Li Zhe, Sun Liyan, Lan Jinshuai, Wu Ya, Yang Siqi, Zhang Tong, Ding Yue
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Mater Today Bio. 2024 Aug 10;28:101200. doi: 10.1016/j.mtbio.2024.101200. eCollection 2024 Oct.
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 and , 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.
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）进行的热介导消融在根除乳腺癌方面显示出巨大的前景。然而，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）表达的增加。这些作为ATP依赖分子伴侣发挥作用的蛋白质，为癌细胞提供保护，使其免受PTT过程中产生的细胞毒性热的影响。糖酵解是乳腺癌细胞产生ATP的重要途径，可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，抑制乳腺癌的生长，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，靶向糖酵解是一种针对HSP表达、乳腺癌增殖并阻碍其转移扩散的策略性方法。在此，我们设计了一种负载吲哚菁绿（ICG）和隐丹参酮（CTS）的透明质酸（HA）包被的沸石咪唑酯骨架-8（ZIF-8）药物递送系统。该药物递送系统具有优异的光热性能，能够达到足以对肿瘤细胞进行光热消融的温度。（ICG + CTS）@HA-ZIF-8还表现出pH响应性药物释放，增强了ICG和CTS的持续释放，以延长它们的全身循环时间。此外，ZIF-8的HA修饰通过增强的渗透和滞留（EPR）效应以及通过CD44受体途径的主动肿瘤靶向作用，增强了其靶向能力，从而在肿瘤中产生更高的药物浓度和更好的治疗效果。（ICG + CTS）@HA-ZIF-8可以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，并提高PTT效果。它对乳腺癌细胞的增殖和迁移均表现出显著的抑制作用，可能为乳腺癌治疗中的可视化PTT提供创新见解。
