Responsive Drug-Polymer Conjugate

响应性药物-聚合物缀合物

• 批准号: 1309525
• 负责人: Jianjun Cheng
• 金额: $ 39万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1309525&HistoricalAwards=false
• 关键词: Responsive; Drug; Polymer; Conjugate

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.

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-药物缀合物，能够精确控制聚合物-药物成分、结构、药物负载和释放。传统的聚合物-药物缀合物具有共同的特征，例如预合成的水溶性聚合物，其药物分子通过裂解连接体共价缀合至易于缀合的侧基。 这种聚合物-药物缀合物设计的一个主要缺点是缺乏对化学结构和组成的控制，尤其是对用于药物缀合的侧基的控制。所得材料本质上是多种结构和成分不同的聚合物药物缀合物的混合物，每种聚合物药物缀合物都有自己的治疗特性、清除率、分布特性、组织渗透效率等。所提出的新一代聚合物药物缀合物（链断裂聚合物治疗剂）将导致对聚合物药物成分、结构、药物负载和释放的精确控制。该系统基本上是“AB”型嵌段共聚物，由于聚氨酯和碳酸酯主链结构，所得纳米粒子被设计为在水溶液中稳定。 然而，一旦施加特定的触发并且触发响应结构域“A”的保护基团被去除，链断裂聚合物治疗系统的主链结构立即变得不稳定并迅速破碎成单体片段，导致药物释放。所提出的系统的技术更广泛的影响可能是开发良好控制的药物递送材料，该材料允许在体外和体内对药物释放进行触发响应和精确控制。该系统还具有与药物封装系统类似的特性，即原始形式的药物可以立即释放并表现出治疗效果。从事该项目的学生将接受多学科领域的培训，例如有机合成、进行受控聚合、聚合物药物缀合物的制备和细胞培养。材料研究将通过校园内的不同外展活动得到广泛传播。目前广泛使用的基于聚合物的药物递送系统具有共同的特征，例如预合成的水溶性聚合物，药物分子通过裂解连接体连接到侧链和适合缀合的基团。使用当前的系统，很难克服药物在到达目标之前从递送系统中过早释放的问题。为了克服其中一些缺点，该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缀合系统（聚合物前药）。此外，这种被称为链断裂聚合物疗法的系统将具有类似于药物封装系统的特性，其中药物以其原始形式可以立即释放以产生即时治疗效果。当药物输送材料到达目标或病变组织后触发，可以精确控制药物释放的时间、部位和量，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有关基于聚合物的药物输送系统的材料研究不同方面的培训。拟议的研究将纳入针对从本科到 K-12 不同级别的代表性不足的学生的外展活动。伊利诺伊大学拟议的其他外展活动包括探索工程夏令营计划和工程开放日计划。