Dual-payload small-molecule drug conjugates enable bystander anticancer activity with reduced nonspecific release
文献类型：期刊论文
| 作者 | Chen, Chuanjie5,6; Pan, Yongzhang1,2,7; Zhang, Na3; Yang, Ting4; Shi, Jiaxin4,5; Ren, Bige1,2,7; He, Yonghan1,2,7; Zhang, Xuan2,5 |
| 刊名 | JOURNAL OF CONTROLLED RELEASE
 |
| 出版日期 | 2026-04-10 |
| 卷号 | 392页码:11 |
| 关键词 | Small-molecule drug conjugate (SMDC) Dual-payload strategy Bystander effect Therapeutic window PROTAC |
| ISSN号 | 0168-3659 |
| DOI | 10.1016/j.jconrel.2026.114695 |
| 通讯作者 | He, Yonghan(heyonghan@mail.kiz.ac.cn) ; Zhang, Xuan(zhangxuan@simm.ac.cn) |
| 英文摘要 | Small-molecule drug conjugates (SMDCs) have emerged as a promising class of targeted therapeutics, yet their clinical translation has been hindered by suboptimal efficacy and safety, with conventional optimization largely restricted to variations in ligand design and linker chemistry. We propose a dual-payload strategy that enhances therapeutic efficacy while concurrently minimizing off-target diffusion that contributes to systemic toxicity. In this proof-of-concept study, a representative SMDC bearing two degrader payloads, termed Bi-LIVTAC (XZ1618), demonstrates improved targeted cytotoxicity and a robust bystander effect, accompanied by a significant reduction in receptor-independent uptake. Notably, XZ1618 achieves complete tumor regression in combination with sorafenib in a Huh-7 xenograft model, thereby markedly expanding the therapeutic window without inducing hematological toxicity or organ damage. Moreover, this dual-payload design is broadly applicable to SMDCs targeting other membrane receptors, such as folate receptor, and to diverse payload types, including conventional cytotoxins and fluorescent probes. These findings establish the dual-payload strategy as a versatile and translatable platform for developing next-generation SMDCs with improved therapeutic windows. |
| WOS关键词 | OVARIAN-CANCER ; DOXORUBICIN ; DESIGN |
| 资助项目 | Innovative Drug Research and Development National Science and Technology Major Project[2025ZD1804100] ; National Natural Science Foundation of China[22277131] ; National Natural Science Foundation of China[82471599] ; Pioneer Hundred Talents Program of the Chinese Academy of Sciences |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001692197200001 |
| 出版者 | ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/323050]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | He, Yonghan; Zhang, Xuan |
| 作者单位 | 1.Chinese Acad Sci, Kunming Inst Zool, Key Lab Hlth Aging Res Yunnan Prov, Kunming 650201, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai 201203, Peoples R China 6.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 211112, Peoples R China 7.Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Evolut & Anim Models, Kunming 650201, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Chuanjie,Pan, Yongzhang,Zhang, Na,et al. Dual-payload small-molecule drug conjugates enable bystander anticancer activity with reduced nonspecific release[J]. JOURNAL OF CONTROLLED RELEASE,2026,392:11. |
| APA | Chen, Chuanjie.,Pan, Yongzhang.,Zhang, Na.,Yang, Ting.,Shi, Jiaxin.,...&Zhang, Xuan.(2026).Dual-payload small-molecule drug conjugates enable bystander anticancer activity with reduced nonspecific release.JOURNAL OF CONTROLLED RELEASE,392,11. |
| MLA | Chen, Chuanjie,et al."Dual-payload small-molecule drug conjugates enable bystander anticancer activity with reduced nonspecific release".JOURNAL OF CONTROLLED RELEASE 392(2026):11. |
入库方式： OAI收割
来源：上海药物研究所
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