Dual-drug loaded micelle for combinatorial therapy targeting HIF and mTOR signaling pathways for ovarian cancer treatment

摘要: Mutations in the tumor protein (TP53) and mammalian target of rapamycin (mTOR) pathway have been elucidated as driver mutations ovarian carcinomas that transform into an invasive phenotype under hypoxic conditions. Chetomin (CHE) targets while Everolimus (EVR) acts on mTOR pathway. Poor aqueous solubilities both compounds limit their clinical applications. Diblock copolymer nanoplatforms methoxy poly(ethylene glycol)2000-block-poly (lactic acid)1800 (mPEG2000-b-PLA1800) (mPEG4000-b-PLA2200) were used to formulate individual dual drug loaded micelles (DDM) using solvent evaporation method. The CHE (CHE-M) had a size 21 nm with loading 0.5 mg/mL EVR (EVR-M) DDM around 35 39 nm, respectively, up 2.3 mg/mL. anti-proliferative effects these tested vitro three cell lines (ES2, OVCAR3 TOV21G) exhibiting strong synergistic effect ES2 TOV21G cells. able significantly induce regression xenograft mouse models by inhibiting angiogenesis inducing apoptosis when compared micelles. inhibition hypoxia inducible factor (HIF) pathways has immunohistochemistry studies. In conclusion, we developed mPEG-b-PLA based micellar nanoplatform could prevent resistance delivering multiple drugs at therapeutically relevant concentrations for effectively treating carcinomas.