Concurrent anti-vascular therapy and chemotherapy in solid tumors using drug-loaded acoustic nanodroplet vaporization

摘要

Drug-loaded nanodroplets (NDs) can be converted into gas bubbles through ultrasound (US) stimulation, termed acoustic droplet vaporization (ADV), which provides a potential strategy to simultaneously induce vascular disruption and release drugs for combined physical anti-vascular therapy and chemotherapy. Doxorubicin-loaded NDs (DOX-NDs) with a mean size of 214 nm containing 2.48 mg DOX/mL were used in this study. High-speed images displayed bubble formation and cell debris, demonstrating the reduction in cell viability after ADV. Intravital imaging provided direct visualization of disrupted tumor vessels (vessel size <30 mu m), the extravasation distance was 12 mu m in the DOX-NDs group and increased over 100 mu m in the DOX-NDs + US group. Solid tumor perfusion on US imaging was significantly reduced to 23% after DOX-NDs vaporization, but gradually recovered to 41%, especially at the tumor periphery after 24 h. Histological images of the DOX-NDs + US group revealed tissue necrosis, a large amount of drug extravasation, vascular disruption, and immune cell infiltration at the tumor center. Tumor sizes decreased 22%, 36%, and 68% for NDs + US, DOX-NDs, and DOX-NDs + US, respectively, to prolong the survival of tumor-bearing mice. Therefore, this study demonstrates that the combination of physical anti-vascular therapy and chemotherapy with DOX-NDs vaporization promotes uniform treatment to improve therapeutic efficacy.