State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
University of Science and Technology of China, Hefei 230026, China.
Biomater Sci. 2022 Oct 11;10(20):5947-5955. doi: 10.1039/d2bm00956k.
Mitigating cellular resistance, which could enhance the sensitivity of tumor cells to treatment, is a promising approach for obtaining better therapeutic outcomes. However, the present designs of materials generally disregard this point, or only focus on a single specific resistance. Herein, a strategy based on a series of cascade reactions aiming to suppress multiple cellular resistances is designed by integrating photothermal and chemotherapy into a mitochondria targeted nanosystem (AuBPs@TD). The intelligent nanosystem is fabricated by modifying gold nanobipyramids (AuBPs) with triphenylphosphonium (TPP) functionalized dichloroacetic acid (DCA). TPP serves as a "navigation system" and facilitates the location of AuBPs@TD in the mitochondria. Moreover, the released DCA promoted by the photothermal effect of AuBPs, as the mitochondrial kinase inhibitor, could inhibit glycolysis, and lead to a repressed expression of heat shock protein 90, which is the main resistance protein in cancer cells against photothermal therapy (PTT). Thus, the photothermal antitumor effect can be significantly improved. For the other cascade passage, the hyperthermal atmosphere depresses the expression of P-glycoprotein, a protein associated with drug resistance, and consequently prevents DCA molecules from being expelled in return. Furthermore, the retained DCA molecules elevate the concentration of intracellular hydrogen peroxide, and due to the peroxidase-like activity of AuBPs, increased intracellular reactive oxygen species could be obtained to accelerate apoptosis. As a result, these cascade reactions lead to significant inhibition of cellular resistance and greatly improve the therapeutic performance. This work paves a new way for suppressing cellular resistance to achieve the desired therapeutic effect.
克服细胞耐药性可以增强肿瘤细胞对治疗的敏感性，是获得更好治疗效果的有前途的方法。然而，目前的材料设计通常忽略了这一点，或者只关注单一的特定耐药性。在此，通过将光热疗法和化学疗法整合到一个靶向线粒体的纳米系统（AuBPs@TD）中，设计了一种基于一系列级联反应以抑制多种细胞耐药性的策略。智能纳米系统是通过用三苯基膦（TPP）功能化的二氯乙酸（DCA）修饰金纳米双锥体（AuBPs）来制备的。TPP 作为“导航系统”，有助于 AuBPs@TD 在线粒体中的定位。此外，AuBPs 的光热效应促进释放的 DCA 作为线粒体激酶抑制剂，可以抑制糖酵解，并导致热休克蛋白 90 的表达受到抑制，这是癌细胞对光热疗法（PTT）的主要耐药蛋白。因此，可以显著提高光热抗肿瘤效果。对于另一个级联通道，过热气氛会抑制与耐药性相关的 P-糖蛋白的表达，从而防止 DCA 分子被排出。此外，保留的 DCA 分子会提高细胞内过氧化氢的浓度，并且由于 AuBPs 的过氧化物酶样活性，可以获得更多的细胞内活性氧来加速细胞凋亡。因此，这些级联反应导致显著抑制细胞耐药性，并大大提高治疗效果。这项工作为抑制细胞耐药性以实现理想的治疗效果开辟了新途径。
