Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery
Authors Lee SJ, Jeong Y, Park H, Kang DH, Oh J, Lee S, Lee HC
Received 22 April 2015
Accepted for publication 18 July 2015
Published 28 August 2015 Volume 2015:10(1) Pages 5489—5503
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Govarthanan Muthusamy
Peer reviewer comments 3
Editor who approved publication: Dr Thomas Webster
Sang Joon Lee,1,* Young-Il Jeong,2,* Hyung-Kyu Park,3 Dae Hwan Kang,2,4 Jong-Suk Oh,3 Sam-Gyu Lee,5 Hyun Chul Lee3
1Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, 2Biomedical Research Institute, Pusan National University Hospital, Busan, 3Department of Microbiology, Chonnam National University Medical School, Gwangju, 4Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Gyeongnam, 5Department of Physical and Rehabilitation Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
*These authors contributed equally to this work
Background: Since cancer cells are normally over-expressed cathepsin B, we synthesized dendrimer-methoxy poly(ethylene glycol) (MPEG)-doxorubicin (DOX) conjugates using a cathepsin B-cleavable peptide for anticancer drug targeting.
Methods: Gly-Phe-Leu-Gly peptide was conjugated with the carboxylic acid end groups of a dendrimer, which was then conjugated with MPEG amine and doxorubicin by aid of carbodiimide chemistry (abbreviated as DendGDP). Dendrimer-MPEG-DOX conjugates without Gly-Phe-Leu-Gly peptide linkage was also synthesized for comparison (DendDP). Nanoparticles were then prepared using a dialysis procedure.
Results: The synthesized DendGDP was confirmed with 1H nuclear magnetic resonance spectroscopy. The DendDP and DendGDP nanoparticles had a small particle size of less than 200 nm and had a spherical morphology. DendGDP had cathepsin B-sensitive drug release properties while DendDP did not show cathepsin B sensitivity. Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles. The DendGDP nanoparticles were found to be relatively concentrated in the tumor tissue and revealed stronger fluorescence intensity than at other body sites while doxorubicin and DendDP nanoparticles showed strong fluorescence intensity in the various organs, indicating that DendGDP has cathepsin B sensitivity.
Conclusion: DendGDP is sensitive to cathepsin B in tumor cells and can be used as a cathepsin B-responsive drug targeting strategy. We suggest that DendGDP is a promising vehicle for cancer cell targeting.
Keywords: cathepsin B, CT26 cell, enzyme-sensitive dendrimer, tumor targeting, tetra peptide
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