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

Abstract

Purpose 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 IC 50 , 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.

Spironolactone hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism: in silico studies, statistical optimization, ex vivo, and in vivo studies

“…Despite that SP possesses several hydrogen bond acceptors ( n = 5), only single polar interaction (hydrogen bonding) was depicted toward the PC since the latter only furnish a single hydrogen bond donor at its phosphate functionality (–OPO(O)OH). The latter predicted docking pose came in good agreement with reported literatures showing preferential binding of several drugs: including metformin and rosuvastatin, at the phosphate head of the PC molecule (Abd-Elsalam et al., 2018 ; Farag et al., 2021 ). However, the skewness of the SP structure toward the hydrophobic PC extended acyl chains was reasoned since SP incorporates a highly hydrophobic cage-like core skeleton resembled in its steroidal nucleus.…”

Repurposing levocetirizine hydrochloride loaded into cationic ceramide/phospholipid composite (CCPCs) for management of alopecia: central composite design optimization, in- silico and in-vivo studies

“…Generally, LVC was anchored at the PC phosphate head exhibiting polar interaction with the PC’s polar phosphate head (–OPO(O)O - ) through the ligand’s terminal carboxylic group (H-bond angle 163.10° length 1.20 Å) ( Figure 4 ). The obtained LVC-PC pose was considered relevant since several reported small molecules, including the oral hypoglycemic agent metformin and hypolipidemic drug rosuvastatin and metformin, illustrated preferential orientations toward the phosphate scaffold of the PC molecule (Abd-Elsalam et al, 2018 ; Farag et al, 2021 ). Stability of the LVC-PC complex was further mediated through combined polar/hydrophobic interactions with CCPCs additives.…”

Exosomal ANXA2 derived from ovarian cancer cells regulates epithelial‐mesenchymal plasticity of human peritoneal mesothelial cells

“…The process of ovarian cancer peritoneal metastasis was involved in multi‐steps including local infiltration, abdominal dissemination, distant invasion, anchoring and adhesion to peritoneum, and synergy with the tumour microenvironment 4,5 . In above process, peritoneal mesothelial cells, as the main components of the human peritoneum, 6,7 could create a suitable environment for tumour intraperitoneal implantation and metastasis through the change of biological properties 8,9 . Accumulating studies have suggested that various tumour cells could modulate the characteristics of peritoneal mesothelial cells by secreting various cytokines and bioactive substances, thus leading to intraperitoneal implantation 10–12 .…”

“… 4 , 5 In above process, peritoneal mesothelial cells, as the main components of the human peritoneum, 6 , 7 could create a suitable environment for tumour intraperitoneal implantation and metastasis through the change of biological properties. 8 , 9 Accumulating studies have suggested that various tumour cells could modulate the characteristics of peritoneal mesothelial cells by secreting various cytokines and bioactive substances, thus leading to intraperitoneal implantation. 10 , 11 , 12 Therefore, a better understanding of the underlying molecular mechanism of malignant progression and peritoneal metastasis of ovarian cancer are essential to improve the survival and prognosis of patients and explore new therapeutic targets with ovarian cancer.…”