Synthesis and Evaluation of Polymer-Antibody Hybrid with Pharmacologically Active Domains

“导弹药物”是一种将药物选择性地输送到需要医疗的器官或组织的技术，从而抑制药物的副作用。通过中间载体聚合物将抗体与药物偶联是最有前途的导弹药物类型之一。在这种类型的缀合物中，中间载体聚合物起到通过与抗体的最小连接点将尽可能多的药物与抗体连接的作用，因此获得抗体的抗原结合能力降低最小的高活性缀合物。我们认为，中间载体聚合物的分子设计是至关重要的，以获得最佳质量的这类导弹药物。从这个角度来看，聚（乙二醇）-聚（天冬氨酸）嵌段共聚物被用作中间载体聚合物。聚乙二醇链被认为可以降低导弹药物的抗原性，增加水溶性和在血液中的稳定性。多聚天冬氨酸链以共价键的形式作为抗癌药物阿霉素的载体，预期被靶细胞摄取后会被降解。本研究合成了一种新型的抗癌药物阿霉素-聚乙二醇-聚天冬氨酸-免疫球蛋白G偶联物。聚乙二醇-聚天冬氨酸嵌段共聚物（Poly（ethylene glycol）-block-poly（asparticacid））是一种将阿霉素结合在聚天冬氨酸链上的嵌段共聚物，尽管引入了大量的强疏水性阿霉素，但仍表现出良好的水溶性，并在水溶液中形成胶束结构。通过二硫键实现了聚乙二醇-嵌段-聚天冬氨酸结合阿霉素和免疫球蛋白G之间的有效偶联。

"Missile drug" is a technique to deliver drugs selectively to the organs or tissues where a medical treatment is needed, and as a result, to inhibit the side effects of drugs. One of the most promising types of missile drug is a conjugate of antibody with drugs via intermediate carrier polymer. In a conjugate of this type, intermediate carrier polymer plays a role in connecting as much drug as possible to antibody by minimum connecting points with antibody, and consequently a highly active conjugate with minimum decrease in antigen binding capacity of antibody is obtained. We consider that molecular design of intermediate carrier polymer is critically important to obtain the best quality of this type of missile drug. From this point of view, poly(ethylene glycol)-poly(aspartic acid) block copolymer is used as an intermediate carrier polymer. Poly(ethylene glycol) chain is considered to decrease antigenicity af missile drug, and to increase water- solubility and stability in blood stream. Poly(aspartic acid) chain carriers anti-cancer drug (adriamycin) with covalent bond and is expected to be degraded after the uptake by target cells. In this research, synthesis of a novel conjugate of anti-cancer drug adriamycin, poly(ethylene glycol)-block-poly(aspartic acid), and immunoglobulin G is conducted. Poly(ethylene glycol)-block-poly(aspartic acid), binding adriamycin on the poly( aspartic acid) chain, showed an excellent water-solubility despite the introduction of a large amount of strongly hydrophobic adriamycin, and was found to form a micellar structure in aqueous salution. Efficient coupling between poly(ethylene glycol)-block-poly( aspartic acid) binding adriamycin and immunaglobulin G was achieved via disulfide linkages.