Multifunctional pH-Sensitive Biodegradable Brush Polymer-Drug Conjugates

该奖项授予布法罗的纽约州立大学，由材料研究部的生物材料项目和化学部的大分子、超分子和纳米化学项目共同资助。该项目旨在开发可生物降解的刷状聚合物-药物缀合物（BPDC），其具有高载药量、pH敏感的缀合键、成像功能和靶向配体，用于临床治疗疾病，包括癌症。使用生物可降解支架的药物递送以实现高治疗功效和最小副作用已经吸引了显著的兴趣。 相对于药物包封系统，聚合物-药物缀合物可以导致药物持续释放而没有突释效应。 线性、轻度支化和树枝状聚合物已被用作聚合物-药物缀合物。 然而，聚合物-药物偶联物的相对较低的最佳载药量仍然是其生物医学应用的瓶颈。 在这个项目中，提出了BPDCs用于癌症治疗的全面研究。 这些BPDC的结构设计是通过pH敏感性连接将抗癌药物与可生物降解的聚丙交酯主链缀合，并用许多亲水性聚（乙二醇）链修饰主链。 设计这些新型BPDC的基本原理是：（1）最佳的药物负载和高的最大耐受剂量，因为药物部分在BPDC的核心结构域处被良好地屏蔽;（2）具有密集PEG接枝的纳米结构，它们可以通过被动肿瘤靶向而具有延长的循环半衰期、改善的抗肿瘤功效和降低的全身毒性;（3）骨架降解后，可通过肾清除作用从生物系统中完全清除。这些BPDC将通过点击化学通过“接枝”策略制备，并通过接枝末端反应与成像造影剂和靶向配体进一步官能化以增强其生物医学功能。将对BPDC进行表征、性质研究和生物医学评估，以了解其结构依赖性性质和治疗活性。研究结果不仅为聚合物-药物偶联物的设计提供了指导，而且对多功能药物传递系统的结构-功能原理产生了新的见解。基于生物可降解聚合物、敏感连接和点击化学的合成策略可以进一步用于创建各种环境响应性生物可降解材料。不同层次的学生，包括来自科学和工程专业代表性不足的群体的学生，将在这个跨学科的研究项目中接受培训。该项目的成果还将加强几门研究生和本科生课程。通过网上视频教育活动，广泛宣传PI的研究活动。药物传递领域的研究对不同疾病的治疗具有重要意义。该研究的成功将有助于建立新型的可生物降解的刷状聚合物-药物偶联物作为具有优异和综合生物医学性能的药物递送系统。具体而言，本项目的研究结果可为多功能刷状聚合物-药物缀合物治疗癌症的广泛体内研究和临床转化提供坚实的基础。 由于癌症是美国和世界上人类死亡的主要原因，该项目可能有助于改善国家和全球健康。该项目将为不同的学生提供一个很好的跨学科研究机会，以及来自代表性不足群体的学生的研究参与。 将开展基于视频的在线教育活动，通过YouTube和其他网站广泛传播该研究项目的各个方面。

This award to State University of New York at Buffalo is cofunded by the Biomaterials program in the Division of Materials Research and the Macromolecular, Supramolecular and Nanochemistry program in the Chemistry Division. This project is to develop biodegradable brush polymer-drug conjugates (BPDCs) that have high drug loading capacities, pH-sensitive conjugation linkages, imaging functionalities and targeting ligands for potential applications in clinical treatment of diseases, including cancer. Drug delivery using biodegradable scaffolds to achieve high therapeutic efficacy with minimal side effects has attracted significant interest. Relative to drug encapsulation systems, polymer-drug conjugates can lead to sustained drug release without burst effect. Linear, lightly branched and dendritic polymers have been used as polymer-drug conjugates. However, relatively low optimal drug loading of polymer-drug conjugates remains a bottleneck for their biomedical applications. In this project, comprehensive studies of BPDCs for cancer therapy are proposed. The structural design of these BPDCs is to conjugate anticancer drugs with biodegradable polylactide backbone via pH-sensitive linkages and to modify the backbone with numerous hydrophilic poly(ethylene glycol) chains. The rationales for the design of these novel BPDCs are: (1) optimal drug loadings and high maximum tolerance doses because drug moieties are well-shielded at core domains of BPDCs; (2) with densely PEG-grafted nanostructures, they may have prolonged circulating half-time, improved antitumor efficacy and reduced systemic toxicity through passive tumor targeting; and (3) the polymer scaffolds can be completely removed from biological system by renal clearance after backbone degradation. These BPDCs will be prepared via click chemistries through "grafting-onto" strategy, and further functionalized with imaging contrast agents and targeting ligands through graft-end reactions to enhance their biomedical functions. Characterization, property study, and biomedical assessment of the BPDCs will be conducted to understand their structure-dependent properties and therapeutic activities. The research findings would not only provide a guideline for designing polymer-drug conjugates, but also generate new insights on the structure-function principles of multifunctional drug delivery systems. The synthetic strategy based on biodegradable polymer, sensitive linkage, and click chemistries used in this project may be further employed to create a broad variety of environmentally responsive biodegradable materials. Students at different levels, including these from underrepresented groups in science and engineering professions, will be trained in this interdisciplinary research project. The outcome of this project will also enhance several graduate and undergraduate courses. Video-based online educational activities will be conducted to broadly disseminate the PIs research activities.The research in drug delivery field has tremendous importance for the treatment of different diseases. The success of the proposed research may help to establish biodegradable novel brush polymer-drug conjugates as drug delivery systems with excellent and comprehensive biomedical properties. Specifically, the research results of this project may provide a solid basis for extensive in vivo study and clinical translation of the multifunctional brush polymer-drug conjugates in the treatment of cancer. Because cancer is a leading cause of death of human beings in the U.S. and in the world, this project potentially can help to improve the national and global health. The project will provide an excellent interdisciplinary research opportunity for various students, and the research participation of students from underrepresented groups. Video-based online educational activities will be conducted to broadly disseminate different aspects of this research project via YouTube and other websites.