The effective nuclear delivery of doxorubicin from dextran-coated gold nanoparticles larger than nuclear pores

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• 作者：Hongje Jang^b ; Soo-Ryoon Ryoo^a ; Kostas Kostarelos^c ; Sang Woo Han^b ; ^d ; ^{sangwoohan@kaist.ac.kr} ; Dal-Hee Min^a ; ^{dalheemin@snu.ac.kr}
• 关键词：Cancer ; Dextran ; Doxorubicin ; Gold nanoparticle ; Nuclear delivery
• 刊名：Biomaterials
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：34
• 期：13
• 页码：3503-3510
• 全文大小：950 K

文摘

To date, gold nanoparticles (AuNPs) have been investigated for diverse bioapplications. Generally, AuNPs are engineered to possess surface coating with organic/inorganic shells to increase colloidal stability in biological solutions and to facilitate chemical conjugation. In the present study, we developed a strategy to prepare dextran-coated AuNPs with control over its size by simply boiling an aqueous solution of Au salt and dextran, in which dextran serves as both reducing agent for AuNP (Au(0)) formation from Au(III) and AuNP surface coating material. The prepared dextran-coated AuNPs (dAuNPs) maintained its colloidal stability under high temperature, high salt concentration, and extreme pH. Importantly, the dAuNP remarkably improved efficacy of an anti-cancer agent, doxorubicin (Dox), when harnessed as a Dox delivery carrier. The half-maximal inhibitory concentration (EC50) of Dox-conjugated dAuNP with diameter of 170?nm was ¡«9 pM in HeLa cells, which was 1.1?¡Á?10⁵ times lower than that of free Dox and lower than any previously reported values of Dox-nanoparticle complex. Interestingly, smaller AuNPs with 30 and 70?nm showed about 10 times higher EC50 than 170?nm AuNPs when treated to HeLa cells after conjugation with Dox. To achieve high cytotoxicity as cancer therapeutics, Dox should be delivered into nucleus to intercalate with DNA double helix. We show here that Dox-AuNPs was far more efficient as an anti-cancer drug than free Dox by releasing from AuNPs through spontaneous degradation of dextran, allowing free diffusion and nuclear uptake of Dox. We also revealed that larger AuNPs with lower degree of dextran crosslinking promoted faster degradation of dextran shells.