Tumor targeting in vivo by means of thermolabile fusogenic liposomes.

Thermolabile fusogenic liposomes were devised based on the stoichiometric 1/2 mixtures of dipalmitoylphosphatidylcholine (DPPC) and elaidic acid (ELA) and from the similar stoichiometric mixtures of DPPC, dipalmitoylphosphatidylglycerol (DPPG) and elaidoyl alcohol (EL-OH) or palmitelaidoyl alcohol (PEL-OH). The resulting vesicle suspensions are fusogenic in the region of hyperthermia (> or = 42 degrees C) and can be targeted selectively to the heated tumor tissue. Incorporation of DPPG or fatty alcohols into the vesicle membranes also leads to a non-specific, temporary vesicle material accumulation in the lung, however, probably due to platelet activation. Vesicle material accumulation in A-431 tumors, xenotransplanted in nude mice, after 30 min of local hyperthermia (42 degrees C) is 4-fold higher for the DPPC/ELA (1/2), 2.8-fold higher for the DPPC/DPPG/EL-OH (0.8/0.2/2) and 3.7-fold higher for the DPPC/ELA/EL-OH (1/1/1) mixtures than for similar vesicles used at the physiological temperature. Extension of hyperthermia to 60 min induces a 7.8-fold relative material accumulation in the tumor tissue when the thermolabile, fusogenic DPPC/ELA/EL-OH (1/1/1) vesicles are used. Simple DPPC vesicles only reach concentrations in the heated tumor or muscle tissue that are 1.85-fold and 1.38-fold higher than in the normothermic control, respectively. This is probably a consequence of simple vasodilatation. In vitro experiments revealed that the adsorption of serum proteins to the vesicle membrane decreases the chain-melting phase transition temperature and the transition enthalpy of vesicle suspension. Adsorption is most prominent at the chain-melting phase transition temperature of the mixed lipid bilayers, which is also the critical temperature for the induction of liposome fusion. This hampers the practical use of the resulting vesicle suspension in vivo. The serum-induced decrease of the chain-melting phase transition temperature, which is likely to change as a function of time in vivo, depends on the lipid composition and on the local surface charge density of vesicles. Incorporation of ELA and DPPG concentrations above 15 mol-%, for example, reduce the extent of protein adsorption onto vesicles. This has to be borne in mind when devising vesicles for practical applications.