Size Dependent Liposome Degradation in Blood:In vivo/In vitroCorrelation by Kinetic Modeling

Abstract

The degradation of liposomes in blood circulation is important in regulating the releasing rate of encapsulated compounds. In this study, the effect of liposome size--one of the principal determining factors in liposome disposition--on their degradation in serum/blood was evaluated quantitatively both in vitro and in vivo. In the in vitro study, the time courses of the degradation of liposomes in fresh rat serum were measured continuously using 5(6)-carboxyfluorescein (CF) as an aqueous phase marker and were described by the kinetic model with the lag time (tau), first order degradation rate constant (k), and the maximum degradation (alpha). Both k and alpha increased with the increase of liposome size, which indicated a higher affinity of larger liposomes for complement activation. In the in vivo study, the degradation of liposomes was evaluated sensitively by a first order degradation rate constant (kd) in blood circulation. The kd was obtained by kinetically modeling the liposome degradation in vivo using 3H-inulin as an aqueous phase marker. The size dependent kd correlated well with the hepatic uptake clearance, which suggests an underlying complement activation mechanism common to both degradation and hepatic uptake of liposomes. There was a good correlation in the degradation rate constant between in vitro and in vivo trials. These kinetic analyses validate the quantitative evaluation of liposome degradation in blood circulation and provide a useful way to predict the degradation of liposomes in vivo from in vitro experiments.

Photodynamic therapy with conventional and PEGylated liposomal formulations of mTHPC (temoporfin): comparison of treatment efficacy and distribution characteristics in vivo

“…Although the estimation of liposome stability was carried out in serum in vitro (not in vivo), a direct correlation between the stability in vitro and in vivo had been established before. 31,32 Liposomal mTHPC injected as Foslip ® is almost completely eliminated from the circulation already after 1 hour, while Fospeg ® provides a substantial amount of circulating liposomal drug for up to 6 hours ( Figure 3B). …”

Preparation of Alendronate Liposomes for Enhanced Stability and Bioactivity: In Vitro and In Vivo Characterization

“…The concentration of the drug was determined in all fractions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) as an additional measure of vesicle integrity (Fig. 2, middle column).…”

“…In the spiked formulation, alendronate was detected in fractions 5 to 10 (Fig. 2b, middle column) corresponding to free alendronate, and exceedingly low concentrations of the drug near the detection limit were found in other fractions (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

“…The physicochemical properties of liposomes including size, charge, lipid composition, and cholesterol content are governing factors of stability, blood integrity, and clearance rate from the circulation (11)(12)(13). Premature discharge of the encapsulated drug would reduce bioactivity since less drug will be delivered to the phagocytic cell and may increase the possibility of untoward effects.…”

“…The formulation of alendronate liposomes examined so far by our group (2,3) was of a wide range of size distribution (100 to 500 nm, with fractions >1 μm), the process was not always reproducible, shelf life stability was less than 1 month, and could not be easily up-scaled for manufacturing (14). All liposomal bisphosphonate formulations reported heretofore were prepared by the reverse-phase evaporation (REV) method (1,10,(15)(16)(17) or the evaporation technique (18,19); encapsulation yield was low (3% and 5-7%, for alendronate (20) and clodronate liposomes (19), respectively), stability in vitro was less than 1 month (19,20), in vivo stability had not been determined, liposome size was characterized with a wide-size distribution (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), and filter-sterilization was impossible.…”