端生物素的温度敏感型糖基嵌段共聚物对硼替佐米的负载与双重控释性能的研究

In the past decade, polymer-based drug delivery systems have obtained more attentions for their potential biomedical applications. To improve the efficacy and reduce the toxicity of loading anticancer drug, different environmentally block copolymers containing different pH and/or thermo responsive or pH-labile chains were synthesized and studied as the drug delivery system. Due to the presence of water-soluble and biocompatible polymer chains, this kind of polymer-based drug delivery systems have the well stability in tissue and obtain controlled release of drug in cancer cells via pH or temperature change. However, there are their special own limitations in reported delivery systems. To address the challenges, this project focuses on a new polymer-based drug delivery system prepared from thermo-responsive Biotinylated glycopolymer. this glycopolymer have the stimuli-responsiveness and can bind with boronic acid of Bortezomib at basic or neutral conditions to form a stable boronate ester but dissociate their aggregates upon the pH change to pH 5. Those properties of Biotinylated glycopolymer were rendered as the effect drug delivery system to study the covalently loading of this kind of drugs bearing boronic acid moiety without complicated modification of used Drug and controlled release by the change of pH and/or temperature, and improve the cellular uptake of this carrier and the drug toxicity only in cancer cells. those investigations will provide the basic understanding for the further study of in Vivo .

目前，对于抗癌药物负载和释放的研究一直是癌症治疗领域内的研究热点。为了提高药效和减少药物的毒性，常选用带有不同环境敏感型或pH可降解链段的嵌段共聚物作为聚合物载体，利用其水溶性和生物相容性，来提高药物在体液和组织间传输的稳定性，实现药物在体内的可控释放。已报道的聚合物载体尽管有各自的优势，但还存在着有待改进的地方。为了进一步探索新型药物负载和释放的体系，本项目拟利用端基生物素的温度敏感型含糖嵌段共聚物的多羟基与含有硼酸基团的抗癌药物硼替佐米pH依赖的相互作用，实现这类载体对硼替佐米的负载和可控释放，即在不需要对抗癌药物进行化学修饰的前提下，也可实现在生理条件下对抗癌药物的化学键络合和在pH 5时的解络合而达到药物可控释放的目的。由于环境敏感性和靶向分子的存在，这类载体将仅被癌症细胞内吞，且在癌症细胞内的微环境下，实现药物智能性地释放。这些研究必将为下步的动物体内实验提供研究基础。

以化疗为主的癌症治疗，其重要性不言而喻。借助巧妙的设计和有效的合成手段，构筑和探索新型的纳米抗癌药物载体，一直是化疗研究的热点和难点。本研究主要以硼替佐米和阿霉素为抗癌药物模型，通过聚合物组成设计和结构调控，合成和构筑出对抗癌药物具有有效负载和可控释放特点的聚合物载体，摸索对药物具有控释行为的聚合物载体设计所需的规律，并揭示聚合物载体对药物的控释行为机理，从而可研发出更高效、安全的新型抗癌药物聚合物纳米载体，其中主要研究内容如下：.1、采用活性聚合手段, 选择合适反应条件和聚合物链延伸技术，分别合成和构筑出化学组分相同，但拓扑结构不同或链段聚合度不同的含糖环境响应性嵌段聚合物。借助各种分析手段，系统地研究了这些含糖环境响应性聚合物间自组装能力的差异性：由环境响应性链段所处的化学环境决定。这种组装能力以及所形成组装体结构的差异性对模型药物阿霉素(Dox)存在不同释放规律，这种释放规律是聚合物载体的环境响应与抗癌药物扩散协同作用的结果。.2、在已有的研究基础上，进一步研究不能组装、可组装成憎水内核以及pH碱性可组装和酸性下解组装的三种含糖嵌段共聚物，详细研究其对含硼酸基团的抗癌药物硼替佐米的负载和释放行为。体外释放结果显示和证实硼替佐米与PEG-b-PGAMA的糖基具有pH依赖性：在碱性或pH 7.4时络合(负载作用)，而在酸性条件下的解络合(释放行为);对PEG113-b-PS50-b-PGAMA20和 PEG113-b-PDEA50-b-PGAMA15由于憎水内核的存在以及pH诱导组装和解组装的特性导致释放速率和释放量可调的药物动力学行为。.鉴于前面的研究，可通过对聚合物化学组成以及拓扑结构的精细调控，实现对抗癌药物的可控释放。进而根据对癌症病情严重程度不同，采取不同需求且具有不同控释行为、良好生物相容性的聚合物载体，从而为其他抗癌药物载体的研发提供新型构筑思路和借鉴意义。