Autophagy blockade synergistically enhances nanosonosensitizer-enabled sonodynamic cancer nanotherapeutics

• Published in: Journal of nanobiotechnology Vol. 19; no. 1; pp. 112 - 15
• Main Authors: Zhou, Liqiang, Huo, Minfeng, Qian, Xiaoqin, Ding, Li, Yu, Luodan, Feng, Wei, Cui, Xinwu, Chen, Yu
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.04.2021; BioMed Central; BMC
• Subjects: Animal models; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; Autophagy; Autophagy (Cytology); Autophagy - drug effects; Autophagy inhibition; Biotechnology; Cancer; Cancer therapies; Care and treatment; Cell culture; Cell Line, Tumor; Cell survival; Combinatorial analysis; Female; Health aspects; Humans; Kinases; MAP kinase; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoliposomes; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Neoplasms - therapy; Oxidation resistance; Oxidative stress; Phagocytosis; Polyethylene glycol; Proteins; Protoporphyrin; Protoporphyrin IX; Protoporphyrins - pharmacology; Radiation; Radiation-Sensitizing Agents; Signal transduction; Signaling; Sonication - methods; Sonodynamic therapy; Survival; Synergistic effect; Transcriptome; Tumor therapy; Tumors; Ultrasonic imaging; Ultrasonic Therapy - methods; Ultrasonics in medicine; Ultrasound; China; United States > US; Nanoliposomes; Autophagy; Tumor therapy; Autophagy inhibition; Sonodynamic therapy
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-021-00855-y

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.