三阴性乳腺癌(TNBC)的特点是复发率和死亡率较高。通过光热疗法(PTT)进行的热介导消融证明了根除乳腺癌的巨大希望。尽管如此,PTT的疗效受到肿瘤细胞热耐受性的阻碍,这归因于热休克蛋白(HSPs)的表达增强。这些蛋白质,作为ATP依赖性分子伴侣,保护癌细胞免受PTT过程中产生的细胞毒性热。糖酵解是乳腺癌细胞产生ATP的重要途径,能促进乳腺癌肺转移的发生和发展。因此,抑制糖酵解可能会减少HSPs的表达,减少乳腺癌的生长,并防止其转移。糖酵解代谢在乳腺癌细胞内的ATP生物合成中起关键作用,促进肺转移的进展和扩散。因此,靶向糖酵解提出了一种HSP表达的战略方法,乳腺癌的增殖,并阻止其转移扩散。在这里,我们设计了一种吲哚菁绿(ICG)和隐丹参酮(CTS)负载透明质酸(HA)的沸石咪唑酯框架-8(ZIF-8)药物递送系统。该给药系统具有优异的光热性能,可以达到足以对肿瘤细胞进行光热消融的温度。(ICG+CTS)@HA-ZIF-8也显示pH响应性药物释放,增强ICG和CTS的持续释放,以延长其体循环持续时间。此外,ZIF-8的HA修饰用于增强其体外和体内靶向能力,利用增强的渗透和保留(EPR)效应,以及通过CD44受体途径主动靶向肿瘤,导致在肿瘤中更高的药物浓度和更好的治疗效果。(ICG+CTS)@HA-ZIF-8下调糖酵解相关蛋白丙酮酸激酶-M2(PKM2)的表达,从而抑制糖酵解过程,进一步抑制肿瘤细胞能量代谢,下调HSPs的表达,克服肿瘤细胞的耐热性,提高PTT效果。它对乳腺癌细胞的增殖和迁移都表现出明显的抑制作用,可能为可视化PTT在乳腺癌治疗中的应用提供创新见解。
Triple-negative breast cancer (TNBC) is characterized by higher recurrence rate and mortality. Thermally-mediated ablation via photothermal therapy (PTT) demonstrates considerable promise for the eradication of breast cancer. Nonetheless, the efficacy of PTT is impeded by the thermal tolerance of tumor cells, which is attributed to the augmented expression of heat shock proteins (HSPs). These proteins, which function as ATP-dependent molecular chaperones, confer protection to cancer cells against the cytotoxic heat generated during PTT. Glycolysis is an important way for breast cancer cells to produce ATP, which can promote the occurrence and development of lung metastasis of breast cancer. Therefore, inhibiting glycolysis may diminish the expression of HSPs, curtail the growth of breast cancer, and prevent its metastasis. Glycolytic metabolism plays a pivotal role in the ATP biosynthesis within breast cancer cells, facilitating the progression and dissemination of pulmonary metastases. Consequently, targeting glycolysis presents a strategic approach to HSP expression, the proliferation of breast cancer, and impede its metastatic spread. Herein, we designed an indocyanine green (ICG) and cryptotanshinone (CTS) loaded hyaluronic acid (HA) coated Zeolitic Imidazolate Framework-8 (ZIF-8) drug delivery system. The drug delivery system had excellent photothermal properties, which could reach temperature sufficient for photothermal ablation of tumor cells. (ICG + CTS)@HA-ZIF-8 also showed pH-responsive drug release, enhancing the sustained release of ICG and CTS to extend their systemic circulation duration. Moreover, the HA modification of ZIF-8 served to augment its targeting capabilities both in vitro and in vivo, leveraging the enhanced permeation and retention (EPR) effect, as well as active tumor targeting via the CD44 receptor pathway, resulting in a higher drug concentration and a better therapeutic effect in tumor. (ICG + CTS)@HA-ZIF-8 could downregulate the expression of glycolysis-related protein pyruvate kinase-M2 (PKM2), thereby inhibiting the glycolysis process, further suppressing tumor cell energy metabolism, downregulating the expression of HSPs, overcoming tumor cell heat resistance, and improving PTT effect. It exhibited a notable suppressive impact on both the proliferation and migration of breast cancer cells, potentially offering innovative insights for the visualized PTT in breast cancer treatment.