Multi-functionalized graphene oxide based anticancer drug-carrier with dual-targeting function and pH-sensitivity†‡ Xiaoying Yang, * a Yinsong Wang, a Xin Huang, b Yanfeng Ma, c Yi Huang, c Rongcun Yang, b Hongquan Duan a and Yongsheng Chen * c Received 1st August 2010, Accepted 28th September 2010 DOI: 10.1039/c0jm02494e A dual-targeting drug delivery and pH-sensitive controlled release system based on multi- functionalized graphene oxide (GO) was established in order to enhance the effect of targeted drug delivery and realize intelligently controlled release. A superparamagnetic GO–Fe 3 O 4 nanohybrid was firstly prepared via a simple and effective chemical precipitation method. Then folic acid, a targeting agent toward some tumor cells, was conjugated onto Fe 3 O 4 nanoparticles via the chemical linkage with amino groups of the 3-aminopropyl triethoxysilane (APS) modified superparamagnetic GO–Fe 3 O 4 nanohybrid, to give the multi-functionalized GO. Doxorubicin hydrochloride (Dox) as an anti-tumor drug model was loaded onto the surface of this multi-functionalized GO via p–p stacking. The drug loading capacity of this multi-functionalized GO is as high as 0.387 mg mg 1 and the drug release depends strongly on pH values. Cell uptake studies were carried out using fluorescein isothiocyanate labeled or Dox loaded multi-functionalized GO to evaluate their targeted delivery property and toxicity to tumor cells. The results show that this multi-functionalized GO has potential applications for targeted delivery and the controlled release of anticancer drugs. 1. Introduction Since the discovery of the novel nanomaterial graphene in 2004, 1 graphene has attracted much attention for various biological deliveries, including gene and drug delivery and intracellular tracking, etc, due to its capability for traversing the plasma membrane and promoting the cellular uptake of small mole- cules 2,3 and macro-molecules. 4,5 One of the advantages of this nanomaterial is that graphene oxide (GO) can be well-dispersed in water and physiological environments due to its abundant hydrophilic groups, such as hydroxyl, epoxide and carboxylic groups on its large surfaces. In addition, its good biocompati- bility and lack of obvious toxicity make it a promising material for drug carrier substances. 2,3 Although many existing drug carriers have shown numerous advantages such as drug solubilization and prolonged blood circulation, their efficacy is largely constrained by their lack of the ability to achieve high targeting efficiency at tumor sites, because of their limited loading capacity and low degree of functionalization capability. Moreover, insufficient cell uptake further decreases the therapeutic efficacy of the anti-tumor drug, and nonspecific accumulation in normal tissues leads to serious side effects and thus limits their clinical usage. Therefore, many studies have focused on the development of efficient delivery systems with the abilities to enhance special cellular uptake of anti-tumor drugs and to realize intelligent controlled release. A well-known strategy to achieve efficient tumor targeting is to conjugate drug carriers with specific ligands that can recognize molecular signatures on the cancer cell surface. Targeting ligands that can serve such a purpose include folic acid (FA), 6 peptides, 7 transferrin, 8 polysaccharides 9 and monoclonal antibodies. 10 However, the drug delivery systems need to be directed to tumor sites in the first place before recognizing cell surface receptors. Therefore, an external targeting strategy, such as a guided magnetic field, is expected to improve drug delivery efficiency by driving the drug carriers effectively into tumor tissues. Magnetic nanoparticles have been widely used for targeted drug delivery. 11–13 It is believed that drug nanocarriers can be taken up by cells via the endocytosis process. 14,15 While the endocytic pathway begins near the physiological pH of 7.4, it drops to a lower pH value (5.5–6.0) in endosomes and approaches pH 5.0 in lysosomes. 