Tandem Molecular Self-Assembly Selectively Inhibits Lung Cancer Cells by Inducing Endoplasmic Reticulum Stress

Abstract

<jats:p>The selective formation of nanomaterials in cancer cells and tumors holds great promise for cancer diagnostics and therapy. Until now, most strategies rely on a single trigger to control the formation of nanomaterials <jats:italic>in situ</jats:italic>. The combination of two or more triggers may provide for more sophisticated means of manipulation. In this study, we rationally designed a molecule (<jats:italic>Comp. 1</jats:italic>) capable of responding to two enzymes, alkaline phosphatase (ALP), and reductase. Since the A549 lung cancer cell line showed elevated levels of extracellular ALP and intracellular reductase, we demonstrated that <jats:italic>Comp. 1</jats:italic> responded in a stepwise fashion to those two enzymes and displayed a tandem molecular self-assembly behavior. The selective formation of nanofibers in the mitochondria of the lung cancer cells led to the disruption of the mitochondrial membrane, resulting in an increased level of reactive oxygen species (ROS) and the release of cytochrome C (Cyt C). ROS can react with proteins, resulting in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This severe ER stress led to disruption of the ER, formation of vacuoles, and ultimately, apoptosis of the A549 cells. Therefore, <jats:italic>Comp. 1</jats:italic> could selectively inhibit lung cancer cells <jats:italic>in vitro</jats:italic> and A549 xenograft tumors <jats:italic>in vivo</jats:italic>. Our study provides a novel strategy for the selective formation of nanomaterials in lung cancer cells, which is powerful and promising for the diagnosis and treatment of lung cancer.</jats:p>

Photothermally Responsive Conjugated Polymeric Singlet Oxygen Carrier for Phase Change-Controlled and Sustainable Phototherapy for Hypoxic Tumor

“…The red fluorescence in the cytoplasm was found from the cells cultured with CP1-NCs through the confocal images, indicating the abundant uptake and excellent dispersion of CP1-NCs in HeLa cells (Figure S9 ). To investigate the phototherapy performance of the CP1-NCs including 1 O 2 generation, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) [ 65 ], which could be transformed into DCF with green luminescence in the presence of 1 O 2 , was used as a 1 O 2 indicator. As exhibited in Figure 4(b) , the strong green luminescence was observed from the HeLa cells treated with CP1-NCs under 21% and 5% O 2 level, illustrating the production of abundant intracellular 1 O 2 under irradiation.…”

In Situ Construction of Functional Assemblies in Living Cells for Cancer Therapy

“…Based on the above study, Yang group [43] further used the tandem self-assembly to treat lung cancer cells by two enzymes. Lung cancer cells express high levels of extracellular ALP and intracellular reductase.…”

“…(c,d) Reproduced with permission. [43] copyright 2019, AAAS. [44] Copyright 2016, American Chemical Society.…”

“…Copyright 2018, American Association for the Advancement of Science (AAAS). (c,d) Reproduced with permission [43]. copyright 2019, AAAS.…”

Biomaterials based on noncovalent interactions of small molecules

“…Aside from targeting an enzyme or a protein, cell type-specific, dual-targeting nanomedicines offer a better chance for successful targeting cancer cells without inducing acquired drug resistance. Common combinations of dual targets include enzymes and receptors (Wang et al, 2019[ 92 ]), enzymes and ligands (Wang et al, 2016[ 82 ]), two different enzymes (Zheng et al, 2019[ 117 ]), and simply two drugs with different targets (Mang et al, 2019[ 63 ]). The dual-targeting concept is highly useful in designing compounds to control cell fates (Zhou et al, 2017[ 125 ]), including targeting downregulation in cancer cells (Feng et al, 2017[ 25 ]).…”