程序化二级靶向多功能纳米递药系统用于抗乳腺癌的研究

Breast cancer possesses serious threat to women's health. Raquimod (RES) has the ability to induce repolarization of tumor-associated macrophages (TAMs) from M2 toward M1 phenotype. Buthioninesul foximine (BSO) can induce ferroptosis of cancer cells. Both of them have been used to treat breast cancer. However, the systemic administration of RES has some problems, such as low drug enrichment in tumor sites and serious toxicity. Additionally, the curative effect of targeting TAMs or cancer cells alone is not satisfactory. In view of the problems above during treatment, we intend to construct mannose polymer-RES conjugates to improve the efficacy of RES and reduce the toxicity based on the present research on macromolecular drug delivery systems of our group. Afterwards, we will integrate the tumor cell membrane, BSO and acetalated conjugates into multifunctional nanoscale drug delivery systems by using iron ion/tannic acid coordination complex. This drug delivery systems may utilize the "Neighboring Effect" to target cancer cells and TAMs sequentially in order to achieve effective treatment of breast cancer. The project will build programmed two-stage targeted drug delivery systems. In addition, we will study the interdependence between the different physicochemical properties of nanoparticles and their targeted therapeutic effect. Further, we will study the synergistic mechanism of ferroptosis (induced by iron ion and BSO) and anti-tumor immunity (elicited by RES). Successful completion of the project will provide important fundamentals for the development of novel drug delivery systems with synergistic therapeutic effect.

乳腺癌严重威胁女性健康，可诱导M2型肿瘤相关巨噬细胞（TAMs）极化为M1型的药物瑞喹莫德（RES），以及可诱导肿瘤细胞铁死亡的药物（丁硫氨酸亚砜胺（BSO））已被用于治疗乳腺癌。然而，全身给予RES存在肿瘤部位药物含量低、毒副作用严重等问题，并且单独调控TAMs或杀伤肿瘤细胞的疗效不理想。针对上述治疗难题，申请人基于在大分子递药系统研究中的积累，拟先构建甘露糖聚合物RES偶联物以提高RES疗效并减弱毒副作用，之后以铁离子/单宁酸配位复合物将肿瘤细胞细胞膜、BSO、缩醛化偶联物整合为多功能纳米递药系统，利用“邻近效应”解决对肿瘤细胞和TAMs进行程序化依次靶向治疗的难题，实现有效治疗乳腺癌的目的；建立程序化二级靶向递药系统的构建方法；研究纳米粒不同理化性能与其靶向治疗效果之间的相关性；研究铁死亡诱导作用与RES抗肿瘤免疫作用的协同作用机制，为开发具有协同治疗作用的新型递药系统奠定研究基础。

乳腺癌严重威胁女性健康，紫杉醇（PTX）以及肿瘤细胞铁死亡激活剂（RSL3）已被用于治疗乳腺癌。然而，全身给予PTX和RSL3存在肿瘤部位药物含量低、毒副作用严重等问题。传统的活性氧（ROS）响应性递药系统在肿瘤中药物释放不充分。并且，依靠单一的RSL3难以促进大量的LPO积累，无法在肿瘤组中引起足够的铁死亡。针对上述治疗难题，我们构建了两种不同的递药系统用于分别解决这两个问题。首先，我们通过化学合成和RAFT聚合等方法将肉桂醛与PTX引入聚合物，构建ROS响应性的纳米递药系统。我们研究了肉桂醛促进PTX释放的机制，以及ROS响应性聚合物PTX偶联物的体内外抗肿瘤作用机制。PEG修饰的ROS响应性纳米递药系统在体内血液循环系统中的具有高稳定性，药物PTX在肿瘤组织/细胞内快速释放以及聚合物骨架可快速降解，实现了对乳腺癌的高效治疗。聚合物骨架具有了良好生物相容性的聚合物PTX偶联物的肿瘤生长抑制率可达58.9%。这项研究为ROS响应性聚合物药物偶联物提供了一种新颖的设计，实现了偶联物中药物在肿瘤部位的充分释放；其次，我们利用天然多糖海藻酸钠在生理浓度的钙离子下迅速形成水凝胶的特点，设计了一种原位凝胶化策略，将葡萄糖氧化酶（GOx）、RSL3与铁离子一起限制在肿瘤局部。研究了水凝胶的成胶能力，体内外抗肿瘤活性，以及GOx与RSL3诱导抗肿瘤免疫的协同作用机制。水凝胶的肿瘤生长抑制率可达82.46%。此项研究为开发具有协同治疗作用的新型递药系统奠定了研究基础。