| Lung cancer is one of the malignant tumors with the highest morbidity and mortality in the world.Chemotherapy is the main strategy for those with advanced lung cancer or unsuitable for surgery with metastasis.Unfortunately,the use of chemotherapy drug is limited by its unsatisfied efficacy,poor selectivity,high drug resistance and toxicities to normal tissue.Curcumin(Cur)exerts the anti-lung cancer effects by promoting apoptosis as well as inhibiting cell proliferation,metastasis and angiogenesis.However,its clinical application is limited owing to its poor solubility and bioavailability.Therefore,it is in urgent need of a new Cur formulation with higher water solubility and better biocompatibility to improve its clinical anti-tumor effects.Part 1 Study on the anti-tumor activity of curcumin loaded mPEG-PLA micellesObjective:To explore the effect of Curcumin loaded polymeric micelles on the lung caner.Methods:In this work,Cur-loaded methoxy polyethylene glycol-polylactide polymeric micelles(Cur/mPEG-PLA micelles)were prepared by a thin-film hydration method.Their characteristics and anti-tutmor effects were evaluated subsequently.Results:The averaged size of Cur/mPEG-PLA micelles was 34.9±2.1nm with its polydispersity index(PDI)is 0.109±0.049.The encapsulation efficiency and drug loading were 90.2±0.78%and 9.0±0.07%,respectively.The Cur was constantly released from the Cur/mPEG-PLA micelles and its cellular uptake in A549 was significantly increased.It was also found that Cur/mPEG-PLA micelles inhibited A549 cells proliferation,increased the cell cytotoxicity,induced G2/M stage arrested and promoted cell apoptosis.Moreover,the Cur/mPEG-PLA micelles suppressed the migration and invasion of A549 cells more obviously than free Cur.Additionally,Cur/mPEG-PLA micelles inhibited human umbilical vein endothelial cells(HUVECs)migration,invasion and corresponding tube formation,implying the anti-angiogenesis ability.Its enhanced anti-tumor mechanism may be related to the reduced expression of VEGF,MMP-2,MMP-9 and Bcl-2 as well as the increased expression of Bax.Conclusion:The mPEG-PLA copolymer micelles can serve as an efficient carrier for Cur.The Cur/mPEG-PLA micelles have promising clinical potential in treating non-small cell lung cancer.Part 2 mPEG-PLA/TPGS mixed micelles for delivery of Curcumin for overcoming durg-resistance in lung cancerObjective:To study the effect of Curcumin loaded mixed micelles on proliferation and multidrug resistance of lung cancer cells.Methods:A mixed micelle carrier system,self-assembled by mPEG-PLA and d-a-Tocopherol polyethylene glycol succinate(TPGS)was developed for delivery of Cur.Results:The Cur load mPEG-PLA/TPGS mixed micelles(Cur mixed micelles)with drug loading of 10.7±0.15%had a narrow size distribution around average size 104.35±5.04 nm,and released Cur over an extended period in vitro,DSC and XRD studies also confirmed that Cur was in amorphous or molecular form within mixed micelles.Cur mixed micelles induced cisplatin(DDP)-resistant lung cancer A549/DDP cells cyctotoxicity and apoptosis more effectively than free Cur in vitro.Furthermore,Cur loaded mPEG-PLA/TPGS mixed micelles can also achieve the effect of reversing A549/DDP cells multidrug resistance by inhibiting the activity of P-gp.The Cur mixed micelles were more effective on suppressing tumor growth compared with free Cur.Conclusion:These results suggest that mPEG-PLA/TPGS mixed micelles might be a suitable nanocarrier for Cur to treat drug resistant lung cancer. |
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