Liu Xi, Dhumal Dinesh, Santofimia-Castaño Patricia, Liu Juan, Casanova Marion, Garcia-Muñoz Alicia Comino, Perles-Barbacaru Teodora-Adriana, Elkihel Abdechakour, Zhang Wenzheng, Roussel Tom, Galanakou Christina, Wu Jing, Zerva Eleni, Dusetti Nelson, Xia Yi, Liang Xing-Jie, Viola Angèle, Iovanna Juan L, Peng Ling
Aix Marseille University, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), UMR 7325, Equipe Labellisée Ligue Contre le Cancer, 13288 Marseille, France.
Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS, UMR 7258, Institut Paoli-Calmettes, Aix Marseille Université, 13273 Marseille, France.
Sci Adv. 2025 Jun 27;11(26):eadu9948. doi: 10.1126/sciadv.adu9948. Epub 2025 Jun 25.
Cardiotoxicity, especially human ether-a-go-go-related gene (hERG)-related toxicity, is a leading cause of drug failure or market withdrawal. Reducing hERG binding to obviate potential cardiac toxicity is crucial. Nanotechnology has been applied to drug delivery for reducing drug toxicity and improving efficacy, but few studies have addressed hERG-related cardiotoxicity. We report the use of self-assembling dendrimer nanosystems for drug formulation and delivery, which effectively reduced hERG binding and associated toxicity while promoting therapeutic efficacy. Specifically, these dendrimer nanosystems efficiently encapsulated the antimalarial drug chloroquine, the anticancer agent doxorubicin, and the NUPR1 inhibitor ZZW115, all three having high affinity to hERG channels. These nanoformulations showed three- to eightfold reduced hERG binding affinity, which, in animal models, translated to abolished toxicity. These nanodrugs exhibited prolonged circulation, leading to enhanced accumulation at disease sites and improved treatment outcomes. This study highlights the potential of nanotechnology to reduce hERG binding and related toxicity while improving drug efficacy, offering valuable perspectives for drug development.
心脏毒性，尤其是与人醚 - 去极化相关基因（hERG）相关的毒性，是药物研发失败或撤市的主要原因。减少hERG结合以避免潜在的心脏毒性至关重要。纳米技术已应用于药物递送以降低药物毒性并提高疗效，但很少有研究涉及与hERG相关的心脏毒性。我们报道了使用自组装树枝状大分子纳米系统进行药物制剂和递送，其有效降低了hERG结合及相关毒性，同时提高了治疗效果。具体而言，这些树枝状大分子纳米系统有效地包封了抗疟药物氯喹、抗癌药物阿霉素和NUPR1抑制剂ZZW115，这三种药物对hERG通道均具有高亲和力。这些纳米制剂显示出hERG结合亲和力降低了三到八倍，在动物模型中，这转化为毒性消除。这些纳米药物表现出延长的循环时间，导致在疾病部位的蓄积增强和治疗效果改善。本研究突出了纳米技术在降低hERG结合及相关毒性同时提高药物疗效方面的潜力，为药物开发提供了有价值的观点。
