Deciphering the role of charge, hydration, and hydrophobicity for cytotoxic activities and membrane interactions of bile acid based facial amphiphiles

Abstract

We synthesized four cationic bile acid based facial amphiphiles featuring trimethyl ammonium head groups. We evaluated the role of these amphiphiles for cytotoxic activities against colon cancer cells and their membrane interactions by varying charge, hydration and hydrophobicity. The singly charged cationic Lithocholic acid based amphiphile (LCA-TMA1) is most cytotoxic, whereas the triply charged cationic Cholic acid based amphiphile (CA-TMA3) is least cytotoxic. Light microscopy and Annexin-FITC assay revealed that these facial amphiphiles caused late apoptosis. In addition, we studied the interactions of these amphiphiles with model membrane systems by Prodan-based hydration, DPH-based anisotropy, and differential scanning calorimetry. LCA-TMA1 is most hydrophobic with a hard charge causing efficient dehydration and maximum perturbations of membranes thereby facilitating translocation and high cytotoxicity against colon cancer cells. In contrast, the highly hydrated and multiple charged CA-TMA3 caused least membrane perturbations leading to low translocation and less cytotoxicity. As expected, Chenodeoxycholic acid and Deoxycholic acid based amphiphiles (CDCA-TMA2, DCA-TMA2) featuring two charged head groups showed intermediate behavior. Thus, we deciphered that charge, hydration, and hydrophobicity of these amphiphiles govern membrane interactions, translocation, and resulting cytoxicity against colon cancer cells.

A Structure–Property Relationship Study of the Well-Defined Telodendrimers to Improve Hemocompatibility of Nanocarriers for Anticancer Drug Delivery

“…Similar phenomena have been reported in the literature. 16 The above NMR results indicated that CA-5OH derivative may have two different isomers, e.g. 3,7- and 3,12-disubstitutions.…”

Effect of a glucose-triazole-hydrogenated cardanol conjugate on lipid bilayer membrane organization and thermotropic phase transition

“…The GTHCC compound was prepared according to the synthetic scheme disclosed earlier [10,11]. All the solvents used were of spectroscopic grade.…”

“…5) [27]. Certain amphiphilic molecules are known to change the T M of lipid bilayer membranes at lower concentration and at higher concentration they are known to solubilise the lipid membranes to form mixed lipid complex aggregate systems [2,4,6,[10][11][12][13][14].…”

“…Such interactions result in significant changes in the structure and dynamics of lipid bilayer membranes [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Solubilisation and perturbation of lipid bilayer membranes using synthetic and biocompatible amphiphilic compounds has been used for isolation and purification of different membrane components [1][2][3][4][5][6][7][8][9][10][11][12][13][14].…”

“…Such interactions result in significant changes in the structure and dynamics of lipid bilayer membranes [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Solubilisation and perturbation of lipid bilayer membranes using synthetic and biocompatible amphiphilic compounds has been used for isolation and purification of different membrane components [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. It is well known that the bioactivity and mechanistic properties of these amphiphilic compounds strongly depend on the nature of hydrophilic and hydrophobic groups [3][4][5][6][7][8][9][10][11][12][13][14]17] solubilisation of lipid bilayer membrane and thermotropic phase behaviour generally depends upon the molecular properties and concentration of the employed compound [1][2]…”