背景:癌细胞与正常细胞之间活性氧(ROS)利用的差异构成了精确治疗癌症的关键时刻,描绘了靶向治疗领域值得注意的轨迹。这种现象在纳米药物精准治疗领域尤为突出。尽管在使用纳米粒子来破坏ROS用于癌症治疗方面取得了长足的进步,当前的策略继续努力应对与疗效和特异性有关的挑战。主要障碍之一在于细胞内谷胱甘肽(GSH)的水平升高。目前,减轻细胞内GSH的主要方法涉及抑制其合成或促进GSH流出。然而,由于缺乏能够直接有效清除GSH的策略,仍然存在明显的差距。
方法:我们最初阐明了支持冬凌草甲素的化学机制,一种被证明能扰乱活性氧的小型药物,通过它与谷胱甘肽的共价相互作用。随后,我们采用了马来酰亚胺脂质体的掺入,以破坏ROS传输系统的能力而闻名,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,我们利用马来酰亚胺和硫醇的反应机理,促进Toll样受体2(TLR2)肽通过马来酰亚胺偶联到脂质体表面。这种战略方法为GSH的精确去除提供了一种新颖的方法,其增强努力旨在加强药物对AML靶标的影响的准确性和有效性。
结果:我们证明了这种肽-脂质体-小分子机制靶向AML,从而通过三种不同的机制在体外和体内诱导细胞凋亡:(I)冬凌草甲素,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,与冬凌草甲素一起加重氧化还原失衡。(III)肽靶向TLR2,增强AML细胞内冬凌草甲素的方向性和富集。
结论:合理设计的纳米复合物提供了ROS药物增强和靶向递送平台,代表通过破坏AML治疗的氧化还原平衡的潜在解决方案。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.