Physicochemical characterization and toxicity evaluation of steroid-based surfactants designed for solubilization of poorly soluble drugs.
To overcome poor water-solubility of new drug candidates, four innovative surfactants based on naturally-occuring hydrophilic and hydrophobic moities were designed and synthesized: cholesteryl-glutamic acid, cholesteryl-poly[N-2-hydroxyethyl-l-glutamine] (PHEG), ursodeoxycholanyl-PHEG (UDCA-PHEG) and ursodeoxycholanyl-poly-l-glutamic acid (UDCA-PGA). Their self-assembling capacity was evaluated using pyrene fluorescence measurements which allow to determine their critical aggregation concentration (CAC). Size measurements were carried out using dynamic light scattering (DLS). Surfactant cytotoxicity was investigated on human umbilical vein endothelial cells (HUVEC) by determining tetrazolium salt (MTT) activity and lactate dehydrogenase (LDH) release. In addition, surfactant haemolytic activity was assessed using rat red blood cells (RBCs). Finally, the ability of these surfactants to solubilize a model poorly soluble drug was quantified. Surfactant self-assembly, cytotoxicity and solubilization properties were compared to those obtained with polysorbate 80, a model solubilizer. Except for cholesteryl-glutamic acid, surfactants were water-soluble. UDCA-PGA was not able to self-assemble or to increase significantly drug solubility. Results showed that cholesteryl-PHEG and UDCA-PHEG were self-assembling with low CAC values (17 and 120μg/ml) into nano-structures with mean diameters of 13 and 250nm, respectively. Cholesteryl-PHEG was the most efficient surfactant in increasing drug solubility (2mg/ml) but exhibited a similar or higher toxicity than polysorbate 80. UDCA-PHEG did not present any cytotoxicity but was far less efficient to solubilize the drug (0.2mg/ml). These results evidence interesting properties of cholesteryl-PHEG and UDCA-PHEG as novel solubilizers.
Technologie Servier, Orléans, France. nathalie.menard@fr.netgrs.com
Nathalie
N
Ménard
Nicolas
N
Tsapis
Cécile
C
Poirier
Thomas
T
Arnauld
Laurence
L
Moine
François
F
Lefoulon
Jean-Manuel
JM
Péan
Elias
E
Fattal
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002788:Cholesterol Esters / Q000737:chemistry*; D018698:Glutamic Acid / Q000737:chemistry*; D006461:Hemolysis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D010316:Particle Size; D010455:Peptides / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000737:chemistry*; D011136:Polysorbates / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013501:Surface-Active Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D014580:Ursodeoxycholic Acid / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D002788:Cholesterol Esters; D010455:Peptides; D011136:Polysorbates; D013501:Surface-Active Agents; D014867:Water; D011099:Polyglutamic Acid; C027887:poly-N(5)-(2-hydroxyethyl)glutamine; D018698:Glutamic Acid; D014580:Ursodeoxycholic Acid; D007770:L-Lactate Dehydrogenase