Macrophage membrane entrapped rapamycin-loaded TPGS/F127 micelles through intratracheal instillation for enhanced drug delivery and therapy to lung cancer with pulmonary fibrosis.

PURPOSE: Patients with pulmonary fibrosis are prone to developing lung cancer. Pulmonary fibrosis and lung cancer have many common pathogenic factors and similar pathological features. For patients with IPF combined with lung cancer, there is currently no better treatment method available now. The purpose of this study is to develop a rapamycin pulmonary administration preparation that can treat lung cancer with pulmonary fibrosis, thereby overcoming the limitations of rapamycin treatment.

METHODS

In this study, rapamycin-loaded mixed micelle nanoparticles (TPGS/F127@RAPA) were first prepared by the film dispersion method. Then biomimetic nanoparticles (MM@TPGS/F127@RAPA) were obtained by coating the surface of TPGS/F127@RAPA with macrophage membranes (MM) using a co-incubation method.

RESULTS

TPGS/F127@RAPA and MM@TPGS/F127@RAPA showed particle sizes of about 15 nm and 260 nm respectively. Transmission electron microscope results showed that TPGS/F127@RAPA and MM@TPGS/F127@RAPA had homogeneous spherical shape morphologies and that the TPGS/F127@RAPA core was successfully covered with the macrophage membrane. In vitro studies demonstrated that MM@TPGS/F127@RAPA could effectively inhibit the excessive proliferation and migration of A549 cells and activated-Mlg cells. Moreover, MM@TPGS/F127@RAPA could increase the uptake of rapamycin by cells. By inhibiting the TGF-β1/Smad3 and PI3K/AKT/mTOR signaling pathways, TPGS/F127@RAPA and MM@TPGS/F127@RAPA could further reduce collagen deposition, inhibit tumor cell proliferation and improve lung function. Mice suffering from lung cancer with pulmonary fibrosis were treated with MM@TPGS/F127@RAPA through intratracheal instillation. The results showed that compared with TPGS/F127@RAPA, MM@TPGS/F127@RAPA could better reduce the area of pulmonary fibrosis and collagen deposition, inhibit tumor cell proliferation and improve lung function, exhibit longer retention time in lung and better lung distribution and deposition.

CONCLUSION

Our results revealed that the biomimetic strategy of MM@TPGS/F127@RAPA may be a good choice for the treatment of lung cancer patients with pulmonary fibrosis.