RESUMEN
Lung carcinoma has become a more and more serious health problem as platinum-based chemotherapy remains a limited benefit. Accumulating evidences indicate that autophagy plays a signiï¬cant role in decreased curative effect and chemotherapy failure. Inhibition of autophagy can potentiate anti-proliferation effect and contribute to tumor regression in lung carcinoma. Here, we showed that the expectorant drug ambroxol (Ax) promoted autophagosomes accumulation by blocking late-stage autophagic flux in lung carcinoma cells. Furthermore, Ax treatment caused alkalization of lysosome and impaired lysosomal degradation capacity, which contributed to decreased autophagosomes-lysosomes fusion and interrupted normal cargo degradation. Ax potentiated cell-killing sensitivity of paclitaxel (PTX) and docetaxel (DTX), which had nothing to do with cell uptake but was associated with enhanced autophagy level. Moreover, Ax in combination with PTX exerted a significantly enhanced tumor-shrinking effect and prolonged survival time in subcutaneous and pulmonary metastatic tumor nude mice models. Considering the superiority of lung protection and excellent safety, Ax shows enormous translational potential and preponderance in clinical lung carcinoma therapy. Together, our findings suggested that the novel function of Ax, namely autophagy inhibition, resulted from alkalization and impaired degradation capacity of lysosome. The combination of Ax and PTX showed an enhanced cytotoxicity in vitro and improved satisfactory curative outcome in vivo. Our research provides a promising therapeutic strategy to lung carcinoma, which has clinical transformation potential and practical application value.
RESUMEN
The antitumor effect of chemotherapeutics loaded micelles mainly depends on two aspects: the accumulation in the tumor region and the penetration into the tumor interior. These two processes have different demands on particle size. The optimal particle size for enhanced permeability and retention (EPR) is commonly believed to be around 100 nm, while much smaller size is desired for deeper penetration into the tumor interior. To address these two different requirements, we constructed size-shifting micelle nanoclusters (MNC) based on a cross-linked framework interspersed with micelles. The particle size of the micelles was 14.6 ± 0.8 nm and increased to 104.2 ± 8.1 nm after the MNC were formed, leading to an effective utilization of the EPR effect. MNC were shifted to independent micelles in lysosomes, so that a more favorable particle size for penetration could be realized. The results of antitumor growth in vivo demonstrated that size-shifting MNC were more beneficial for tumor therapy than micelles.
