基于硫酸软骨素靶向 CD44 的纳米药物通过诱导线粒体凋亡通路治疗黑色素瘤。
CD44 targeting nanodrug based on chondroitin sulfate for melanoma therapy by inducing mitochondrial apoptosis pathways.
机构信息
National Glycoengineering Research Center, Shandong University, Qingdao 266237, China; NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Shandong University, Qingdao 266237, China; Shandong Provincial Technology Innovation Center of Carbohydrate, Shandong University, Qingdao 266237, China.
National Glycoengineering Research Center, Shandong University, Qingdao 266237, China; NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Shandong University, Qingdao 266237, China; Shandong Provincial Technology Innovation Center of Carbohydrate, Shandong University, Qingdao 266237, China; School of Pharmaceutical sciences, Shandong University, Jinan 250012, China.
出版信息
Carbohydr Polym. 2023 Nov 15;320:121255. doi: 10.1016/j.carbpol.2023.121255. Epub 2023 Aug 2.
Neovascularization is crucial to the occurrence and progression of tumors, and the development of antiangiogenic drugs has essential theoretical value and clinical significance. However, antiangiogenesis therapy alone cannot meet the needs of tumor therapy. Meanwhile, polysaccharides are ideal drug carriers with promising applications in drug modification and delivery. In this research, we developed a novel redox and acid sensitive nanodrug (CDDP-CS-Cys-EA, CCEA) composed of chondroitin sulfate (CS), antiangiogenic peptide (endostatin2-alft1, EA) and chemotherapeutic drug (cisplatin, CDDP). CCEA exhibited redox and acid responsiveness, better blood hemocompatibility (hemolysis rate < 5 %), the ability to target tumors (CD44-mediated endocytosis), and strong antiangiogenesis and antitumor characteristics in vitro. Moreover, CCEA showed excellent antitumor activity and low toxicity in B16 xenograft mice. It also has been confirmed that CCEA induced tumor cell apoptosis through promoting the expression of Bax, suppressing the expression of Bcl-2, decreasing mitochondrial membrane potential, releasing cytochrome C (Cyto C), and enhancing the activities of Caspase 9 and Caspase 3. The results of this paper provided a theoretical basis and insight for the development of antitumor drugs.
血管新生对肿瘤的发生和发展至关重要,抗血管生成药物的开发具有重要的理论价值和临床意义。然而,单独的抗血管生成治疗并不能满足肿瘤治疗的需求。同时,多糖是药物修饰和递送的理想药物载体,具有广阔的应用前景。在这项研究中,我们开发了一种新型的氧化还原和酸敏感的纳米药物(CDDP-CS-Cys-EA,CCEA),由硫酸软骨素(CS)、抗血管生成肽(内皮抑素 2-alft1,EA)和化疗药物(顺铂,CDDP)组成。CCEA 表现出氧化还原和酸响应性、更好的血液血液相容性(溶血率<5%)、靶向肿瘤的能力(CD44 介导的内吞作用)以及体外强大的抗血管生成和抗肿瘤特性。此外,CCEA 在 B16 异种移植小鼠中显示出优异的抗肿瘤活性和低毒性。还证实 CCEA 通过促进 Bax 的表达、抑制 Bcl-2 的表达、降低线粒体膜电位、释放细胞色素 C(Cyto C)以及增强 Caspase 9 和 Caspase 3 的活性诱导肿瘤细胞凋亡。本文的结果为抗肿瘤药物的开发提供了理论依据和见解。