Abstract
Modification of ultrasmall gold nanoparticles (AuNPs) with the lipoic acid derivative of folic acid was found to enhance their accumulation in the cancer cell, as compared to AuNPs without addressing units. The application of lipoic acid enabled the control of the gold nanoparticle functionalities leading to enhanced solubility and allowing for attachment of both the folic acid and the cytotoxic drug, doxorubicin. More robust attachment of doxorubicin to the nanoparticle through the amide bond resulted in toxicity comparable with that of the drug alone, opening a new perspective for designing more potent, but less toxic nanopharmaceuticals. The increased uptake was accompanied by pronounced nuclear accumulation and observable cytotoxicity. Doxorubicin binding via covalent amide bonds enhanced stability of the whole drug vehicle and provided much better control over doxorubicin release in the cell environment, as compared to physical adsorption or pH sensitive bonding commonly used for anthracycline carriers. Confocal microscopy revealed that the bond was stable in the cytoplasm for 22 h. The ability to slow down the rate of drug release may be crucial for the application in sustained anticancer drug delivery. Biological analyses performed using MTT assay and confocal microscopy confirmed that the ultrasmall AuNPs with the lipoic acid derivative of folic acid exhibit relatively low cytotoxicity, however when loaded with a chemotherapeutic, they cause a significant reduction in the cell viability.
Highlights
A modern targeted anticancer therapy utilizes antineoplastic drugs attached to biologically active molecules, which can selectively access the malformed tissue
E-mail: bilewicz@chem.uw.edu.pl; Tel: +48 22 55 26 357 bCzochralski Laboratory of Advanced Crystal Engineering, Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Zwirki i Wigury 101, 02-089 Warsaw, Poland cCenter for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warszawa, Poland dDepartment of Molecular Biology and Translational Research, Institute of Rural Health, Jaczewskiego 2, 20-090 Lublin, Poland † Electronic supplementary information (ESI) available: NMR spectra, evaluation of the AuNPs concentration and the concentration of the ligands on the AuNPs surfaces that is based on UV-Vis spectroscopy results, thermogravimetric analysis, cyclic voltamogramms and uorescence microscopy of live cells treated with AuNPs-lipoic acid (LA)–Dox for 22 h
The modi ed AuNPs were characterized by transmission electron microscopy (TEM), UV-Vis spectroscopy, thermogravimetric analysis (TGA) and voltammetry
Summary
A modern targeted anticancer therapy utilizes antineoplastic drugs attached to biologically active molecules, which can selectively access the malformed tissue. Gold nanoparticles possess some advantages such as a small size and ligand versatility due to the ease of surface functionalization and are promising candidates for medical use.[1] The acceptable toxicity of AuNPs enables their use for drug delivery to living organisms. The sizes of cells and organelles are in the micrometer range; nanoparticles are excellent candidates for transferring drugs into these biological structures.[2,3,4] One-pot synthesis of gold nanoparticles gives the possibility of producing functional nanoparticles with a high monodispersity index and well characterized core and surface properties without additional steps of exchanging ligands,[5] and appropriately chosen monolayers protecting the gold nanoparticles can provide water solubility and appropriate stability under physiological conditions.[6,7]
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