Multifunctional Biodegradable Zwitterionic Polymer-Drug Conjugates for Multidrug Co-Delivery

用于多药联合递送的多功能可生物降解两性离子聚合物-药物缀合物

• 批准号: 10638101
• 负责人: Chong Cheng
• 金额: $ 64.32万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638101
• 关键词: Address; Alkenes; Alkynes; Azides; Behavior; Biochemical; Biocompatible Materials; Biodistribution; Biological Assay; Blood Circulation; Blood Circulation Time; Cells; Chemistry; Circulation; Clinical; Clinical Treatment; Combined Modality Therapy; Comparative Study; Development; Disease; Drug Delivery Systems; Drug Kinetics; Dyes; Encapsulated; Environment; Esters; Evaluation; Exhibits; FDA approved; Foundations; Goals; Guidelines; Hydrophobicity; Image; Immune response; Immunocompetent; In Vitro; Libraries; Ligands; Link; Malignant neoplasm of pancreas; Measurement; Methodology; Methods; Modeling; Mus; Outcome; Paclitaxel; Peptides; Periodicity; Pharmaceutical Preparations; Polyesters; Polyethylene Glycols; Polymers; Property; Publishing; Research; Research Activity; Series; Solid; Structure; System; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; Vertebral column; Work; Xenograft procedure; beta-Hydroxybutyrate; biological systems; biomaterial compatibility; cancer therapy; cell type; clinical application; clinical efficacy; cyanine; cytotoxicity; design; design,build,test; gemcitabine; global health; hydrophilicity; imaging agent; immunogenicity; in vivo; insight; mouse model; multidisciplinary; nanotherapeutic; novel; pancreatic cancer patients; plectin; poly(lactide); polymerization; prototype; scaffold; side effect; targeted agent; technology platform; therapeutic evaluation; uptake; Address; Alkenes; Alkynes; Azides; Behavior; Biochemical; Biocompatible Materials; Biodistribution; Biological Assay; Blood Circulation; Blood Circulation Time; Cells; Chemistry; Circulation; Clinical; Clinical Treatment; Combined Modality Therapy; Comparative Study; Development; Disease; Drug Delivery Systems; Drug Kinetics; Dyes; Encapsulated; Environment; Esters; Evaluation; Exhibits; FDA approved; Foundations; Goals; Guidelines; Hydrophobicity; Image; Immune response; Immunocompetent; In Vitro; Libraries; Ligands; Link; Malignant neoplasm of pancreas; Measurement; Methodology; Methods; Modeling; Mus; Outcome; Paclitaxel; Peptides; Periodicity; Pharmaceutical Preparations; Polyesters; Polyethylene Glycols; Polymers; Property; Publishing; Research; Research Activity; Series; Solid; Structure; System; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; Vertebral column; Work; Xenograft procedure; beta-Hydroxybutyrate; biological systems; biomaterial compatibility; cancer therapy; cell type; clinical application; clinical efficacy; cyanine; cytotoxicity; design; design,build,test; gemcitabine; global health; hydrophilicity; imaging agent; immunogenicity; in vivo; insight; mouse model; multidisciplinary; nanotherapeutic; novel; pancreatic cancer patients; plectin; poly(lactide); polymerization; prototype; scaffold; side effect; targeted agent; technology platform; therapeutic evaluation; uptake

