Treatment of Experimental Brain Metastasis with MTO-Liposomes: Impact of Fluidity and LRP-Targeting on the Therapeutic Result
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- Orthmann, A., Zeisig, R., Süss, R. et al. Pharm Res (2012) 29: 1949. doi:10.1007/s11095-012-0723-7
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To test targeted liposomes in an effort to improve drug transport across cellular barriers into the brain.
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.
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 t1/2 was extended for liposomes.
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.
KEY WORDSbrain metastases LRP targeting transcytosis uptake
Dulbecco’s Modified Eagle Medium
foetal calf serum
LDL-lipoprotein receptor related protein
large unilamellar vesicles
Madin-Darby canine kidney
post insertion technology
relative tumor volume