Nanostructured Interfaces for Targeted Drug Delivery

用于靶向药物输送的纳米结构界面

• 批准号: 0553682
• 负责人: Efrosini Kokkoli
• 金额: $ 5万
• 依托单位: University of Minnesota-Twin Cities
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0553682&HistoricalAwards=false
• 关键词: Nanostructured; Interfaces; Targeted; Drug; Delivery

ABSTRACTProject Summary: Nanostructured Interfaces for Targeted Drug DeliveryIntellectual Merit of the Proposed ActivityCurrently, the main problems associated with systemic drug administration are the necessity of a large drug dose to achieve high local concentration, non-specific toxicity, and other adverse side-effects due to high drug doses. Targeted drug delivery can bring a solution to all these problems. With the emergence of stealth liposomes (liposomes covered with polyethylene glycol), the use of liposomes as drug delivery vehicles has received a new impetus, and several successes have been reported. In order to further improve upon different therapies, clinically active stealth liposomes need to include site-directed ligands to enhance their specificity for the pathological site. Peptides that recognize specific cell types or specific macromolecules on the cell surface can serve as targeting agents. The project focuses on engineering peptide-amphiphiles, and designing nanostructured interfaces that specifically target fractalkine, a novel adhesion molecule on the surface of endothelial cells that is expressed only at sites of infection or inflammation. The hypothesis of this research is that fractalkine can serve as a specific target moiety for drug delivery targeting. The PIs group is the first one that is engineering fractalkine-targeted drug delivery systems. The proposed approach will utilize fractalkine as of the N-terminus of the fractalkine receptor (NTFRpeptide-amphiphile), as the bullet. Preliminary work in the PIs lab has demonstrated that liposomes functionalized with the NTFR bind preferentially to inflamed human umbilical vein endothelial cells (HUVECs) in a concentration dependant manner. In addition, targeting of liposomes to inflamed HUVECs over healthy HUVECs is significantly increased when two adhesion receptors are employed, and the interface of the liposome is functionalized with NTFR that binds to fractalkine, and a second peptide-amphiphile that binds to 5 1 integrin. This one year project will engineer different formulations of fractalkine-targeted stealth liposomes, with nanostructured interfaces composed of peptide-amphiphiles that bind to the target(s), and polyethylene glycol of varying density and molecular weight. The designs will be evaluated in vitro in terms of binding, specificity, and internalization efficiency.Broader Impacts of the Proposed ResearchFractalkine has been detected in a variety of diseases such as: cardiac allograft rejection; prostate, lung, and colorectal cancer; pulmonary arterial hypertension; AIDS; atherosclerotic coronary artery disease, the leading cause of death in the USA; rheumatoid arthritis; and other inflammatory conditions. Therefore, the selection of fractalkine as a target for drug delivery is of great therapeutic value. This project will be the seed for future interdisciplinary research at the interface of synthetic chemistry, biology, nanotechnology, and engineering, with applications such as targeted drug delivery, and biosensors.

摘要项目总结：纳米结构界面用于靶向药物递送目前，与全身给药相关的主要问题是需要大剂量药物以达到高局部浓度、非特异性毒性以及由于高剂量药物引起的其他不良副作用。靶向给药可以解决所有这些问题。随着隐形脂质体（用聚乙二醇覆盖的脂质体）的出现，脂质体作为药物递送载体的使用获得了新的动力，并且已经报道了几项成功。为了进一步改进不同的治疗方法，临床活性隐形脂质体需要包括定点配体以增强其对病理部位的特异性。识别细胞表面上的特定细胞类型或特定大分子的肽可以用作靶向剂。 该项目的重点是工程肽两亲物，并设计专门针对fractalkine的纳米结构界面，fractalkine是一种仅在感染或炎症部位表达的内皮细胞表面上的新型粘附分子。本研究的假设是，fractalkine可以作为药物递送靶向的特异性靶向部分。PI小组是第一个设计fractalkine靶向药物递送系统的小组。所提出的方法将利用fractalkine作为fractalkine受体（NTFR肽-两亲物）的N-末端作为子弹。PI实验室的初步工作已经证明，用NTFR功能化的脂质体以浓度依赖性方式优先结合发炎的人脐静脉内皮细胞（HUVEC）。此外，当使用两种粘附受体时，脂质体对发炎的HUVEC的靶向相对于健康的HUVEC显著增加，并且脂质体的界面用与fractalkine结合的NTFR和与β 1整联蛋白结合的第二肽-两亲物官能化。这个为期一年的项目将设计不同配方的fractalkine靶向隐形脂质体，其纳米结构界面由结合到目标的肽-两亲物和不同密度和分子量的聚乙二醇组成。这些设计将在体外结合、特异性和内化效率方面进行评估。拟议研究的更广泛影响Fractalkine已在多种疾病中被检测到，如：心脏同种异体移植排斥;前列腺癌、肺癌和结直肠癌;肺动脉高压;艾滋病;动脉粥样硬化性冠状动脉疾病，美国的主要死因;类风湿性关节炎;和其他炎症性疾病。因此，选择fractalkine作为药物递送的靶点具有重要的治疗价值。该项目将是未来跨学科研究的种子，在合成化学，生物学，纳米技术和工程的接口，如靶向药物输送和生物传感器的应用。