Hemocompatibility of liposomes loaded with lipophilic prodrugs of methotrexate and melphalan in the lipid bilayer.
A panel of in vitro tests intended for evaluation of the nano-sized drug delivery systems' compliance with human blood was applied to liposomal formulations of anticancer lipophilic prodrugs incorporated into the lipid bilayer. Liposomes on the basis of natural phosphatidylcholine (PC) and phosphatidylinositol (PI), 8:1 (mol) were loaded with 10 mol% of either methotrexate or melphalan 1,2-dioleoylglyceride esters (MTX-DOG and Mlph-DOG respectively) and either decorated with 2 mol% of sialyl Lewis X/A (SiaLe(X/A)) tetrasaccharide ligand or not. Hemolysis rate, red blood cells and platelets integrity and size distribution, complement (C) activation, and coagulation cascade functioning were analyzed upon the material incubation with whole blood. Both formulations were negatively charged with the zeta potential value being higher in the case of MTX-DOG liposomes, which also were larger than Mlph-DOG liposomes and more prone to aggregation. Accordingly, in hemocompatibility tests Mlph-DOG liposomes did not provoke any undesirable effects, while MTX-DOG liposomes induced significant C activation and abnormal coagulation times in a concentration-dependent manner. Reactivity of the liposome surface was not affected by the presence of SiaLe(X/A) or PI. Decrease in liposome loading with MTX-DOG from 10 to 2.5% resulted in lower surface charge density, smaller liposome size and considerably reduced impact on C activation and coagulation cascades.
Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, 117997, Moscow, Russian Federation. natalia@lipids.ibch.ru
Natalia R
NR
Kuznetsova
Chantal
C
Sevrin
David
D
Lespineux
Nicolai V
NV
Bovin
Elena L
EL
Vodovozova
Tamás
T
Mészáros
Janos
J
Szebeni
Christian
C
Grandfils
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008051:Lipid Bilayers / Q000009:adverse effects / Q000097:blood / Q000737:chemistry; D008081:Liposomes / Q000009:adverse effects / Q000097:blood / Q000737:chemistry; D008558:Melphalan / Q000008:administration & dosage*; D008727:Methotrexate / Q000008:administration & dosage*; D053758:Nanoparticles / Q000737:chemistry; D010316:Particle Size; D010713:Phosphatidylcholines / Q000009:adverse effects / Q000097:blood / Q000737:chemistry; D010716:Phosphatidylinositols / Q000009:adverse effects / Q000097:blood / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage*; D013499:Surface Properties
D008051:Lipid Bilayers; D008081:Liposomes; D010713:Phosphatidylcholines; D010716:Phosphatidylinositols; D011355:Prodrugs; D008558:Melphalan; D008727:Methotrexate