Engineered redox-responsive PEG detachment mechanism in PEGylated nano-graphene oxide for intracellular drug delivery.
In biomedical applications, polyethylene glycol (PEG) functionalization has been a major approach to modify nanocarriers such as nano-graphene oxide for particular biological requirements. However, incorporation of a PEG shell poses a significant diffusion barrier that adversely affects the release of the loaded drugs. This study addresses this critical issue by employing a redox-responsive PEG detachment mechanism. A PEGylated nano-graphene oxide (NGO-SS-mPEG) with redox-responsive detachable PEG shell is developed that can rapidly release an encapsulated payload at tumor-relevant glutathione (GSH) levels. The PEG shell grafted onto NGO sheets gives the nanocomposite high physiological solubility and stability in circulation. It can selectively detach from NGO upon intracellular GSH stimulation. The surface-engineered structures are shown to accelerate the release of doxorubicin hydrochloride (DXR) from NGO-SS-mPEG 1.55 times faster than in the absence of GSH. Confocal microscopy shows clear evidence of NGO-SS-mPEG endocytosis in HeLa cells, mainly accumulated in cytoplasm. Furthermore, upon internalization of DXR-loaded NGO with a disulfide-linked PEG shell into HeLa cells, DXR is effectively released in the presence of an elevated GSH reducing environment, as observed in confocal microscopy and flow cytometric experiments. Importantly, inhibition of cell proliferation is directly correlated with increased intracellular GSH concentrations due to rapid DXR release.
The Institute for Advanced Materials and Nano Biomedicine, Tongji University School of Medicine, Shanghai 200092, P.R. China.
Huiyun
H
Wen
Chunyan
C
Dong
Haiqing
H
Dong
Aijun
A
Shen
Wenjuan
W
Xia
Xiaojun
X
Cai
Yanyan
Y
Song
Xuequan
X
Li
Yongyong
Y
Li
Donglu
D
Shi
D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006108:Graphite / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D010084:Oxidation-Reduction / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry*
D004337:Drug Carriers; D011092:Polyethylene Glycols; D006108:Graphite; D004317:Doxorubicin; D005978:Glutathione