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Authors Zhang Y, Peng L, Chu J, Zhang M, Sun L, Zhong B, Wu Q
Received 3 July 2018
Accepted for publication 8 August 2018
Published 16 October 2018 Volume 2018:13 Pages 6499—6515
DOI https://doi.org/10.2147/IJN.S179046
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Govarthanan Muthusamy
Peer reviewer comments 2
Editor who approved publication: Dr Linlin Sun
Background: Co-delivery all-trans-retinoic acid (ATRA) and paclitaxel (PTX) is
an effective strategy for cancer therapy. However, in many previous reported
ATRA conjugated co-delivery systems, the ATRA was released slower than PTX, and
the total drug release of ATRA far lower than that of PTX.
Purpose: We designed and prepared a pH and redox
dual responsive drug delivery system (DA-ss-NPs) co-delivery ATRA and PTX for
cancer therapy. The surface charge of DA-ss-NPs could change from negative to
positive under tumor slightly acidic microenvironment, and both drugs could be
quickly released from DA-ss-NPs under intracellular high concentration of
glutathione (GSH).
Methods: The DA-ss-NPs were constructed by encapsulating PTX into the
hydrophobic core of the polymer micelles, in which the polymer was synthesized
by conjugating ATRA and 2,3-Dimethylmalefic anhydride (DMA) on side chains of
Cystamine dihydrochloride (Cys) modified PEG-b -PAsp (named
DA-ss-NPs). The surface charge of DA-ss-NPs under different pH conditions were
detected. And the drug release was also measured under different concentration
of GSH. The therapeutic effect of DA-ss-NPs were investigated in Human lung
cancer A549 cells and A549 tumor-bearing mice.
Results: The zeta potential of DA-ss-NPs was -16.3 mV at pH 7.4, and which
changed to 16 mV at pH 6.5. Cell uptake experiment showed that more DA-ss-NPs
were internalized by A549 cells at pH 6.5 than that at pH 7.4. In addition, in
presence of 10 mM GSH at pH 7.4, about 75%-85% ATRA was released from DA-ss-NPs
within 48 h; but less than 20% ATRA was released without GSH. In vivo antitumor
efficiency showed that the DA-ss-NPs could affectively inhibite the tumor in
compared with control groups.
Conclusion: The charge-reversal and GSH-responsive DA-ss-NPs provide an
excellent platform for potential tumor therapy.
Keywords: all-trans -retionic
acid, dual-responsive, charge reversal, PAsp, PEG-b -PLGA