Autophagy blockade synergistically enhances nanosonosensitizer-enabled sonodynamic cancer nanotherapeutics.
Liqiang ZhouMinfeng HuoXiaoqin QianLi DingLuodan YuWei FengXinwu CuiYu ChenPublished in: Journal of nanobiotechnology (2021)
Ultrasound-triggered sonodynamic therapy (SDT) represents an emerging therapeutic modality for cancer treatment based on its specific feature of noninvasiveness, high tissue-penetrating depth and desirable therapeutic efficacy, but the SDT-induced pro-survival cancer-cell autophagy would significantly lower the SDT efficacy for cancer treatment. Here we propose an "all-in-one" combined tumor-therapeutic strategy by integrating nanosonosensitizers-augmented noninvasive SDT with autophagy inhibition based on the rationally constructed nanoliposomes that co-encapsulates clinically approved sonosensitizers protoporphyrin IX (PpIX) and early-phase autophagy-blocking agent 3-methyladenine (3-MA). It has been systematically demonstrated that nanosonosensitizers-augmented SDT induced cytoprotective pro-survival autophagy through activation of MAPK signaling pathway and inhibition of AMPK signaling pathway, and this could be efficaciously inhibited by 3-MA in early-phase autophagy, which significantly decreased the cell resistance to intracellular oxidative stress and complied a remarkable synergistic effect on SDT medicated cancer-cell apoptosis both in vitro at cellular level and in vivo on tumor-bearing animal model. Therefore, our results provide a proof-of-concept combinatorial tumor therapeutics based on nanosonosensitizers for the treatment of ROS-resistant cancer by autophagy inhibition-augmented SDT.
Keyphrases
- signaling pathway
- oxidative stress
- cell death
- endoplasmic reticulum stress
- diabetic rats
- induced apoptosis
- pi k akt
- papillary thyroid
- epithelial mesenchymal transition
- magnetic resonance imaging
- squamous cell
- squamous cell carcinoma
- stem cells
- wastewater treatment
- machine learning
- small molecule
- reactive oxygen species
- cell therapy
- combination therapy
- heat shock
- mesenchymal stem cells
- heat stress