Sonocomplexation as an effective tool to enhance the antitumorigenic effect of metformin: Preparation, in vitro characterization, molecular dynamic simulation & MiaPaCa-2 cell line hypoxia evaluation

This study aimed to prepare metformin-phospholipid sonocomplexes (MPS) to enhance the lipophilicity, hence the permeability of this highly water-soluble drug. Metformin (MET) is an old antidiabetic drug gaining interest for being recently investigated for its antitumorigenic properties. The polarity of MET makes its cellular uptake dependent on cell membrane transporters which poses a challenging limitation to combat cancer at supraphysiological concentrations unachievable in patients. A D-optimal design was adopted to statistically optimize the formulation variables, namely phospholipid: MET ratio, sonication time and phospholipid type. MPS showed a lipophilicity enhancement up to 19 folds based on the partition coefficient comparative study with pure MET. This vast improvement was explained using the packing parameter theory as we hypothesized the self-assembly of MPS in the lipid phase in the form of inverted micelles. This was confirmed by studying MPS on the molecular level using molecular docking and molecular dynamics simulation. The optimal sonocomplex showed 3.2 folds lower IC50, reduced oxygen consumption rate (OCR), hypoxia-inducible factor (HIF-1 alpha) and reactive oxygen species (ROS) in MiaPaCa-2 cells compared to pure MET. These results revealed the potentiality of MPS to alleviate tumor hypoxia more effectively which could be useful for resistant cancers like pancreatic ductal adenocarcinoma (PDAC).