Multifunctional pH-Sensitive Biodegradable Brush Polymer-Drug Conjugates

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.