Dual-Functional Zwitterionic Biomaterials for Targeted Drug Delivery

这项由材料研究部生物材料项目授予华盛顿大学的奖项是为了开发一种基于羧基甜菜碱(CB)的双功能两性离子生物材料，作为聚乙二醇靶向给药的替代品。CB是一种双功能材料，不仅对非特异性蛋白质的吸附有很高的抵抗力，而且还具有丰富的有利于配体固定的官能团。在非污染背景下获得丰富的官能团对于在复杂环境中靶向给药的成功至关重要。丰富的官能团将使人们能够制备含有鸡尾酒药物的结合物以获得更好的药物效率，引入多个官能团进行多步给药，并固定小配体以改善药物给药动力学。此外，羧基甜菜碱是一种对离子强度和pH值变化做出反应的智能材料，这是药物控制释放所需的。由于与蛋白质相似的两性离子性质，炭黑包裹的纳米颗粒(NPs)在生理条件下空间非常稳定。羧基甜菜碱在结构上类似于甘氨酸甜菜碱，因此是仿生的。这项工作的目的是证明炭黑包裹的纳米颗粒作为靶向药物传递载体的独特性(即双功能和两性离子特性)。将50-150 nm的NPS包覆一层炭黑。基于CB的聚合物的链长和密度以及CB单体的两个带电基团之间的碳原子数将是不同的。我们将评估CB包裹的纳米粒子的物理化学性质，生理条件下的空间稳定性，以及它们对血浆中非特异性蛋白质吸附的抵抗力。炭黑包裹的纳米粒子将通过碳二胺化学作用于肿瘤细胞，并评估它们的细胞结合和摄取。不同的配基密度将研究它们对靶向传递的影响。将对这些改性NPs的循环时间进行评估。结果将与有或没有靶向基团的聚乙二醇改性纳米粒的结果进行比较。药物载体靶向特定细胞类型的能力对于有效的药物传递至关重要。虽然聚乙二醇已被广泛用于提高药物载体的有效性，但可用于固定靶向特异性配体的官能团数量非常有限。本文提出的双功能两性离子生物材料非常适合于这一目的。这项工作的成功将为建立更好的药物输送系统开辟新的方向。虽然这项工作中将展示用于药物输送载体的CB基材料，但它们在组织工程、医疗器械涂层和生物医学诊断方面有着非常广泛的应用。研究生和本科生将参与这个项目，特别是那些来自代表性不足群体的学生。本科生研究人员将通过在当地研究中心建立的良好外展计划招募，国际和平研究所一直积极参与其中。此外，这些知识将通过由该协会教授或正在开发的各种课程来传播。拟议的工作还将涉及国际合作。

This award to University of Washington by the Biomaterials program in the Division of Materials Research is to develop a dual-functional zwitterionic biomaterial based on carboxybetaine (CB) as an alternative to poly(ethylene glycol) for targeted drug delivery. CB is a dual-functional material, which is not only highly resistant to nonspecific protein adsorption, but also has abundant functional groups convenient for ligand immobilization. The availability of abundant functional groups in a non-fouling background is essential to the success of targeted drug delivery in complex environments. Abundant functional groups will allow one to prepare conjugates containing cocktail drugs for better drug efficiency, to introduce multiple functional groups for multiple-step drug delivery, and to immobilize small ligands for improved drug delivery kinetics. Furthermore, carboxybetaine is a smart material responsive to changes in ionic strengths and pH values, which are desirable for drug controlled release. Due to a zwitterionic nature similar to proteins, CB-coated nanoparticles (NPs) are sterically very stable under physiological conditions. Carboxybetaine is similar to glycine-betaine in structure and is thus biomimetic. The objective of this work is to demonstrate the uniqueness (i.e., dual-functional and zwitterionic characteristics) of CB-coated nanoparticles as targeted drug delivery carriers. NPs of 50-150nm will be coated with CB. The chain lengths and densities of the CB-based polymer and the number of carbon atoms between the two charged groups of the CB monomer will be varied. CB-coated NPs will be evaluated for their physicochemical properties, their steric stability under physiological conditions, and their resistance to nonspecific protein adsorption from blood plasma. CB-coated NPs will be functionalized with targeting groups for cancer cells via carbodimide chemistry and evaluated for their cell association and uptake. Ligand densities will be varied to study their effects on targeted delivery. The circulation time of these modified NPs will be evaluated. Results will be compared with those from poly(ethylene glycol)-modified NPs with or without the targeting groups. The ability of drug carriers to target specific cell types is critical for effective drug delivery. While PEG has been widely used to improve the efficacy of drug delivery carriers, there are a very limited number of functional groups available to immobilize target-specific ligands. The dual-functional zwitterionic biomaterial proposed in this work is well suited for this purpose. The success of this work will open a new direction to build better drug delivery systems. Although CB-based materials used for drug delivery carriers will be demonstrated in this work, they have a very broad range of applications in tissue engineering, coatings for medical devices, and biomedical diagnostics. Graduate and undergraduate students will be involved in this project, particularly those from underrepresented groups. Undergraduate researchers will be recruited through well-established outreach programs at local research centers, in which the PI has been actively involved. In addition, the knowledge will be disseminated through various courses taught or under development by the PI. The proposed work will also involve international collaborations.