Journal
JOURNAL OF CONTROLLED RELEASE
Volume 343, Issue -, Pages 66-77Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2022.01.009
Keywords
Ultrasound; Autophagy; Charge conversion; Theranostics; Tumor metastasis
Funding
- National Natural Science Foundation of China [82071937, 81771843]
- Shandong Provincial Natural Science Foundation of China [ZR2019PH067]
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The inhibition of autophagy is a feasible clinical strategy in tumor therapy. In this study, hydroxychloroquine-loaded nanodroplets (HCQ-NDs) were developed to overcome the limitations of traditional autophagy inhibitors. The combination of ultrasound targeted microbubble destruction (UTMD) and HCQ-NDs effectively disrupted the tumor cell homeostasis, blocking autophagic flux and showing strong synergistic antitumor efficacy. HCQ-NDs also exhibited excellent tumor-targeting, biocompatibility, biosafety, and contrast-enhanced ultrasound imaging properties.
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.
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