16,17 Therefore, the pH-sensitivity of drug release is very important to avoid undesired drug release during the drug transportation in blood circulation and to improve the effective release of the anti-tumor drug in the tumor tissue or within tumor cells. Due to their high aspect ratio 18 and abundant surface chem- istry, 19,20 functionalized GO has shown great promise as a novel drug delivery system with high efficiency loading, multi-targeted drug delivery and intelligent controlled release. The use of functionalized GO for targeted drug delivery of small molecules such as anticancer drugs is seldom explored. Dai et al. reported PEG-ylated nanographene oxide for delivery of water-insoluble a School of Pharmaceutical Sciences, Basic Medical Research Center, Tianjin Medical University, Tianjin, 300070, China. E-mail: [email protected]b Department of Immunology, College of Medicine, Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, 300071, China c Center for Nanoscale Science and Technology and Key Laboratory of Functional Polymer Materials, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China. E-mail: [email protected]; Fax: +86 (22) 2349-9992; Tel: +86 (22) 2350-0693 † This paper is part of a Journal of Materials Chemistry themed issue on Chemically Modified Graphenes. Guest editor: Rod Ruoff. ‡ Electronic supplementary information (ESI) available: Additional TEM, magnetization curves and FTIR spectrum. See DOI: 10.1039/c0jm02494e This journal is ª The Royal Society of Chemistry 2010 J. Mater. Chem. PAPER www.rsc.org/materials | Journal of Materials Chemistry Downloaded by Nankai University on 24 November 2010 Published on 19 November 2010 on http://pubs.rsc.org | doi:10.1039/C0JM02494E View Online
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Multi-functionalized graphene oxide based anticancer drug-carrier withdual-targeting function and pH-sensitivity†‡
Received 1st August 2010, Accepted 28th September 2010
DOI: 10.1039/c0jm02494e
A dual-targeting drug delivery and pH-sensitive controlled release system based on multi-
functionalized graphene oxide (GO) was established in order to enhance the effect of targeted drug
delivery and realize intelligently controlled release. A superparamagnetic GO–Fe3O4 nanohybrid was
firstly prepared via a simple and effective chemical precipitation method. Then folic acid, a targeting
agent toward some tumor cells, was conjugated onto Fe3O4 nanoparticles via the chemical linkage with
amino groups of the 3-aminopropyl triethoxysilane (APS) modified superparamagnetic GO–Fe3O4
nanohybrid, to give the multi-functionalized GO. Doxorubicin hydrochloride (Dox) as an anti-tumor
drug model was loaded onto the surface of this multi-functionalized GO via p–p stacking. The drug
loading capacity of this multi-functionalized GO is as high as 0.387 mg mg�1 and the drug release
depends strongly on pH values. Cell uptake studies were carried out using fluorescein isothiocyanate
labeled or Dox loaded multi-functionalized GO to evaluate their targeted delivery property and toxicity
to tumor cells. The results show that this multi-functionalized GO has potential applications for
targeted delivery and the controlled release of anticancer drugs.
1. Introduction
Since the discovery of the novel nanomaterial graphene in 2004,1
graphene has attracted much attention for various biological
deliveries, including gene and drug delivery and intracellular
tracking, etc, due to its capability for traversing the plasma
membrane and promoting the cellular uptake of small mole-
cules2,3 and macro-molecules.4,5 One of the advantages of this
nanomaterial is that graphene oxide (GO) can be well-dispersed
in water and physiological environments due to its abundant
hydrophilic groups, such as hydroxyl, epoxide and carboxylic
groups on its large surfaces. In addition, its good biocompati-
bility and lack of obvious toxicity make it a promising material
for drug carrier substances.2,3
Although many existing drug carriers have shown numerous
advantages such as drug solubilization and prolonged blood
circulation, their efficacy is largely constrained by their lack of
the ability to achieve high targeting efficiency at tumor sites,
because of their limited loading capacity and low degree of
aSchool of Pharmaceutical Sciences, Basic Medical Research Center,Tianjin Medical University, Tianjin, 300070, China. E-mail:[email protected] of Immunology, College of Medicine, Key Laboratory ofBioactive Materials, Ministry of Education, Nankai University, Tianjin,300071, ChinacCenter for Nanoscale Science and Technology and Key Laboratory ofFunctional Polymer Materials, Institute of Polymer Chemistry, Collegeof Chemistry, Nankai University, Tianjin, 300071, China. E-mail:[email protected]; Fax: +86 (22) 2349-9992; Tel: +86 (22)2350-0693
† This paper is part of a Journal of Materials Chemistry themed issue onChemically Modified Graphenes. Guest editor: Rod Ruoff.
‡ Electronic supplementary information (ESI) available: AdditionalTEM, magnetization curves and FTIR spectrum. See DOI:10.1039/c0jm02494e
This journal is ª The Royal Society of Chemistry 2010