International Journal of Nanomedicine (Feb 2021)

Hyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment

  • Farag MM,
  • Abd El Malak NS,
  • Yehia SA,
  • Ahmed MA

Journal volume & issue
Vol. Volume 16
pp. 1005 – 1019

Abstract

Read online

Michael M Farag,1 Nevine S Abd El Malak,1,2 Soad A Yehia,1 Mohammed A Ahmed1,2 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 2School of Pharmacy, New Giza University, Giza, EgyptCorrespondence: Michael M FaragDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, EgyptTel +002-01228150250Email [email protected]: Development of hyaluronic acid conjugated metformin-phospholipid sonocomplexes (HA-MPS), a biphasic complexation product compiled for enhancing both the lipophilicity and targeting potential of Metformin (MET) to CD44 receptors on pancreatic cancer.Methods: MET was chemically conjugated to hyaluronic acid (HA) via amide coupling reaction. Then, the HA conjugated MET was physically conjugated to Lipoid™S100 via ultrasound irradiation. A combined D-optimal design was implemented to statistically optimize formulation variables. The HA-MPS were characterized through solubility studies, partition coefficient, drug content uniformity, particle size and zeta potential. The optimized HA-MPS was tested via proton nuclear magnetic resonance, infrared spectroscopy to elucidate the nature of physicochemical interactions in the complex which was further scrutinized on molecular level via molecular docking and dynamic simulation.Results: The solubility and partition studies showed a lipophilicity enhancement up to 67 folds as they adopted inverted micelles configuration based on the packing parameter hypothesis. The optimized HA-MPS showed 11.5 folds lower IC50, extra 25% reduction in oxygen consumption rate, better reduction in hypoxia-inducible factor and reactive oxygen species in MiaPaCa-2 cells.Conclusion: These results proved better internalization of MET which was reflected by abolishing hypoxic tumour microenvironment, a mainstay toward a normoxic and less resistant pancreatic cancer.Keywords: metformin, pancreatic ductal adenocarcinoma, hypoxia-inducible factor, MiaPaCa-2, hyaluronic acid

Keywords