Internalization and Intracellular Trafficking of Poly(propylene imine) Glycodendrimers with Maltose Shell in Melanoma Cells
2012
The diagnosis and treatment of malignant melanoma by means of the formulation of active principles with dendrimeric
nanoparticles is an area of great current interest. The identification and understanding of molecular mechanisms which ensure the integration
of particular dendrimeric nanostructures in tumor cellular environment can provide valuable guidance in their coupling strategies
with antitumor or diagnostic agents. Two structurally distinct maltose-shell modified 5th generation (G5) poly(propylene imine) (PPI)
glycodendrimers fluorescently labeled, (a) with open maltose shell, cationic charged G5-PPI-OS and (b) with dense maltose shell and
nearly neutral G5-PPI-DS, were tested in relation with several melanoma cell lines. We found that three melanoma cell lines internalize
G5-PPI-DS structure more efficiently than non tumoral HEK297T cells. Furthermore, the internalization pathways of G5-PPI-OS and
G5-PPI-DS are characteristic for each tumor cell phenotype and include more than one mechanism. As a general trend, large amounts of
both G5-PPI-OS and G5-PPI-DS are internalized on cholesterol-dependent pathway in MJS primary melanoma cells and on non conventional
pathways in SK28 metastatic melanoma cells. G5-PPI-OS, temporarily retained at plasma membrane in both cell lines, is internalized
slower in metastatic than in primary phenotype. Unlike G5-PPI-OS, G5-PPI-DS is immediately endocytosed in both cell lines. The
unconventional internalization pathway and trafficking, exclusively used by G5-PPI-DS in metastatic cells, is described at molecular
level. The decay kinetics of fluorescent labeled G5-PPI-OS and G5-PPI-DS is distinct in the two cellular phenotypes. Both cationic and
neutral maltose G5-PPI glycodendrimeric structures represent molecules based on which designing of new formulations for therapy
or/and diagnosis of melanoma can be further developed.
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