title: pH-sensitive immunoliposomes specific to the CD33 cell surface antigen of leukemic cells.
abstract: A promising avenue in cancer therapy using liposomal formulations is the combination of site-specific delivery with triggered drug release. The use of trigger mechanisms in liposomes could be relevant for drugs susceptible to lysosomal hydrolytic/enzymatic degradation. Here, we propose a polymeric pH-sensitive liposome system that is designed to release its content inside the endosomes through a polymer structural change following receptor-mediated internalization. Specifically, pH-sensitive immunoliposomes (ILs) were obtained by including a terminally alkylated copolymer of N-isopropylacrylamide (NIPAM) in the liposome bilayer and by coupling the anti-CD33 monoclonal antibody to target leukemic cells. In vitro release of encapsulated fluorescent probes and cytosine arabinoside (ara-C) revealed that pH-sensitivity of the vector was retained in the presence of the antibody upon incubation in plasma. Flow cytometry and confocal microscopy analyses demonstrated that the pH-sensitive ILs were efficiently internalized by various CD33+ leukemic cell lines while limited interaction was found for liposomes decorated with an isotype-matched control antibody. Finally, the pH-sensitive ILs-CD33 formulation exhibited the highest cytotoxicity against HL60 cells, confirming the role of the NIPAM copolymer in promoting the escape of intact ara-C in the endosomes. These results suggest that this pH-sensitive liposomal formulation could be beneficial in the treatment of acute myeloid leukemia.
authors.affiliation: Canada Research Chair in Drug Delivery, Faculty of Pharmacy, University of Montreal, P.C. 6128 Downtown Station, Montreal (Qc), Canada H3C 3J7.
authors.forename: Pierre
authors.initials: P
authors.lastname: Simard
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000180:Acrylic Resins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D000478:Alkylation; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology; D000915:Antibody Affinity; D000918:Antibody Specificity; D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003080:Cold Temperature; D003561:Cytarabine / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D004705:Endocytosis; D005456:Fluorescent Dyes; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018796:Immunoconjugates / Q000493:pharmacokinetics* / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology; D011109:Polymethacrylic Acids / Q000737:chemistry; D063268:Sialic Acid Binding Ig-like Lectin 3
chemical_list: D000178:Acrylamides; D000180:Acrylic Resins; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D005456:Fluorescent Dyes; D018796:Immunoconjugates; D008081:Liposomes; D011109:Polymethacrylic Acids; D063268:Sialic Acid Binding Ig-like Lectin 3; D003561:Cytarabine; C085085:poly(N-isopropylacrylamide-co-methacrylic acid)