Polymer based pH-sensitive carriers as a means to improve the cytoplasmic delivery of drugs

pH-sensitive mosomal and liposomal formulations bearing alkylated N-isopropylacrylamide (NIPAM) copolymers were characterized with regard to vesicle-polymer interaction, pH-responsiveness and stability in human serum. The interactions between the pH-sensitive NIPAM copolymer and the vesicles were studied by spectrofluorimetry, using covalently-attached pyrene as a probe. In contrast to liposomes, where complexation of copolymer to the lipid bilayer is essentially mediated by hydrophobic interactions, the binding between niosomes and PNIPAM was mainly driven by hydrogen bonding. Both formulations were found to rapidly release their contents under mildly acidic conditions. However, the niosomes lost their pH-sensitivity after incubation in serum, whereas liposomes maintained their ability to respond to pH only when complexed with a copolymer containing a high proportion of hydrophobic anchor. The ability of pH-sensitive liposome/polymer complexes to enhance the cytotoxicity of cytosine arabinofuranoside (ara-C) was evaluated in vitro using macrophage-like J774 cells. Ara-C encapsulated in pl-l-sensitive liposomes exhibited a higher cytotoxicity than the control formulation. This study showed that both niosomes and liposomes can be rendered pH-sensitive by anchoring a randomly-alkylated NIPAM copolymer to their surface. The interactions that take place between the polymer and the vesicles strongly depend on the vesicle nature. pH-sensitive PNIPAM-based liposomes can improve the in vitro efficiency of ara-C. (C) 2002 Elsevier Science B.V. All rights reserved.