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Pharmaceutical Research 29 (7): 1949-1959 (2012-07)

Orthmann A.; Zeisig R.; Suess R.; Lorenz D.; Lemm M.; Fichtner I.

Treatment of experimental brain metastasis with MTO-liposomes: impact of fluidity and LRP-targeting on the therapeutic result

PURPOSE: To test targeted liposomes in an effort to improve drug transport across cellular barriers into the brain. METHODS: Therefore we prepared Mitoxantrone (MTO) entrapping, rigid and fluid liposomes, equipped with a 19-mer angiopeptide as ligand for LDL lipoprotein receptor related protein (LRP) targeting. RESULTS: Fluid, ligand bearing liposomes showed in vitro the highest cellular uptake and transcytosis and were significantly better than the corresponding ligand-free liposomes and rigid, ligand-bearing vesicles. Treatment of mice, transplanted with human breast cancer cells subcutaneously and into the brain, with fluid membrane liposomes resulted in a significant reduction in the tumor volume by more than 80% and in a clear reduction in drug toxicity. The improvement was mainly depended on liposome fluidity while the targeting contributed only to a minor degree. Pharmacokinetic parameters were also improved for liposomal MTO formulations in comparison to the free drug. So the area under the curve was increased and t(1/2) was extended for liposomes. CONCLUSION: Our data show that it is possible to significantly improve the therapy of brain metastases if MTO-encapsulating, fluid membrane liposomes are used instead of free MTO. This effect could be further enhanced by fluid, ligand bearing liposomes.

Keywords: Mice, Animals, Uptake, Transcytosis, Targeting, LRP, Brain Metastases

Type: Article

PubMed: 22399388
Official URL: https://doi.org/10.1007/s11095-012-0723-7
MDC Repository: https://edoc.mdc-berlin.de/12186/