Pharmaceutical Research, 2012, Vol.29(7), pp.1949-1959
Byline: Andrea Orthmann (1), Reiner Zeisig (2), Regine Suss (3), Dorothea Lorenz (4), Margit Lemm (1), Iduna Fichtner (1) Keywords: brain metastases; LRP; targeting; transcytosis; uptake Abstract: 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.sub.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. Author Affiliation: (1) Experimental Pharmacology, Max Delbruck Center for Molecular Medicine, Robert-Rossle-Str. 10, 13125, Berlin-Buch, Germany (2) Experimental Pharmacology & Oncology Berlin-Buch GmbH, Robert-Rossle-Str. 10, 13125, Berlin-Buch, Germany (3) Department of Pharmaceutical Technology and Biopharmacy, Albert-Ludwigs University, Stefan-Meier-Str. 19, 79104, Freiburg, Germany (4) Cellular Imaging Leibniz-Institut fur Molekulare Pharmakologie (FMP), Robert-Rossle-Str. 10, 13125, Berlin, Germany Article History: Registration Date: 24/02/2012 Received Date: 05/01/2012 Accepted Date: 24/02/2012 Online Date: 08/03/2012 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s11095-012-0723-7) contains supplementary material, which is available to authorized users.
brain metastases ; LRP ; targeting ; transcytosis ; uptake
View full text in Springer (Subscribers only)