Anticancer Cationic Ruthenium Nanovectors: From Rational Molecular Design to Cellular Uptake and Bioactivity

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• 作者：Gaetano Mangiapia ; Giuseppe Vitiello ; Carlo Irace ; Rita Santamaria ; Alfredo Colonna ; Ruggero Angelico ; Aurel Radulescu ; Gerardino D鈥橢rrico ; Daniela Montesarchio ; Luigi Paduano
• 刊名：Biomacromolecules
• 出版年：2013
• 出版时间：August 12, 2013
• 年：2013
• 卷：14
• 期：8
• 页码：2549-2560
• 全文大小：733K
• 年卷期：v.14,no.8(August 12, 2013)
• ISSN：1526-4602

文摘

An efficient drug delivery strategy is presented for novel anticancer amphiphilic ruthenium anionic complexes, based on the formation of stable nanoparticles with the cationic lipid 1,2-dioleyl-3-trimethylammoniumpropane chloride (DOTAP). This strategy is aimed at ensuring high ruthenium content within the formulation, long half-life in physiological media, and enhanced cell uptake. An in-depth microstructural characterization of the aggregates obtained mixing the ruthenium complex and the phospholipid carrier at 50/50 molar ratio is realized by combining a variety of techniques, including dynamic light scattering (DLS), small angle neutron scattering (SANS), neutron reflectivity (NR), electron paramagnetic resonance (EPR), and zeta potential measurements. The in vitro bioactivity profile of the Ru-loaded nanoparticles is investigated on human and non-human cancer cell lines, showing IC₅₀ values in the low 渭M range against MCF-7 and WiDr cells, that is, proving to be 10鈥?0-fold more active than AziRu, a previously synthesized NAMI-A analog, used for control. Fluorescence microscopy studies demonstrate that the amphiphilic Ru-complex/DOTAP formulations, added with rhodamine-B, are efficiently and rapidly incorporated in human MCF-7 breast adenocarcinoma cells. The intracellular fate of the amphiphilic Ru-complexes was investigated in the same in vitro model by means of an ad hoc designed fluorescently tagged analog, which exhibited a marked tendency to accumulate within or in proximity of the nuclei.