The functional roles of poly(ethylene glycol)‐lipid and lysolipid in the drug retention and release from lysolipid‐containing thermosensitive liposomes in vitro and in vivo

Triggered release of liposomal contents following tumor accumulation and mild local heating is pursued as a means of improving the therapeutic index of chemotherapeutic drugs. Lysolipid‐containing thermosensitive liposomes (LTSLs) are composed of dipalmitoylphosphatidylcholine (DPPC), the lysolipid monostearoylphosphatidylcholine (MSPC), and poly(ethylene glycol)‐conjugated distearoylphosphatidylethanolamine (DSPE‐PEG₂₀₀₀). We investigated the roles of DSPE‐PEG₂₀₀₀ and lysolipid in the functional performance of the LTSL–doxorubicin formulation. Varying PEG‐lipid concentration (0–5 mol%) or bilayer orientation did not affect the release; however, lysolipid (0–10 mol%) had a concentration‐dependent effect on drug release at 42°C in vitro. Pharmacokinetics of various LTSL formulations were compared in mice with body temperature controlled at 37°C. As expected, incorporation of the PEG‐lipid increased doxorubicin plasma half‐life; however, PEG‐lipid orientation (bilayer vs. external leaflet) did not significantly improve circulation lifetime or drug retention in LTSL. Approximately 70% of lysolipid was lost within 1 h postinjection of LTSL, which could be due to interactions with the large membrane pool of the biological milieu. Considering that the present LTSL–doxorubicin formulation exhibits significant therapeutic activity when used in conjunction with mild heating, our current study provided critical insights into how the physicochemical properties of LTSL can be tailored to achieve better therapeutic activity. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2295–2308, 2010