Title:A Novel pH-sensitive Nanocomposite Based on Graphene Oxide for
Improving Doxorubicin Release
Volume: 21
Issue: 1
Author(s): Marziye Javaheri Kachousangi*, Amir Shadboorestan, Azam Shamsian, Mohsen Amini, Fatemeh Atyabi and Mohammad Hossein Ghahremani*
Affiliation:
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran,
Iran
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Department of
Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
Keywords:
Functionalized graphene oxide, polyethyleneimine, doxorubicin, hydrazide linker, pH-sensitive, EPR.
Abstract:
Background: Doxorubicin (DOX) as a chemotherapeutic drug has been widely used for
treatment of cancer but because of adverse side effects of this drug, different drug delivery systems have
been tested. One of them has been immobilization of DOX on the graphene oxide (GO) sheets through
non-covalent interactions (GO-DOX) with high efficiency however the release was very low and slow
due to strong forces between DOX and GO.
Objective: The aim of this research was to increase the release of DOX and this goal was achieved
through the covalent binding of DOX to the GO-poly(ethyleneimine) 2KDa conjugate.
Methods: A novel nanocarrier for delivering DOX was fabricated using GO as a basic plane for conjugating
and assembling other compounds. DOX was attached to GO-poly(ethyleneimine) 2KDa conjugate
via a linker containing hydrazide bond. Drug loading and release was investigated at pH 7.5 and pH
5.5. Cytotoxicity was determined by MTT on MCF7 cells and compared with previous nanocarrier.
Results: The fabrication of the nanocarrier and the covalent attachment of DOX to the nanocarrier were
confirmed through FT-IR spectroscopy. The capacity of nanocarrier to load drug was as high as 383%.
96% of initial drug was loaded in the nanocarrier. The weight percentage of the drug in the nanocarrierdrug
conjugate was 79%. Release of drug at pH 5.5 was two times more than release at pH 7.5 and this
evidence supports conjugation of DOX to nanocarrier through hydrazide bond and pH-sensitivity of
related bond. Because of the reliable results, ease of operation, safety and high reproducibility, MTT
was chosen to evaluate the cytotoxicity of samples. Nanocarrier didn’t show significant toxicity even at
high concentrations. IC50 value for chemically-bound DOX to hydrazide-containing GO nanocomposite
was 9.5 μg/ml whereas the IC50 value for GO-DOX was 39 μg/ml after 72 h. Loading of DOX via hydrazide
bond was as low as 4% versus near 75% physical loading of drug while hydrazide bondcontaining
nanocomposite was 4 to 6 fold more toxic than GO-DOX.
Conclusion: Based on the obtained data, the covalent attachment of DOX to the nanocarrier through
hydrazide linkers was an interesting idea that increased drug release and toxicity despite much lower
percentage of covalent attachment compared to non-covalent immobilization.
As could be concluded from this study, nanocarriers based on hydrazide bond could be a good candidate for
drug delivery.
