Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, China.
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, Shaanxi, 710061, China.
J Nanobiotechnology. 2024 May 30;22(1):299. doi: 10.1186/s12951-024-02574-6.
Discrepancies in the utilization of reactive oxygen species (ROS) between cancer cells and their normal counterparts constitute a pivotal juncture for the precise treatment of cancer, delineating a noteworthy trajectory in the field of targeted therapies. This phenomenon is particularly conspicuous in the domain of nano-drug precision treatment. Despite substantial strides in employing nanoparticles to disrupt ROS for cancer therapy, current strategies continue to grapple with challenges pertaining to efficacy and specificity. One of the primary hurdles lies in the elevated levels of intracellular glutathione (GSH). Presently, predominant methods to mitigate intracellular GSH involve inhibiting its synthesis or promoting GSH efflux. However, a conspicuous gap remains in the absence of a strategy capable of directly and efficiently clearing GSH.
We initially elucidated the chemical mechanism underpinning oridonin, a diminutive pharmacological agent demonstrated to perturb reactive oxygen species, through its covalent interaction with glutathione. Subsequently, we employed the incorporation of maleimide-liposomes, renowned for their capacity to disrupt the ROS delivery system, to ameliorate the drug's water solubility and pharmacokinetics, thereby enhancing its ROS-disruptive efficacy. In a pursuit to further refine the targeting for acute myeloid leukemia (AML), we harnessed the maleic imide and thiol reaction mechanism, facilitating the coupling of Toll-like receptor 2 (TLR2) peptides to the liposomes' surface via maleic imide. This strategic approach offers a novel method for the precise removal of GSH, and its enhancement endeavors are directed towards fortifying the precision and efficacy of the drug's impact on AML targets.
We demonstrated that this peptide-liposome-small molecule machinery targets AML and consequently induces cell apoptosis both in vitro and in vivo through three disparate mechanisms: (I) Oridonin, as a Michael acceptor molecule, inhibits GSH function through covalent bonding, triggering an initial imbalance of oxidative stress. (II) Maleimide further induces GSH exhaustion, aggravating redox imbalance as a complementary augment with oridonin. (III) Peptide targets TLR2, enhances the directivity and enrichment of oridonin within AML cells.
The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.
癌细胞与正常细胞之间活性氧（ROS）利用的差异是癌症精确治疗的关键，这在靶向治疗领域开辟了一条值得关注的轨迹。这种现象在纳米药物精确治疗领域尤为明显。尽管利用纳米颗粒破坏 ROS 进行癌症治疗已经取得了很大进展，但目前的策略仍然面临着疗效和特异性的挑战。其中一个主要障碍是细胞内谷胱甘肽（GSH）水平升高。目前，减轻细胞内 GSH 的主要方法包括抑制其合成或促进 GSH 外排。然而，缺乏一种能够直接有效清除 GSH 的策略仍然是一个明显的差距。
我们首先阐明了小檗碱的化学机制，小檗碱是一种被证明可以扰乱活性氧的微小药理学试剂，通过与谷胱甘肽的共价相互作用。随后，我们采用马来酰亚胺脂质体的掺入，众所周知，马来酰亚胺脂质体能够破坏 ROS 递药系统，从而改善药物的水溶性和药代动力学，从而增强其 ROS 破坏功效。为了进一步完善急性髓系白血病（AML）的靶向治疗，我们利用马来酰亚胺和巯基反应机制，通过马来酰亚胺将 Toll 样受体 2（TLR2）肽偶联到脂质体表面。这种策略为精确去除 GSH 提供了一种新方法，其增强努力旨在加强药物对 AML 靶点的精确性和功效。
我们证明了这种肽-脂质体-小分子机制靶向 AML，并通过三种不同的机制在体外和体内诱导细胞凋亡：（I）小檗碱作为迈克尔受体分子，通过共价键抑制 GSH 功能，引发氧化应激的初始失衡。（II）马来酰亚胺进一步诱导 GSH 耗竭，加剧氧化还原失衡，作为与小檗碱的互补增强。（III）肽靶向 TLR2，增强了 AML 细胞内小檗碱的定向性和富集。
合理设计的纳米复合物提供了一种 ROS 药物增强和靶向递送平台，通过破坏氧化还原平衡为 AML 治疗提供了一种潜在的解决方案。
