癌症干细胞（CSCs）的存在主要负责导致癌症患者的化疗耐药性、癌症复发和治疗失败。消灭CSCs和体积肿瘤一起是实现完全阻断癌症的必要条件。盐霉素（SAL）具有一定潜力，可以同时阻断多种途径，以特异性地靶向和杀死CSCs。已经报道当SAL与基于化学疗法的药物结合使用时，可以提高抗癌疗效。然而，SAL的临床应用受到其高离靶毒性的限制。因此，我们开发了基于聚乳酸（PLA）的混合嵌段共聚物，以同时释放SAL和多柔比星（DOX），旨在减少其不良副作用并增强治疗的疗效。设计的PLA基纳米平台显示出对两种药物的高包封效率和持续释放性能。对癌细胞系的细胞毒性评估证实了SAL：DOX共载NPs的协同作用。此外，准备的SAL NPs也被发现对化疗耐药的癌细胞和来自癌症患者的CSCs非常有效。最重要的是，SAL在PLA NPs中的包封改善了其的药物代谢动力学和生物分布特征。因此，SAL NPs的不良毒性显著降低，这反过来提高了小鼠的耐受剂量，相比于纯自由的SAL。将SAL：DOX共载NPs用于EAC肿瘤承载的小鼠治疗后，结果显示出良好的肿瘤回归和完全抑制。这些结果证明了使用基于PLA的嵌段共聚物纳米载体同时释放SAL和DOX在癌症治疗中的潜力。 版权所有 © 2023 Elsevier B.V.

Existence of cancer stem cells (CSCs) are primarily responsible for chemoresistance, cancer reoccurrence and treatment failure in cancer patients. Eliminating CSCs along with bulk tumor is a necessity to achieve complete cancer inhibition. Salinomycin (SAL) has potential to specifically target and kill CSCs through blocking their multiple pathways simultaneously. SAL has also been reported to improve anti-cancer efficacy of numerous chemo-based drugs when used in combination therapy. However, clinical use of SAL is restricted due to its high off targeted toxicity. Herein, we have developed a PLA based hybrid block copolymer for concomitant delivery of SAL and doxorubicin (DOX) with an aim to reduce their adverse side effects and enhance the therapeutic efficacy of the treatment. Designed PLA based nanoplatform showed high encapsulation and sustained release profile for both the drugs. Cytotoxicity evaluation on cancer cell lines confirmed the synergistic effect of SAL:DOX co-loaded NPs. Additionally, prepared SAL NPs were also found to be highly effective against chemo-resistant cancer cells and CSCs derived from cancer patient. Most importantly, encapsulation of SAL in PLA NPs improved its pharmacokinetics and biodistribution profile. Consequently, undesired toxicity with SAL NPs was significantly reduced which in-turn increased the dose tolerability in mice as compared to free SAL. Treatment of EAC tumor bearing mice with SAL:DOX co-loaded NPs resulted in excellent tumor regression and complete inhibition of cancer reoccurrence. These results conclude that concomitant delivery of SAL and DOX using PLA based block copolymeric nano-carrier have a strong potential for cancer therapy.Copyright © 2023 Elsevier B.V. All rights reserved.