可注射抗癌药物小分子水凝胶的制备及功能研究

Cancer chemotherapy is usually necessary and to date remains the best way to eliminate tumor residues and prevent tumor metastasis after surgery. However, these anti-cancer drugs frequently sufer from low water solubility and result in adverse side e?ects. Many kinds of drug carriers have been developed to overcome these Shortcomings. Among the delivery systems reported, liposome, nanocapsules formed by block polymer, conjugates of anti-cancer drugs and hydrophilic polymer or proteins, and polymerichydrogels are very promising, and several of them have been used in clinics. In addition to these successful examples of delivery systems, molecular hydrogels based on therapeutic agents with high loading weight percentages of drug molecules have recently been demonstrated as a novel self-delivery system for long-term and sustained release of different kinds of drugs..In this proposal, we will prepare a novel self-delivery system based on the anti-cancer drugs. We design and synthesize R-FFFK(FA)E-ss-EE as a precursor of molecular hydrogelators. The principles of the design are described as follows: (1) R is an anti-cancer drug such as BTZ and CPT ; (2) it has the folic acid (FA) moiety, which has a strong tendency to form a stable tetramer and offers the FA-R conjugate the targeting effect to cancer cells; (3) dipeptide and tripeptide of phenylalanine (F) have been widely used to construct molecular hydrogelators; (4) the derivative of diGlutamic acid (EE) improves solubility of the precursors of gelators; (5) the disulfide bond serves as a cleavable linker to connect molecular hydrogelators and the hydrophilic parts; and (6) the first E on R-FFFK(FA)E adjusts the balance between hydrophobicity and hydrophilicity and helps stabilize the resulting hydrogels. Upon the treatment of the reductants such as glutathione (GSH) and dithiothreitol (DTT), R-FFFK(FA)E-ss-EE can be converted to R-FFFK(FA)E-SH that can self-assemble into molecular hydrogels. We image that this novel self-delivery system that has high loading weight percentages of drug molecules (>50% ) will improves anti-cancer efficiency, reduces side effects, and overcomes drug resistance during chemotherapy.

疏水性的抗癌药物需要有机溶剂助溶，产生较大毒副作用；同时化疗也带来系统性的全身毒副作用并导致各种并发症。本研究拟制备可注射的抗癌药物小分子水凝胶，用于局部缓释抗癌药物，提高局部药物浓度的同时减轻系统性毒副作用。疏水性抗癌药物首先通过可降解键与适当的多肽连接从而具有自组装成各种纳米结构的能力，最终形成含单一抗癌药物或者多种抗癌药物结合的小分子水凝胶。由于抗癌药物衍生物既作为载体也作为缓释的对象，因此该体系具有药物包载率高（大于50%）、无需载体的特点和优点。同时通过两种或多种药物分子的协同作用能提高化疗的效果、降低副作用和克服耐药性。我们将研究小分子水凝胶成胶因子化学结构、组装体形貌和成胶因子浓度等性质对药物释放速率和药物疗效的影响并进行生物学评价。本药物体系将用到肿瘤切除后所留下的空腔中，长期缓释抗癌药物；或者采用瘤内注射的方式治疗晚期肿瘤，延长患者生命。

疏水性的抗癌药物需要有机溶剂助溶，产生较大毒副作用；同时化疗也带来系统性的全身毒副作用并导致各种并发症，所以我们发展了两种含有抗癌药物的小分子水凝胶。1）基于抗癌药物硼替佐米的多肽衍生物水凝胶的研究，该多肽衍生物自组装形成的水凝胶具有纳米结构，并对BTZ具有药物缓释作用。细胞实验结果表明Nap-GFFYEE-Cat-BTZ对癌细胞的杀伤作用高于非癌细胞，降低了硼替佐米的毒副作用。2）一种主要由紫杉醇自己所组成的水凝胶，动物实验证实该水凝胶能直接注射进实体瘤阻止肿瘤的生长和迁移。血液中低浓度的紫杉醇和高的抗癌活性表明我们的紫杉醇水凝胶在化疗中有很大的应用前景。水凝胶中纳米纤维既是载体又是传输的对象。这种新型的药物自传输体系具有较大的希望应用于临床。3）不同芳香基封端基团的短肽化合物混合，形成的水凝胶力学性能将会大幅度提高。我们设计合成了四种多肽序列Nap-GFFY, PTZ-GFFY, Nap-GDFDFDY, PTZ- GDFDFDY,研究不同的封端基团Nap和PTZ、不同的氨基酸构型L型和D型多肽序列，分别相互混合，产生的水凝胶力学性能发生了明显提高。具有不同力学强度的水凝胶在药物控释中具有重要的应用前景。