Nanostructured Interfaces for Targeted Drug Delivery

目前，与全身给药相关的主要问题是需要大剂量药物来实现高局部浓度、非特异性毒性以及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（聚乙二醇覆盖的脂质体）的出现，脂质体作为药物传递载体的使用得到了新的推动，并有一些成功的报道。为了进一步改进不同的治疗方法，临床活性隐身脂质体需要包含位点定向配体，以增强其对病理部位的特异性。识别特定细胞类型或细胞表面特定大分子的肽可以作为靶向剂。该项目的重点是工程肽-两亲体，并设计纳米结构的界面，专门针对fractalkine，一种在内皮细胞表面仅在感染或炎症部位表达的新型粘附分子。本研究的假设是fractalkine可以作为药物递送靶向的特定靶标片段。PIs团队是第一个设计分形因子靶向药物输送系统的团队。所提出的方法将利用fractalkine作为fractalkine受体（ntfrpeptide - amphiphilile）的n端作为子弹。PIs实验室的初步工作表明，与NTFR功能化的脂质体以浓度依赖的方式优先结合炎症的人脐静脉内皮细胞（HUVECs）。此外，当使用两种粘附受体时，脂质体对炎症HUVECs的靶向性比健康HUVECs显著增加，并且脂质体的界面被与fractalkine结合的NTFR和与51整合素结合的第二肽-两亲体功能化。这个为期一年的项目将设计不同配方的分形因子靶向隐形脂质体，其纳米结构界面由结合靶标的肽-两亲体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。fractalkine已在多种疾病中被检测到，如：心脏同种异体移植排斥反应；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，美国的主要死亡原因；类风湿性关节炎;以及其他炎症状况。因此，选择fractalkine作为给药靶点具有很大的治疗价值。该项目将成为未来合成化学、生物学、纳米技术和工程学交叉学科研究的种子，其应用领域包括靶向药物输送和生物传感器。

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.