Long-Circulating, pH-Sensitive Liposomes

A major limiting factor for the wide application of pH-sensitive liposomes is their recognition and sequestration by the phagocytes of the reticulo-endothelial system, which conditions a very shortcirculation half-life. Typically prolonged circulation of liposomes is achieved by grafting their membranes with pegylated phospholipids (PEG–lipids), which have been shown, however, to deteriorate membrane integrity on one hand and to hamper the pH-responsiveness on the other. Hence, the need for novel alternative surface modifying agents to ensure effective half-life prolongation of pH-sensitive liposomes is a subject of intensive research. A series of copolymers having short blocks of lipid-mimetic units has been shown to sterically stabilize conventional liposomes based on different phospholipids. This has prompted us to broaden their utilization to pH-sensitive liposomes, too. The present contribution gives thorough account on the chemical synthesis of these copolymers their incorporation in DOPE:CHEMs pH-sensitive liposomes and detailed explanation on the battery of techniques for the biopharmaceutical characterization of the prepared formulations in terms of pH-responsiveness, cellular internalization, in vivo pharmacokinetics and biodistribution.