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

项目摘要 关键的技术挑战已经显著地限制了基于聚合物的药物递送的适用性 DDS系统。脂肪族聚酯，如聚丙交酯（PLA）和聚（3-羟基丁酸酯）（P3 HB），是 但是它们的疏水性和功能性的缺乏限制了它们的生物医学活性。 应用.聚乙二醇（PEG）已广泛用于DDS中，但可引起不期望的损伤。 免疫原性两性离子聚合物（ZPs）已成为PEG的有前途的替代品，但典型的ZPs 是不可生物降解的并且可能导致严重的体内副作用。联合治疗有很大的 临床潜力;然而，缺乏适当的DDS限制了其适用性。环状聚合物已经显示 新的生物界面特性，但需要深入研究，以深入了解其在体外和体内 行为。为了应对这些挑战，我们设计了多功能可生物降解的两性离子聚合物-药物 本文描述了作为新型无PEG DDS的偶联物（ZPDC;具有开链和环状结构两者）。它是假设 这种ZPDC可以具有广泛有利的生物医学相关性质， 共同交付。为了检验这一假设，我们建议系统地研究ZPDC与三个特定的 目的：1）合成多功能可生物降解的含多药ZPDCs，2）了解其 与生化环境和细胞的结构依赖性相互作用，以及3）了解它们的 结构依赖性体内行为。我们将合成具有PLA或PLA的明确定义的ZPDC的文库。 携带基于磺基甜菜碱的两性离子的基于P3 HB的主链、紫杉醇和吉西他滨作为多药治疗剂， 用于胰腺癌的组合疗法，花青5.5作为成像染料，和plectin-1靶向肽作为 靶向配体。这些ZPDC将通过以下物质的活性开环聚合制备： 烯烃/炔官能化的环酯，随后是炔-叠氮化物和硫醇-烯双点击官能化。 将采用全面的分析方法来表征ZPDC，以验证其控制良好 结构.为了深入了解它们的结构依赖性生物界面特性， 将进行ZPDC的生物化学、细胞和体内研究。研究活动将包括 抗生物污损分析，药物释放研究，降解评估，细胞毒性测定，细胞毒性评价， 吸收效率和机制，血液循环时间的测定， 药代动力学和生物分布，免疫反应的检查，以及治疗性的评价。 体内功效总之，拟议的R 01研究将建立ZPDC的合成方法，提供关键的 深入了解其结构依赖性生物界面特性，并阐明其设计规则。这些研究将 为ZPDC作为一种新的无PEG平台技术的发展奠定了坚实的基础。深入 环状和开链ZPDC的比较研究将为拓扑设计提供重要的指导方针， 高分子生物材料该项目的结果也可能使胰腺癌患者受益。

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.