Abstract
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.
Highlights
Autophagy is a highly conserved, lysosome-mediated degradation and recycling process by forming doublemembrane autophagosomes that engulf cytoplasmic cargos for delivery to the lysosome [1, 2]
Inspired by the cross-talk between apoptosis and autophagy induced by sonodynamic therapy (SDT), we establish an “all-inone” combined therapeutic strategy integrated with SDT and autophagy inhibition, which is successfully achieved based on the constructed autophagy inhibitor and sonosensitizers co-loaded nanoliposomes as the therapeutic nanosonosensitizers (Fig. 1)
In summary, we initially demonstrated that nanosonosensitizers-medicated SDT induced cytoprotective autophagy attributing to enhanced production of reactive oxygen species (ROS) in breast cancer cells, and explored the expression profiles of mRNAs in MCF-7 cells treated with SDT by emoloying high-throughput RNA sequencing
Summary
Autophagy is a highly conserved, lysosome-mediated degradation and recycling process by forming doublemembrane autophagosomes that engulf cytoplasmic cargos for delivery to the lysosome [1, 2]. Multiple studies have shown that radiotherapy [21], photothermal therapy (PTT) [22, 23], and chemotherapy [24], could lead to the activation of autophagy and the combination of autophagy blockade with these therapeutics has attained a synergistic effect on cancer treatment [25]. All these therapeutic modalities suffer from inherent defects, including ionizing radiation, poor tissue penetration and high toxicity, which inevitably lead to reduced therapeutic effects and severe side effects [26, 27]
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