A Native Drug-Free Macromolecular Therapeutic to Trigger Mutual Reinforcing of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction for Cancer Treatment.
Wenhui WangYongteng ZhangZeshu WangXueping LiuSiyu LuXianglong HuPublished in: ACS nano (2023)
Drug-free macromolecular therapeutics are promising alternatives to traditional drugs. Nanomedicines with multiple organelles targeting can potentially increase the efficacy. Herein, a drug-free macromolecular therapeutic was designed to formulate endoplasmic reticulum (ER) and mitochondria dual-targeting nanoparticles (EMT-NPs), which can synergistically elicit ER stress and mitochondrial dysfunction. In vitro experiments indicated that EMT-NPs could effectively enter ER and mitochondria at an approximate ratio of 2 to 3. Subsequently, EMT-NPs could upregulate ER stress-related protein expression (IRE1α, CHOP), boosting calcium ion (Ca 2+ ) efflux and activating the caspase-12 signaling cascade in cancer cells. In addition, EMT-NPs induced direct oxidative stress in mitochondria; some mitochondrial-related apoptotic events such as decreased mitochondrial membrane potential (MMP), upregulation of Bax, cytochrome c release, and caspase-3 activation were also observed for tumor cells upon incubation with EMT-NPs. Furthermore, the leaked Ca 2+ from ER could induce mitochondrial Ca 2+ overloading to further augment cancer cell apoptosis. In brief, mitochondrial and ER signaling networks collaborated well to promote cancer cell death. Extended photoacoustic and fluorescence imaging served well for the treatment of in vivo patient-derived xenografts cancer model. This drug-free macromolecular strategy with multiple subcellular targeting provides a potential paradigm for cancer theranostics in precision nanomedicine.
Keyphrases
- endoplasmic reticulum
- cell death
- oxidative stress
- endoplasmic reticulum stress
- papillary thyroid
- induced apoptosis
- epithelial mesenchymal transition
- squamous cell
- fluorescence imaging
- drug induced
- signaling pathway
- cancer therapy
- cell proliferation
- diabetic rats
- squamous cell carcinoma
- small molecule
- reactive oxygen species
- cell cycle arrest
- emergency department
- protein kinase
- estrogen receptor
- photodynamic therapy
- climate change
- ischemia reperfusion injury
- high glucose
- replacement therapy