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Pharmacokinetic characterization of tumor influx and efflux of liposomes by rapid removal of circulating liposomes

University of British Columbia

Studies in this thesis were aimed at developing a versatile strategy to study tumor influx and efflux pharmacokinetics of liposomes, and comparing these kinetic parameters between conventional and sterically stabilized lipid formulations under specified conditions. This research effort was initiated following recently published studies that indicate the lack of benefits associated with steric stabilization of liposomal drug formulations. In these studies, an improvement in the plasma lipid pharmacokinetics was not translated into improved pharmacokinetics and pharmacodynamics in solid tumors. It was thought that a better understanding for liposomal accumulation in tumors can be gained by characterizing the individual influx and efflux kinetics of liposomes that contribute to the net flux, or accumulation, in solid tumors. Avidin-induced cross-linking of biotinylated liposomes was utilized to rapidly deplete liposomes from the blood compartment, thereby allowing liposome tumor efflux and influx rates to be determined. In the conventional [1,2 distearoyl-sn-glycero-3- phosphocholine (DSPC)/cholesterol (Choi) (55:45 mol ratio)] liposomal system (100 nm in diameter), incorporation of 0.5 mol% N-((6 (Biotinoyl)amino)hexanoyl)-l,2- distearoyl-sn-glycero-3-phosphoethanolamine (Biotin-X-DSPE) into the formulation and administration of 50 μg neutravidin resulted in greater than 90% of plasma liposomal lipid (10 mg/kg and 100 mg/kg) removed within 1 hour in female CD-I mice. This rapid removal was achievable at 1, 4 and 8 hours post-injection of liposomes. Using the LSI 80 human colon carcinoma solid tumor xenograft model in SCID/RAG2 mice, the rapid lipid removal permitted characterization and determination of tumor influx and efflux rate constants, which were estimated to be 0.022 hour⁻¹ and 0.041 hour⁻¹respectively when neutravidin was injected 4 hours after liposome injection. Therefore, it appears that DSPC/Chol liposomal accumulation, in LSI80 solid tumor is dictated primarily by plasma liposome concentrations and liposome rate constant is higher for efflux than influx into the tumor. Rapid elimination (>90% plasma lipid removed within 1 hour) of sterically stabilized or PEGylated [DSPC/Chol/l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [Poly(ethyleneglycol)2000] (PEG₂₀₀₀-DSPE) 5%] liposome systems (100 nm in diameter, at 10 mg/kg and 100 mg/kg lipid dose) in female balb/c mice was achieved with 100 jug of avidin and a double biotinylated system formulated with 0.5 mol% biotin-X-DSPE and 0.5 mol% N-[w-(Biotinoylamino)poly(ethyleneglycol)2000] 1,2-distearoyl-sn-glycero-3- phosphoethanolamine (Biotin-PEG2ooo-DSPE). Using the LSI80 solid tumor xenograft model in SCID/RAG2 mice, the rapid lipid removal led to characterization of tumor influx and efflux rate constants, which were estimated to be 0.062 hour⁻¹ and 0.011 hour⁻¹ respectively when avidin was injected 4 hours after liposome injection. Therefore, it appears that DSPC/Chol/PEG₂₀₀₀-DSPE 5% liposomal accumulation, in LSI80 solid tumor is dictated primarily by plasma liposome concentrations and liposome tumor influx rate constant is greater than efflux rate constant. Comparisons between conventional and sterically stabilized formulation in our studies show that PEGylation results in favourable tumor influx and efflux pharmacokinetics. The question related to the conflicting data of PEGylation arising from the few studies still remains unanswered. Nevertheless, the present thesis introduces a novel methodology that allows characterization of the detailed tumor accumulation properties of liposomes, and the application has the potential to be fully utilized to characterize the impact of various liposome parameters such as dose, composition, and size on the tumor accumulation kinetics.

Thesis/Dissertation

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2009-08-20

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http://hdl.handle.net/2429/12465

Pharmaceutical Sciences

University of British Columbia

UBCV

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