Dual-responsive nanodroplets combined with ultrasound-targeted microbubble destruction suppress tumor growth and metastasis via autophagy blockade

The inhibition of autophagy is a feasible clinical strategy in tumor therapy. Traditional autophagy inhibitors are limited in clinical tumor therapy due to nonspecific biodistribution, systemic toxicity and limited antitumor effect. Herein, the autophagy inhibitor hydroxychloroquine (HCQ)-loaded nanodroplets (NDs) are synthesized to overcome these drawbacks. HCQ-NDs are endowed with endogenous pH- and exogenous ultrasound-responsive drug release and contrast enhanced ultrasound imaging performance. The combined application of ultrasound-targeted microbubble destruction (UTMD) and HCQ-NDs can severely break the homeostasis of tumor cells, simultaneously releasing HCQ rapidly to block autophagic flux and thus abolish the cytoprotective function. This strategy presents strong synergistic antitumor efficacy with the tumor growth inhibition value of 80.02% and synchronously inhibits tumor lung metastasis by inhibition of MMP2 and MMP9 production, eventually leading to tumor suppression. In addition, HCQ-NDs show excellent tumor-targeting, biocompatibility, biosafety and contrast-enhanced ultrasound imaging properties. Based on the above findings, this combined strategy rationally regulates the autophagic process of tumor cells and could be instructive for the design of clinical treatment modalities.