Project Summary Critical technological challenges have significantly restricted the applicability of polymer-based drug delivery systems (DDSs). Aliphatic polyesters, such as polylactide (PLA) and poly(3-hydroxybutyrate) (P3HB), are biodegradable and biocompatible, but their hydrophobicity and lack of functionalities limit their biomedical applications. Polyethylene glycol (PEG) has been broadly used in DDSs, but can cause undesired immunogenicity. Zwitterionic polymers (ZPs) have emerged as promising alternatives of PEGs, but typical ZPs are non-biodegradable and may possibly result in severe in vivo side effects. Combination therapy has great clinical potentials; however, the lack of appropriate DDSs limits its applicability. Cyclic polymers have shown novel biointerface properties, but in-depth studies are needed to gain insights into their in vitro and in vivo behaviors. To address these challenges, we design multifunctional biodegradable zwitterionic polymer-drug conjugates (ZPDCs; with both open-chain and cyclic structures) as novel PEG-free DDSs. It is hypothesized that such ZPDCs can possess a broad range of favorable biomedically relevant properties for effective multidrug co-delivery. To examine the hypothesis, we propose to systematically investigate ZPDCs with three specific aims: 1) to synthesize multifunctional biodegradable multidrug-containing ZPDCs, 2) to understand their structure-dependent interactions with biochemical environments & cells, and 3) to understand their structure-dependent in vivo behaviors. We will synthesize a library of well-defined ZPDCs with PLA or P3HB-based backbones that carry sulfobetaine-based zwitterions, paclitaxel and gemcitabine as multidrug as combination therapy for pancreatic cancer, cyanine5.5 as imaging dye, and plectin-1 targeted peptide as targeting ligand. These ZPDCs will be prepared through living ring-opening polymerization of alkene/alkyne-functionalized cyclic esters, followed by alkyne-azide and thiol-ene dual Click functionalization. Comprehensive analytical approaches will be employed to characterize the ZPDCs to verify their well-controlled structures. To achieve insightful understanding on their structure-dependent biointerface properties, systematic biochemical, cellular and in vivo studies of ZPDCs will be performed. Research activities will include anti-biofouling analysis, drug release study, degradation assessment, cytotoxicity assay, evaluation of cellular uptake efficiency and mechanisms, the determination of blood circulation time, the measurements of pharmacokinetics and biodistribution, the examination of immune responses, and the evaluation of therapeutic efficacy in vivo. Together, the proposed R01 studies will establish the synthetic method for ZPDCs, provide key insights into their structure-dependent biointerface properties, and elucidate their design rules. These studies will lay a solid foundation for the development of ZPDCs as a new, PEG-free platform technology. The in-depth comparative studies of cyclic and open-chain ZPDCs will provide critical guideline on topological design of polymeric biomaterials. The outcomes of this project potentially may also benefit patients with pancreatic cancer.

项目摘要 关键的技术挑战极大地限制了基于聚合物的药物的适用性 系统（DDSS）。脂肪族多植物，例如聚乳肽（PLA）和聚（3-羟基丁酸）（P3HB），为 可生物降解和生物相容性，但它们的疏水性和缺乏功能限制了其生物医学 申请。聚乙烯乙二醇（PEG）已广泛用于DDS，但可能导致不希望的 免疫原性。 Zwitterionic聚合物（ZP）已成为PEG的有前途的替代品，但典型的ZP 是不可生物降解的，可能会导致严重的体内副作用。联合疗法有很好的 临床潜力；但是，缺乏适当的DDSS限制了其适用性。循环聚合物已显示 新型的生物界面特性，但需要深入研究才能洞悉其体外和体内 行为。为了应对这些挑战，我们设计了多功能可生物降解的zwitterionic聚合物 - 共轭物（ZPDC；带有开链和环状结构）作为新型的无PEG DDSS。假设 这样的ZPDC可以具有有效多药的一系列有利的生物医学相关特性 联合交付。为了审查该假设，我们建议系统地研究具有三个特定特定的ZPDC 目的：1）综合多功能生物降解的含多剂量的ZPDC，2） 结构依赖于生化环境和细胞的相互作用，以及3） 结构依赖于体内行为。我们将与PLA或PLA合成一个定义明确的ZPDC库 基于P3HB的骨架，携带基于硫贝因的zwitterions，Paclitaxel和Gemcitabine作为多药 胰腺癌，氰胺5.5作为成像染料和PLECTIN-1靶向肽的联合疗法作为 靶向配体。这些ZPDC将通过开环的聚合来制备 烷烃/炔烃功能化的环状酯，其次是炔烃和硫醇双键单击功能化。 将采用全面的分析方法来表征ZPDC来验证其控制良好的 结构。为了深入了解其与结构相关的生物界面属性，系统 将进行ZPDC的生化，细胞和体内研究。研究活动将包括 抗双重分析，药物释放研究，降解评估，细胞毒性测定，评估细胞 摄取效率和机制，确定血液循环时间，测量值 药代动力学和生物分布，免疫反应的检查以及治疗的评估 体内功效。拟议的R01研究将共同​​建立ZPDC的合成方法，提供密钥 深入了解其与结构有关的生物界面属性，并阐明其设计规则。这些研究会 为开发ZPDC作为一种新的，无PEG的平台技术奠定了坚实的基础。深度 循环和开链ZPDC的比较研究将提供有关拓扑设计的关键指南 聚合物生物材料。该项目的结果可能也可能使胰腺癌患者受益。