Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea.
Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea.
Int J Mol Sci. 2024 Aug 12;25(16):8762. doi: 10.3390/ijms25168762.
In this study, we explored the potential of genetically engineered exosomes as vehicles for precise drug delivery in gastric cancer therapy. A novel antitumor strategy using biocompatible exosomes (Ex) was devised by genetically engineering adipose-derived stem cells to express an MKN45-binding peptide (DE532) on their surfaces. 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) was encapsulated in engineered exosomes, resulting in 17-DMAG-loaded DE532 exosomes. In both in vitro and in vivo experiments using mouse gastric cancer xenograft models, we demonstrated that 17-DMAG-loaded DE532 Ex exhibited superior targetability over DE532 Ex, 17-DMAG-loaded Ex, and Ex. Administration of the 17-DMAG-loaded DE532 Ex yielded remarkable antitumor effects, as evidenced by the smallest tumor size, lowest tumor growth rate, and lowest excised tumor weight. Further mechanistic examinations revealed that the 17-DMAG-loaded DE532 Ex induced the highest upregulation of the pro-apoptotic marker B-cell lymphoma-2-like protein 11 and the lowest downregulation of the anti-apoptotic marker B-cell lymphoma-extra large. Concurrently, the 17-DMAG-loaded DE532 Ex demonstrated the lowest suppression of antioxidant enzymes, such as superoxide dismutase 2 and catalase, within tumor tissues. These findings underscore the potential of 17-DMAG-loaded DE532 exosomes as a potent therapeutic strategy for gastric cancer, characterized by precise targetability and the potential to minimize adverse effects.
在这项研究中，我们探讨了基因工程外泌体作为胃癌治疗中精确药物传递载体的潜力。通过基因工程脂肪干细胞，在其表面表达一种与 MKN45 结合的肽（DE532），设计了一种新的抗肿瘤策略。将 17-（二甲氨基乙基氨基）-17-去甲氧基格尔德霉素（17-DMAG）封装在工程化的外泌体中，得到负载 17-DMAG 的 DE532 外泌体。在使用小鼠胃癌异种移植模型的体内和体外实验中，我们证明负载 17-DMAG 的 DE532 Ex 比 DE532 Ex、负载 17-DMAG 的 Ex 和 Ex 具有更好的靶向性。负载 17-DMAG 的 DE532 Ex 的给药产生了显著的抗肿瘤效果，表现为肿瘤体积最小、肿瘤生长率最低和切除的肿瘤重量最低。进一步的机制研究表明，负载 17-DMAG 的 DE532 Ex 诱导了最高的促凋亡标志物 B 细胞淋巴瘤-2 样蛋白 11 的上调和最低的抗凋亡标志物 B 细胞淋巴瘤-额外大的下调。同时，负载 17-DMAG 的 DE532 Ex 表现出肿瘤组织中抗氧化酶（如超氧化物歧化酶 2 和过氧化氢酶）最低的抑制作用。这些发现强调了负载 17-DMAG 的 DE532 外泌体作为胃癌治疗的一种有前途的治疗策略的潜力，其特点是精确的靶向性和最小化不良反应的潜力。
