Hydrolysable Zwitterionic-Based Biomaterials for Effective Gene Delivery

该奖项由华盛顿大学材料研究部的生物材料项目授予，旨在开发一种全新的独立基因递送平台，该平台基于两性离子聚（羧基甜菜碱）（pCB）聚合物的可水解阳离子前体。这种阳离子pCB酯能够将带负电荷的质粒DNA缩合成小的聚合物-DNA复合物。在阳离子pCB酯水解成两性离子pCB时，带负电荷的DNA有效地从聚合物-DNA复合物中释放。所得两性离子pCB是无毒的。该平台结合了所有功能，包括有效的包装/拆包，特异性靶向和低毒性/生物相容性，这些都是基因递送载体在单一生物相容性材料中所必需的。这项工作的成果是一种新的方法，有效地解决基因递送中的两个关键问题，即，疗效好、毒性低。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的群体。他们将接受整合聚合物和生物科学的尖端研究培训。此外，研究小组也将积极接待高中生或教师参加暑期研究和国际交换生。人类基因治疗发展的一个关键限制是缺乏安全有效的基因传递系统。合成基因递送剂通常不具有所需的功效。毒性也是一个很大的问题。解决这些挑战的大多数早期方法往往导致复杂的多材料系统。这项工作的目的是开发一个全新的，独立的基因传递平台的基础上水解阳离子前体的两性离子聚（羧基甜菜碱）聚合物。预期该整合平台能够实现高基因转染效率、高血液稳定性、靶向递送和低毒性。它将为基因输送发展开辟新的研究方向。该项目将为研究生和本科生，特别是那些来自代表性不足的群体，在这个新兴的研究领域的研究机会。PI的小组还将积极接待高中学生和教师进行暑期研究和国际交流学生。

This award by the Biomaterials program in the Division of Materials Research to University of Washington is to develop a completely novel, stand-alone gene delivery platform based on hydrolysable cationic precursors to zwitterionic poly(carboxybetaine) (pCB) polymers. This cationic pCB ester is able to condense negatively charged plasmid DNA into small polymer-DNA complexes. Upon the hydrolysis of cationic pCB ester into zwitterionic pCB, negatively charged DNA is effectively released from polymer-DNA complexes. The resulting zwitterionic pCB is nontoxic. This platform combines all of the features, including effective packaging/ unpackaging, specific targeting, and low toxicity/biocompatibility that are necessary in a gene delivery vehicle in a single biocompatible material. The outcome of this work is a new approach to effectively address two critical issues in gene delivery, i.e., efficacy and low toxicity. Graduate and undergraduate students will be involved in this project, particularly those from underrepresented groups. They will be trained in cutting-edge research integrating polymer and biological sciences. In addition, the PI's group will actively host high school students or teachers for summer research and international exchange students.A key limitation in the development of human gene therapy is the lack of a safe and efficient gene delivery system. Synthetic gene-delivery agents generally do not possess the required efficacy. Toxicity is also of great concern. Most of the earlier approaches to address these challenges often lead to complex multi-material systems. The objective of this work is to develop a completely novel, stand-alone gene delivery platform based on hydrolysable cationic precursors to zwitterionic poly(carboxybetaine) polymers. It is expected that this integrated platform is capable of achieving high gene transfection efficiency, high blood stability, targeted delivery, and low toxicity. It will open up a new research direction in the gene delivery development. This project will provide graduate and undergraduate students, particularly those from underrepresented groups, with research opportunities in this emerging research field. The PI's group will also actively host high school students and teachers for summer research and international exchange students.