Glutathione-Triggered “Off–On” Release of Anticancer Drugs from Dendrimer-Encapsulated Gold Nanoparticles

Abstract

Polymeric nanoparticles that can stably load anticancer drugs and release them in response to a specific trigger such as glutathione are of great interest in cancer therapy. In the present study, dendrimer-encapsulated gold nanoparticles (DEGNPs) were synthesized and used as carriers of thiolated anticancer drugs. Thiol-containing drugs such as captopril and 6-mercaptopurine loaded within DEGNPs showed an "Off−On" release behavior in the presence of thiol-reducing agents such as glutathione and dithiothreitol. Thiolated doxorubicin and cisplatin, loaded within the nanoparticle, showed much reduced cytotoxicity as compared to the free anticancer compounds. The toxicity of drug-loaded DEGNPs can be enhanced by improving the intracellular glutathione. Glutathione-triggered release of thiolated doxorubicin within cancer cells is further confirmed by flow cytometry and confocal laser scan microscopy studies. In addition, DEGNPs showed excellent biocompatibility on several cell lines. This study provides a new insight into biomedical applications of dendrimers and dendrimer-encapsulated nanoparticles.

Endogenous Stimuli-responsive Nanocarriers for Drug Delivery

“…Reduction-sensitive systems can also be adopted in nanocarriers, such as cationic polyamidoamine dendrimers, dendrimer-encapsulated gold nanoparticles, 36 disulfide crosslink nanogels, 37 liposomes, 38 capped mesoporous nanoparticles, 39 etc. For liposome-based systems, they usually have two forms of disulfide-conjugated lipids on their surface.…”

PEGylated mesoporous silica as a redox-responsive drug delivery system for loading thiol-containing drugs

“…This property is particularly important for drugs which are toxic or whose therapeutic dosage demands precise control. Stimuli-responsive DDS can involve a variety of stimuli such as changes in pH (Kim et al, 2010;Lee et al, 2010;Chen et al, 2013), reducing agents (Chen et al, 2013;Wang et al, 2013), enzymes (Park et al, 2009), temperature, and light (He et al, 2012). It is generally accepted that the concentration of glutathione (GSH) between extracellular fluids (2-20 mM) and intracellular fluids (1-10 mM) is significantly different (Cheng et al, 2011).…”

“…The easily functionalized surface facilitates assembly of different moieties. In recent years, strategies based on drugs conjugated onto carriers, such as MSN and polymer or lipids materials, by stimuli-responsive bonds have been developed to achieve a 'zero premature release' ability (Lee et al, 2010;Duan et al, 2013;Wang et al, 2013). In this study, we describe the development of a redox-responsive DDS with the drug covalently grafted onto MSN by disulfide bonds.…”

“…In this study, we describe the development of a redox-responsive DDS with the drug covalently grafted onto MSN by disulfide bonds. Although only a limited number of drugs have a mercapto group, some drugs (such as doxorubicin or cisplatin) can undergo thiol grafting by a simple modified process, and then be covalently grafted to MSN by disulfide bonds (Ahn et al, 2013;Wang et al, 2013).…”

Nanoparticle delivery of photosensitive Pt(IV) drugs for circumventing cisplatin cellular pathway and on-demand drug release

“…In the tumor site, polymeric nanoparticles enter the cancer cells via endocytosis with considerable efficiency [4,26,27]. For this specific aim, a number of drug delivery systems have been developed for the delivery of platinumbased drugs [4,28,29]. Notably, some nanoparticular drug delivery systems are under clinical evaluation.…”