以载药胶束为交联点的可注射水凝胶的构建及应用

The incidence rate of breast cancer is the first place in female malignant tumor. The decreased tumor volume by preoperative local treatment can increase the probability of breast-conserving surgery. In the assays of local treatment, injectable hydrogel is very popular due to its advantages of convenient administration, no operation, no organic solvent, simple operation, good biocompatibility and high local drug concentration. However, drug delivery system using injectable hydrogel has burst release or low release quantity. It is difficult to achieve the combination of effective drug release and slow drug release (so-called zero-order release). How to realize zero-order release of injectable hydrogel is a very challenging task and has very important theoretical significance and clinical application value. This project intends to build a kind of injectable hydrogel with drug-loaded micelles as crosslinking sites by Schiff reaction of aldehyde at the surface of drug-loaded micelles and amino of the polymer. With the degradation of hydrogel, drug-loaded micelles release to achieve zero-order release of injectable hydrogel. The covalent crosslinking will provide the excellent mechanical strength of hydrogel. We expect that the utilization of drugs is improved and drug side effect is reduced through zero-order release of injectable hydrogel. We expect that in clinic the surgical resection range is reduced and the probability of breast-conserving surgery is increased through using injectable hydrogel in local treatment of breast cancer.

乳腺癌的发病率位居女性恶性肿瘤的第一位，通过术前局部治疗以缩小肿块体积的方法可增加保乳手术的成功率。在局部治疗方案中，可注射水凝胶由于给药方便、无需手术、无需有机溶剂、操作简单、生物相容性好、局部给药浓度高等优点而备受青睐。然而，可注射水凝胶体系存在药物释放过快或药物释放量较低等问题，难以实现有效释放药物和缓慢释放药物（零级释药）相统一。如何实现可注射水凝胶体系的零级释药是一个非常有挑战性的课题，具有非常重要的理论意义和临床应用价值。本项目拟通过载药胶束表面的氨基和高分子（水凝胶骨架）的醛基发生席夫碱反应，构建一种以载药胶束为交联点的可注射水凝胶，载药胶束随着水凝胶的降解而逐步释放（零级释药），共价交联赋予水凝胶优良的机械强度。通过可注射水凝胶体系的零级释药，期望提高药物利用率和降低药物毒副作用；将可注射水凝胶应用于乳腺癌局部治疗，期望在临床中缩小乳腺癌手术切除范围以增加保乳手术的成功率。

以载药胶束为交联点的可注射水凝胶有望实现水凝胶的零级释药和高机械强度。通过三年执行期的研究，我们基本完成预期研究目标。（1）可注射水凝胶负载胶束，用于药物释放和3D细胞培养。为了实现在癌症局部治疗中药物的肿瘤细胞靶向输送，我们将电荷翻转载药胶束负载于可注射水凝胶中，基于可注射水凝胶的缓释作用和电荷翻转载药胶束的pH响应，提高了药物的释放时间和利用率。（2）以纳米胶为交联点的可注射水凝胶，实现零级释药。为了实现在癌症局部治疗中药物的零级释放，我们以纳米凝胶为交联点与N-异丙基丙烯酰胺（NIPAM）聚合形成具有温敏性的可注射水凝胶，通过在纳米凝胶中负载抗癌药（如阿霉素），水凝胶中负载姜黄素，构建联合化疗，最后在水凝胶中加入具有光热效应的金纳米棒得到光控释药体系，达到零级释药的效果。（3）高浓度钙离子引导的自修复、粘附、抗冰冻水凝胶，用于应变传感器。人们在研制模拟人体皮肤功能的导电自修复水凝胶方面取得了显著进展。然而，开发一种具有良好自修复和力学性能的一体化导电凝胶仍然是一个巨大的挑战。我们通过向传统的醛基海藻酸钠和明胶共价键形成的水凝胶体系中引入高浓度的钙离子，从而促使钙离子与海藻酸钠的羧基形成离子键，从而设计了一种抗冰冻、自愈、自粘的离子凝胶。（4）快速自愈合纳米材料复合水凝胶，实现光控粘附。自愈合功能广泛存在于生物组织中，在过去的十年中，人们对智能凝胶进行了深入的研究。我们合成了一种金纳米棒PNIPAM水凝胶，采用了动态Au-S配位相互作用作为自愈合机理，具有快速、高效的自愈合特性。这些研究扩展了水凝胶的性能和功能，有望在药物释放、癌症治疗、传感器、伤口愈合等方面得到广泛的应用。