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

Abstract

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

Keywords: Combinatorial therapy; HIF pathway inhibition; Multidrug loaded micelle; Ovarian cancer; Polymeric micelle; mTOR pathway inhibition.