Abstract A111: Mouse models of brain metastases from breast cancer showed sensitivity to treatment with novel targeted MTO liposomes.

Abstract

Abstract A systemic treatment of primary and secondary brain tumors remains challenging, because of the highly efficient blood-brain barrier (BBB) preventing the passage of most anticancer drugs. Vesicular carriers can improve the trans-barrier transport. The aim of the study was therefore to develop liposomes as such drug carriers. We evaluated the impact of membrane fluidity and ligand presence for a targeted drug transport into the brain. In vitro investigations using the monolayer barrier forming Madin-Darby canine kidney (MDCK) cells revealed that cellular uptake of liposomes was mainly depending on membrane fluidity and vesicle charge. Liposomes with a positive charge, and fluid vesicles containing dioleylphosphatidylethanolamine in their membrane were taken up most (A. Orthmann et al.; J. Pharm Sciences, 2010). Coating with the short 19mer peptide ligand angiopep 2 to target the low density lipoprotein receptor-related protein (LRP), which is expressed by MDCK cells, resulted in targeted liposomes, which further improved cellular uptake by a factor of 5.5 in comparison to non-targeted rigid liposomes. In vitro, fluid, targeted liposomes achieved the best transcytosis rate in the MDCK cell barrier model with an increase by more than 400% in comparison to rigid, ligand-free liposomes. The most challenging step of drug validation is the in vivo testing in models of brain metastases. Several experimental models of metastasis have been developed in our labs to simulate brain metastasis (J. Hoffmann, J. et al., Neuro-Oncology, 2009). We selected the human MT-3 breast cancer model to test the therapeutic effect of mitoxantrone (MTO) -loaded liposomes in vivo. Cells were transplanted s.c. and into the brain of nude mice. Pharmacokinetic investigations demonstrated a clear prolongation of liposome circulation in the blood with improved PK parameters in comparison to free MTO. Liposomal MTO was stronger accumulated in the s.c. tumor than the free drug. Enhanced accumulation of the encapsulated drug was also found in the brain immediately after injection of liposomes. In a therapy study mice were treated i.v. with 4 mg/kg free MTO, or encapsulated in targeted liposomes to investigate the therapeutic effect. A treatment with angiopeptide bearing, fluid liposomes at day 3, 7 and 10 resulted in a significant reduction in the tumor volume of 88% (s.c. tumor) and 73% (intracerebral tumor), in comparison to control group. Both fluid liposome formulations were significantly more active than the free drug. In addition, both liposomal formulation reduced the side effects (gastrointestinal toxicity and dehydration) caused by the free drug. To summarize our key findings, we found that the new targeted fluid liposomes- show a higher uptake and improved transcytosis in vitro,- have a longer circulation time and showed an enhanced accumulation in tumors,- are more active against s.c. breast cancer and brain metastases in comparison to free MTO, and- reduce the toxic side effects of MTO. In conclusion, we established new targeted liposomes which may serve as platform technology for different anticancer drugs for improved drug transport across the BBB. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A111.