Zhu Jiaoyang, Huang Lin, Yang Jing, Li Zongheng, Wu Lihe, Xiong Wei, Feng Jie, Yan Chenggong, Chen Chaomin, Li Yan, Shen Zheyu
Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, 1023 Shatai South Road, Baiyun, Guangzhou, Guangdong 510515, China.
Medical Imaging Center, Nanfang Hospital, Southern Medical University, 1023 Shatai South Road, Baiyun, Guangzhou, Guangdong 510515, China.
Theranostics. 2024 Oct 28;14(19):7349-7369. doi: 10.7150/thno.99295. eCollection 2024.
: A common challenge of drug loading and delivery using magnetic resonance imaging (MRI) contrast agents (CAs) is the tendency of aggregation and precipitation at high drug loading conditions. Herein, we propose a generic strategy of controlled ideal aggregation (CIA) to restrict the tendency. : Fe, β-Lapachone (LAP), brequinar (BQR), or Sorafenib (SOR) was respectively loaded onto Gd poly (acrylic acid) macrochelate (GP), an MRI CA, in the hollow core of nitrite-modified hollow mesoporous organosilica nanoparticles (HMON-SNO). The aggregation of FeGP, LAPGP, BQRGP, and SORGP was controlled to be ideal without precipitation by the fixed space of the HMON-SNO hollow core. The sizes of the ideal aggregates are larger than the mesopore size of HMON-SNO, which prevents premature drug leakage and release. : After the accumulation of FeGP@HMON-SNO in tumors, the presence of glutathione (GSH) in the tumor microenvironment (TME) triggers the HMON-SNO degradation to release NO, Fe and GP. The released Fe reacts with endogenous hydrogen peroxide (HO) to generate Fe and hydroxyl radical (OH). The -SNO groups on the surface of HMON-SNO react with GSH, enabling sustained NO generation. The elevated NO level induces mitochondrial dysfunction, down-regulates lipid droplets through the alleviation of hypoxia and consequently promotes the accumulation of lipid peroxidation (LPO) under excess OH to induce tumor cell ferroptosis. Moreover, the released GP facilitates high contrast -weighted MRI of tumors due to its high value, enabling real-time monitoring for the delivery of FeGP@HMON-SNO. : The proposed strategy of CIA with universality was successfully utilized to restrict the aggregation of MRI CAs at high drug loading conditions. The developed FeGP@HMON-SNO with eminent drug loading content were used for tumor ferroptosis-gas synergistic therapy with high efficacy.
使用磁共振成像（MRI）造影剂（CAs）进行药物负载和递送的一个常见挑战是在高药物负载条件下有聚集和沉淀的倾向。在此，我们提出一种可控理想聚集（CIA）的通用策略来抑制这种倾向。将铁（Fe）、β-拉帕醌（LAP）、布喹那（BQR）或索拉非尼（SOR）分别负载到亚硝酸盐修饰的中空介孔有机硅纳米颗粒（HMON-SNO）的中空核内的一种MRI造影剂钆聚（丙烯酸）大环螯合物（GP）上。通过HMON-SNO中空核的固定空间，将FeGP、LAPGP、BQRGP和SORGP的聚集控制为理想状态而不发生沉淀。理想聚集体的尺寸大于HMON-SNO的介孔尺寸，这可防止药物过早泄漏和释放。FeGP@HMON-SNO在肿瘤中蓄积后，肿瘤微环境（TME）中谷胱甘肽（GSH）的存在会触发HMON-SNO降解以释放一氧化氮（NO）、铁（Fe）和GP。释放出的Fe与内源性过氧化氢（HO）反应生成Fe和羟基自由基（OH）。HMON-SNO表面的-SNO基团与GSH反应，实现NO的持续生成。升高的NO水平诱导线粒体功能障碍，通过缓解缺氧下调脂滴，从而在过量OH存在的情况下促进脂质过氧化（LPO）积累以诱导肿瘤细胞铁死亡。此外，释放出的GP因其高弛豫率有助于肿瘤的高对比度T2加权MRI成像，从而能够对FeGP@HMON-SNO的递送进行实时监测。所提出的具有通用性的CIA策略成功用于抑制高药物负载条件下MRI造影剂的聚集。所研发的具有高药物负载量的FeGP@HMON-SNO用于高效的肿瘤铁死亡-气体协同治疗。
