铂配合物-抗体偶联物设计、合成及DNA相互作用研究

As a class of widely used clinical antitumor drugs, platinum drugs have some advantages, such as broad anticancer spectrum, high activity against tumor and so on. However, platinum drugs can hardly distinguish between healthy tissue and tumor tissue, resulting in serious toxic side effects. In order to improve the targeting and reduce the toxic side effects, the project selected monoclonal antibody with high attraction to cancer cells as a carrier for targeted delivery of platinum drugs. The project will design a variety of platinum complexes with active functional groups, then conjugate them with a suitable antibody with high targeting and significant effect, Trastuzumab, by selecting small moleculars which can maintain drugs'' stability and targeted release as linkers, producing plantinum complex-antibody conjugates. Besides, the project will investigate the effect of platinum complexes'' structures and different linkers on the interaction with DNA, providing theoretical foundation for the mechanism study of platinum drugs and the development of novel antitumor plantinum drugs with high effect, low toxicity and good targeting.

铂类药物是目前临床上广泛使用的一类抗肿瘤药，它具有抗癌谱广，抑制肿瘤作用强等特点。但铂药不能识别健康组织和肿瘤组织，对两者皆有细胞毒性，易产生严重的毒副作用。为了提高铂药的靶向性，降低其毒副作用，本项目选择对肿瘤细胞具有高度亲和性的单克隆抗体作为载体，来进行铂药的靶向运输。本项目设计多种含有活性官能团的铂配合物，选择能维持药物稳定性和靶向释放的小分子作为连接基团，将靶向性良好、临床疗效显著的合适抗体——曲妥珠单抗与其偶联，制备一系列铂配合物-抗体偶联物。此外，本项目还将通过开展偶联物与DNA的相互作用，考察铂配合物结构、连接键等因素对偶联物与DNA作用的影响，以便为深入研究该类铂药的作用机理，开发更好的高效、低毒、靶向性良好的新型铂药提供理论基础及实验依据。

本项目选择对肿瘤细胞具有高度亲和性的单克隆抗体作为载体，来进行铂药的靶向运输，以减少铂药对正常组织的伤害。我们合成了三种铂（Ⅳ）配合物，将其与抗体通过酰胺键连接，研究偶联物在内源性还原剂（抗坏血酸及谷胱甘肽）的作用下与DNA 的结合能力及切割活性的变化，以推测铂（Ⅳ）配合物-抗体偶联物在细胞内与DNA作用机理。此外，我们还合成了含可被组织蛋白酶B降解二肽（缬氨酸-瓜氨酸）的连接基团，通过此连接基团将铂（Ⅱ）配合物与抗体连接，研究偶联物与DNA切割活性。本项目通过考察铂配合物结构、连接键等因素对偶联物与DNA 作用的影响，以便为深入研究该类铂药的作用机理，开发更好的高效、低毒、靶向性良好的新型铂药提供理论基础及实验依据。