College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
J Control Release. 2024 Nov;375:574-588. doi: 10.1016/j.jconrel.2024.09.029. Epub 2024 Sep 22.
Erastin, a ferroptosis-inducing system x inhibitor, faces clinical challenges due to suboptimal physicochemical and pharmacokinetic properties, as well as relatively low potency and off-target toxicity. Addressing these, we developed ECINs, a novel laser-responsive erastin-loaded nanomedicine utilizing indocyanine green (ICG)-grafted chondroitin sulfate A (CSA) derivatives. Our aim was to improve erastin's tumor targeting via CSA-CD44 interactions and enhance its antitumor efficacy through ICG's photothermal and photodynamic effects in the laser-on state while minimizing off-target effects in the laser-off state. ECINs, with their nanoscale size of 186.7 ± 1.1 nm and high erastin encapsulation efficiency of 93.0 ± 0.8%, showed excellent colloidal stability and sustained drug release up to 120 h. In vitro, ECINs demonstrated a mechanism of cancer cell inhibition via G1-phase cell cycle arrest, indicating a non-ferroptotic action. In vivo biodistribution studies in SK-HEP-1 xenograft mice revealed that ECINs significantly enhanced tumor distribution of erastin (1.9-fold greater than free erastin) while substantially reducing off-target accumulation in the lungs and spleen by 203-fold and 19.1-fold, respectively. Combined with laser irradiation, ECINs significantly decreased tumor size (2.6-fold, compared to free erastin; 2.4-fold, compared to ECINs without laser irradiation) with minimal systemic toxicity. This study highlights ECINs as a dual-modality approach for liver cancer treatment, demonstrating significant efficacy against tumors overexpressing CD44 and system x.
依拉司群（一种铁死亡诱导的系统 X 抑制剂）由于理化性质和药代动力学性质不理想，以及相对较低的效力和脱靶毒性，在临床上面临挑战。针对这些问题，我们开发了 ECINs，这是一种新型的激光响应的负载依拉司群的纳米药物，利用了吲哚菁绿（ICG）接枝的硫酸软骨素 A（CSA）衍生物。我们的目标是通过 CSA-CD44 相互作用改善依拉司群的肿瘤靶向性，并通过 ICG 在激光开启状态下的光热和光动力效应增强其抗肿瘤功效，同时在激光关闭状态下最小化脱靶效应。ECINs 的纳米尺寸为 186.7±1.1nm，依拉司群的包封效率为 93.0±0.8%，具有优异的胶体稳定性和长达 120h 的持续药物释放。体外实验表明，ECINs 通过 G1 期细胞周期阻滞抑制癌细胞，表明其具有非铁死亡作用。在 SK-HEP-1 异种移植小鼠的体内生物分布研究中，ECINs 显著增强了依拉司群在肿瘤中的分布（比游离依拉司群高 1.9 倍），同时分别减少了 203 倍和 19.1 倍在肺部和脾脏中的非靶标积累。与激光照射相结合，ECINs 显著减小了肿瘤体积（与游离依拉司群相比，减小了 2.6 倍；与未接受激光照射的 ECINs 相比，减小了 2.4 倍），同时系统毒性最小。这项研究强调了 ECINs 作为治疗肝癌的一种双重模式方法，对过度表达 CD44 和系统 X 的肿瘤具有显著的疗效。
