ADAM 8 as a novel target for doxorubicin delivery to TNBC cells using magnetic thermosensitive liposomes.

Metastatic breast cancer is one of the most common causes of cancer-related death in women worldwide. The transmembrane metalloprotease-disintegrin (ADAM8) protein is highly overexpressed in triple-negative breast cancer (TNBC) cells and potentiates tumor cell invasion and extracellular matrix remodeling. Exploiting the high expression levels of ADAM8 in TNBC cells by delivering anti-ADAM8 antibodies efficiently to the targeted site can be a promising strategy for therapy of TNBC. For instance, a targeted approach with the aid of ultra-high field magnetic resonance imaging (UHF-MRI) activatable thermosensitive liposomes (LipTS-GD) could specifically increase the intracellular accumulation of cytotoxic drugs. The surface of doxorubicin-loaded LipTS-GD was modified by covalent coupling of MAB1031 antibody (LipTS-GD-MAB) in order to target the overexpressed ADAM8 in ADAM8 positive MDA-MB-231 cells. Physicochemical characterization of these liposomes was performed using size, surface morphology and UHF-MRI imaging analysis. In vitro cell targeting was investigated by the washing and circulation method. Intracellular trafficking and lysosomal colocalization were assessed by fluorescence microscopy. Cell viability, biocompatibility and in-ovo CAM assays were performed to determine the effectiveness and safety profiles of liposome formulations. Our results show specific binding and induction of doxorubicin release after LipTS-GD-MAB treatment caused a higher cytotoxic effect at the cellular target site.

Nucleic acid carrier composed of a branched fatty acid lysine conjugate-Interaction studies with blood components.

For the development of gene therapeutics for systemic administration several hurdles have to be overcome. In this article we screen the branched fatty acid lysine conjugate T14diLys, a newly designed cationic lipid for lipofection, regarding this problem. The structure and particle size of lipoplexes, prepared with lipid formulations which are based on these lipid as nucleic acid complexing agent, are investigated in absence and presence of serum. Nuclease digestion assays were performed to evaluate the protective characteristics of the lipid formulation for the complexed nucleic acid. Furthermore, the lipid formulation is investigated regarding the interaction with different serum proteins to get first insights into the protein corona formation. Another focus is set on the hemocompatibility using in vitro assays for hemolysis and complement activation and the irritation test at the chorion allantois membrane of the chicken embryo as in vivo model. Finally, preliminary transfection efficiency studies with cell culture models for cells which are assessable via systemic administration are performed to evaluate possibilities for future therapeutic applications of the new lipid formulations. Summarizing, T14diLys with the co-lipid DOPE can be used to prepare a lipoplex formulation which can be applied systemically and can be used to develop gene therapeutics for targeting endothelial cells, macrophages, or leucocytes.