In vivo evaluation of pH-sensitive polymer-based immunoliposomes targeting the CD33 antigen.
The purpose of this study was to evaluate in vivo a targeted pH-sensitive liposomal formulation tailored to promote the efficient intracellular delivery of 1-beta-d-arabinofuranosylcytosine (ara-C) to human myeloid leukemia cells. Specifically, pH-sensitive immunoliposomes were obtained by anchoring a copolymer of dioctadecyl, N-isopropylacrylamide and methacrylic acid in bilayers of PEGylated liposomes (LP) and by coupling the whole anti-CD33 monoclonal antibody (mAb) or its Fab' fragments. Their pharmacokinetic and biodistribution profiles were assessed in Balb/c and leukemic HL60-bearing immunodepressed (SCID) mice. In naive mice, nontargeted and pH-sensitive Fab'-LP had longer circulation times than LP with whole mAb. In SCID/HL60 (CD33(+)) mice, the pharmacokinetic and biodistribution profiles of LP and encapsulated ara-C were comparable between nontargeted and pH-sensitive Fab'-LP. In leukemic mice, only pH-insensitive, ara-C-loaded Fab' induced prolonged survival times. The apparent absence of pH-sensitive Fab'-LP effect could be related to lower exposure to ara-C in SCID mice.
Simard
Pierre
P
Faculty of Pharmacy, University of Montreal, Montreal (QC), Canada H3C 3J7.
Leroux
Jean-Christophe
JC
D000178:Acrylamides / Q000737:chemistry; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015470:Leukemia, Myeloid, Acute / Q000628:therapy; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011108:Polymers / Q000737:chemistry*; D063268:Sialic Acid Binding Ig-like Lectin 3
D000178:Acrylamides; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D008081:Liposomes; D011108:Polymers; D063268:Sialic Acid Binding Ig-like Lectin 3; C067295:N-isopropylacrylamide