Peptide-drug conjugate (PDC) is a promising prodrug in drug delivery systems. To fabricate nanostructures with proper molecular design which can self-assemble to spherical morphologies is very important for PDC chemotherapy. In this study, a novel PDC (PDC-DOX₂), in which two doxorubicin (DOX) molecules are conjugated onto a short peptide (KIGLFRWR) with self-assembly function, was designed and synthesized. PDC-DOX₂ with self-assembly properties forms a spherical structure under hydrophobic interaction in water. Hyaluronic acid (HA) was then coated on PDC-DOX₂ micelles to form a HA-shelled, peptide-doxorubicin conjugate-cored nanomedicine (HA@PDC-DOX₂). The amount of HA can regulate the particle size and stabilization of HA@PDC-DOX₂. In addition, HA can actively enhance the targeting effects of PDC-DOX₂ micelles since it can interact with overexpressed receptors in cancer cells. The core-shell structured HA@PDC-DOX₂ nanomedicine showed significantly enhanced potency against hepatocellular carcinoma compared to PDC-DOX₂ micelles as well as free DOX. In this work, a novel PDC which can self-assemble to spherical morphologies and a core-shell structure HA@PDC-DOX₂ nanomedicine are designed and prepared. It provides a convenient strategy for the size control of PDC assemblies and constructs effective PDC-based drug delivery systems for cancer treatment.

肽-药物偶联物（PDC）是药物输送系统中有希望的前药。用适当的分子设计制造可以自组装成球形形态的纳米结构对于PDC化疗非常重要。在这项研究中，设计并合成了一种新型PDC（PDC-DOX ₂），其中两个阿霉素（DOX）分子缀合到具有自组装功能的短肽（KIGLFRWR）上。具有自组装特性的PDC-DOX ₂在水中疏水作用下形成球形结构。然后将透明质酸（HA）涂在PDC-DOX ₂胶束上，形成HA壳，肽-阿霉素缀合物为核心的纳米药物（HA @ PDC-DOX ₂）。HA的含量可以调节HA @ PDC-DOX的粒径和稳定性₂。此外，HA可以主动增强PDC-DOX ₂胶束的靶向作用，因为它可以与癌细胞中过表达的受体相互作用。与PDC-DOX ₂胶束和游离DOX相比，核-壳结构的HA @ PDC-DOX ₂纳米药物显示出显着增强的抗肝细胞癌效力。在这项工作中，设计并制备了一种可以自组装成球形形态的新型PDC和核壳结构HA @ PDC-DOX ₂纳米药物。它为控制PDC组件的尺寸提供了一种方便的策略，并构建了有效的基于PDC的用于癌症治疗的药物输送系统。