表面活性剂、酰化氨基酸和碳纳米管，开发基于复合纳米颗粒的非侵入性给药系统。