title: Efficient reduction and pH co-triggered DOX-loaded magnetic nanogel carrier using disulfide crosslinking.
abstract: To reduce leakage on the drug-delivery pathway to minimize side effect of reduction or pH sensitive drug delivery systems, we designed a glutathione (GSH)/pH co-triggered magnetic nanogel drug delivery system for doxorubicin (DOX) based on the GSH concentration and pH difference between intracellular and extracellular environments. The introduction of superparamagnetic iron oxide nanoparticles (SPION) was intended for magnetic targeting. The magnetic DOX-loaded nanogel was then prepared by the oxidation of thiolated alginate with thiolated SPION in the presence of DOX. The nanogel size can be readily regulated in a range of 120-320 nm upon preparation conditions, with a negative surface charge of around -40 mV. Saturation magnetization was estimated at 27.4 emu/g Fe by VSM. In vitro release was conducted in simulated cancerous environment conditions such as a high GSH concentration and mild acidity. As a result, the nanogel expressed, upon dual stimuli of pH 5/10 mM GSH, significantly higher accumulative release than upon single stimulus of pH 5 without GSH or pH 7.4/10 mM GSH. In vitro cytotoxicity against HeLa cells clearly illustrated that the nanogel could effectively inhibit cell growth, and the IC50 was figured out to be 2.3 μg/mL of the nanogel, while the nanogel exclusive of DOX was nontoxic. Confocal laser scanning microscopy observation, combined with the result of Prussian blue staining, indicated that DOX was efficiently internalized into HeLa cells through endocytosis, released into the cytoplasm, and then principally entered the nuclei. The quantitative examination of the iron content revealed an exponential increase in the cellular uptake and an exponential decrease in the uptake efficiency with the fed nanogel. This drug-loaded nanogel could be a promising drug carrier for effective tumor-targeted chemotherapy.
authors.affiliation: Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Huang
authors.affiliation: Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Cai
authors.affiliation: Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, China.
authors.forename: Kaikai
authors.initials: K
authors.lastname: Wen
authors.affiliation: Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Luo
authors.affiliation: Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, China.
authors.forename: Sihui
authors.initials: S
authors.lastname: Long
authors.affiliation: Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, China. Electronic address: fyu@mail.wit.edu.cn.
authors.forename: Faquan
authors.initials: F
authors.lastname: Yu
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D004220:Disulfides / Q000737:chemistry*; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry* / Q000633:toxicity; D005978:Glutathione / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D000080385:Nanogels; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000633:toxicity; D011094:Polyethyleneimine / Q000737:chemistry* / Q000633:toxicity
chemical_list: D004220:Disulfides; D004337:Drug Carriers; D058185:Magnetite Nanoparticles; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D004317:Doxorubicin; D011094:Polyethyleneimine; D005978:Glutathione
keywords: Drug delivery system; Dual parameter co-trigger; Endocytosis; Nanogel; Superparamagnetism