Responsive Drug-Polymer Conjugate

该奖项由伊利诺伊大学材料研究部生物材料项目颁发，旨在开发新一代聚合物-药物偶联物，该偶联物可以精确控制聚合物-药物的组成、结构、药物装载和释放。传统的聚合物-药物偶联物具有共同的特征，如预先合成的水溶性聚合物与药物分子通过切割连接剂共价偶联到垂坠的可偶联基团上。这种聚合物-药物偶联设计的一个主要缺点是缺乏对化学结构和组成的控制，特别是对用于药物偶联的垂坠基团的控制。所得到的材料本质上是许多结构和组成不同的聚合物-药物偶联物的混合物，每种偶联物都有自己的治疗特征、清除率、分布特性、组织渗透效率等。提出的新一代聚合物-药物偶联物（链破碎聚合物治疗）将导致对聚合物药物组成、结构、药物装载和释放的精确控制。该体系基本上是一种“AB”型嵌段共聚物，由于其氨基甲酸酯和碳酸盐骨架结构，所得到的纳米颗粒在水溶液中是稳定的。然而，一旦应用特定的触发器，触发反应域“a”的保护基团被移除，散链聚合物治疗系统的骨干结构立即变得不稳定，并迅速破碎成单体碎片，导致药物释放。所提出的系统的更广泛的技术影响可能是开发控制良好的药物递送材料，允许触发响应和精确控制体外和体内的药物释放。该系统还将具有类似于药物封装系统的特性，即药物在其原始形式下可以立即释放并表现出治疗效果。参与该项目的学生将接受多学科领域的培训，如有机合成、控制聚合、聚合物药物偶联物的制备和细胞培养。材料研究将在校园内通过不同的外展活动广泛传播。目前广泛应用的基于聚合物的药物传递系统具有一些共同的特点，如预先合成的水溶性聚合物，药物分子通过切割连接剂附着在垂坠基团和可偶联基团上。使用目前的系统，很难克服药物在到达目标之前过早地从输送系统中释放出来的问题。为了克服这些缺点，本研究项目将重点开发易于处理和加工且不会过早释放药物的药物共轭系统（聚合物前药）。此外，这种被称为链破碎聚合物疗法的系统将具有类似于药物封装系统的特性，药物以其原始形式可以立即释放以获得即时治疗效果。当药物递送材料到达目标组织或病变组织后施加触发器时，可以精确控制药物释放的时间、地点和数量，这使得开发个性化的纳米医学方案成为可能。从事这项研究的学生将接受材料研究的不同方面的培训，包括基于聚合物的药物输送系统。拟议的研究将被纳入外联活动，重点关注从本科到K-12不同层次的代表性不足的学生。其他在伊利诺伊大学提出的推广活动包括发现工程夏令营项目和工程开放日项目。

This award by the Biomaterials program in the Division of Materials Research to University of Illinois is to develop a new generation of polymer-drug conjugates that afford precise control over polymer-drug compositions, structure, drug loading and release. Conventional polymer-drug conjugates share the common feature such as a pre-synthesized water-soluble polymer with drug molecules being covalently conjugated to the pendant, conjugation-amenable groups via cleavage linkers. One key drawback of this design of polymer-drug conjugate is the lack of control of the chemical structure and composition, especially the control over pendant groups used for drug conjugation. The resulting material is essentially a mixture of numerous structure- and composition-distinct polymer-drug conjugates that each has its own therapeutic profile, clearance rate, distribution property, tissue penetration efficiency, etc. The proposed new generation of polymer-drug conjugates (chain-shattering polymeric therapeutic) would result in precise control over polymer-drug compositions, structure, drug loading and release. This system is basically an "AB" type of block copolymer, and the resulting nanoparticles are designed to be stable in aqueous solution because of the urethane and carbonate backbone structure. However, once a specific trigger is applied and the protecting groups of trigger-responsive domain "A" are removed, the backbone structure of chain-shattering polymeric therapeutic system becomes instantly unstable and quickly shatters to monomeric fragments resulting in drug release. The technological broader impact of the proposed system could be the development of well controlled drug-delivery materials that allow trigger-responsive and precise control over drug release both in vitro and in vivo. This system also would have the property similar as drug encapsulated systems that drug in its original form can be instantly released and exhibit therapeutic effects. Students working on this project would be trained in multidisciplinary areas such as organic synthesis, carry out controlled polymerization, preparation of polymer-drug conjugates and cell culture. The materials research will be widely disseminated with different outreach activities at the campus.Widely used present polymer based drug delivery systems share common features such as pre-synthesized water-soluble polymer with drug molecules being attached to pendant and conjugation-amenable groups via cleavage linkers. With this current system, it is difficult to overcome the drug being prematurely released from delivery systems prior to reaching their targets. To overcome some of these drawbacks, this research project will focus the development of drug conjugated systems (polymeric pro-drugs) with ease of handling and processability with no premature drug release. This system called chain-shattering polymeric therapeutics, in addition, would have the property similar to drug encapsulated systems with the drug in its original form that can be instantly be released for instant therapeutic effects. When the trigger is applied after the drug delivery materials arrive at the target or diseased tissue, the time, site and amount of drug released can be precisely controlled, which makes it possible to develop a personalized nanomedicine protocol. Students working on this research will be trained in the different aspects of materials research with respect to polymer based drug delivery system. The proposed research will be incorporated into outreach activities focusing underrepresented students at different levels from undergraduate to K-12. Other proposed outreach activities at University of Illinois include Discover Engineering Summer Camp programs and Engineering Open-House Program.