Hydrolysable Zwitterionic-Based Biomaterials for Effective Gene Delivery

该奖项由华盛顿大学材料研究部生物材料项目颁发，旨在开发一种全新的、独立的基因传递平台，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。这种阳离子多氯联苯酯能够将带负电荷的质粒DNA凝聚成小的聚合物-DNA复合物。当阳离子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复合物中释放出来。所得到的两性离子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，低毒性/生物相容性，这些都是单一生物相容性材料中基因传递载体所必需的。这项工作的结果是有效解决基因传递的两个关键问题，即功效和低毒性的新方法。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。他们将接受整合聚合物和生物科学的前沿研究培训。此外，PI小组将积极接待高中学生或教师进行暑期研究和国际交换学生。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。合成的基因递送剂通常不具备所需的功效。毒性也很值得关注。大多数早期解决这些挑战的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种全新的、独立的基因传递平台，该平台基于两性离子聚（羧甜菜碱）聚合物的可水解阳离子前体。期望该集成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。这将为基因传递发展开辟一个新的研究方向。该项目将为研究生和本科生，特别是那些来自代表性不足群体的学生，提供在这个新兴研究领域的研究机会。PI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换学生。

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.