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

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 an...

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Autores principales:	Farag MM, Abd El Malak NS, Yehia SA, Ahmed MA
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	metformin pancreatic ductal adenocarcinoma hypoxia-inducible factor miapaca-2 hyaluronic acid. Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/d72ef7a85e5746698fa0de9f02c59556
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spelling	oai:doaj.org-article:d72ef7a85e5746698fa0de9f02c595562021-12-02T13:50:53ZHyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment1178-2013https://doaj.org/article/d72ef7a85e5746698fa0de9f02c595562021-02-01T00:00:00Zhttps://www.dovepress.com/hyaluronic-acid-conjugated-metformin-phospholipid-sonocomplex-a-biphas-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Michael 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 michael.farag@pharma.cu.edu.egPurpose: 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 acidFarag MMAbd El Malak NSYehia SAAhmed MADove Medical Pressarticlemetforminpancreatic ductal adenocarcinomahypoxia-inducible factormiapaca-2hyaluronic acid.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 1005-1019 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	metformin pancreatic ductal adenocarcinoma hypoxia-inducible factor miapaca-2 hyaluronic acid. Medicine (General) R5-920
spellingShingle	metformin pancreatic ductal adenocarcinoma hypoxia-inducible factor miapaca-2 hyaluronic acid. Medicine (General) R5-920 Farag MM Abd El Malak NS Yehia SA Ahmed MA Hyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment
description	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 michael.farag@pharma.cu.edu.egPurpose: 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
format	article
author	Farag MM Abd El Malak NS Yehia SA Ahmed MA
author_facet	Farag MM Abd El Malak NS Yehia SA Ahmed MA
author_sort	Farag MM
title	Hyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment
title_short	Hyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment
title_full	Hyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment
title_fullStr	Hyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment
title_full_unstemmed	Hyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment
title_sort	hyaluronic acid conjugated metformin-phospholipid sonocomplex: a biphasic complexation approach to correct hypoxic tumour microenvironment
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/d72ef7a85e5746698fa0de9f02c59556
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Hyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment

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