Enhanced cytotoxicity of a redox-sensitive hyaluronic acid-based nanomedicine toward different oncocytes via various internalization mechanisms
Authors: Yunai Du
Tianhao Zhang
Jiasheng Tu
Sheng Wang
Yan Shen
Dongsheng He
Journal: Drug Delivery (2020)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Hyaluronic acid; anticarcinoma; internalization mechanism; vitamin E succinate.
Affiliations: Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, China.

Abstract:  Receptor-mediated active targeting and tumor microenvironment responsive systems from polymeric micelles have been studied for rapid cellular internalization and triggered drug release. Previously we have constructed redox-responsive polymeric micelles composed of vitamin E succinate conjugated hyaluronic acid (HA-ss-TOS), which are able to actively target CD44 proteins and quickly release loaded drugs upon exposure to high levels of glutathione (GSH) in tumor cells. In the present study, we found that despite different cellular internalization mechanisms, micelles showed strong antineoplastic effects on 4T1 and B16F10 cells due to redox responsiveness. HA-ss-TOS-PTX micelles exhibited an excellent tumor targeting ability and prolonged retention time compared to Taxol in vivo. In addition, a superior antitumor effect was achieved compared to PTX-loaded insensitive micelles (HA-TOS-PTX) and Taxol. Our results revealed that PTX-loaded HA-ss-TOS micelles could enhance the antineoplastic efficacy of PTX for breast cancer and melanoma treatment and, thus, deserve further attention. 

Retracted: No

PubPeer comments:
 The mice in Figure 7 are remarkable in their ability to strike a an identical pose 11 hours later. See green and red boxes. Red circles appear in manuscript. I note that the last author appears to have collaborated with Thomas J. Webster of Northeastern. See https: pubpeer.com publications 8994973E1DC6C384321CBAC47F273C for comments on that paper. ***  , 
 Thank you for paying attention to our manuscript. After checking the raw data, the mouse in red and green cycle was the same one respectively and the two groups of mice( in green and red cycle )were taken under anaesthesia and were not move in 12 hours under this condition . So the two groups strike an identical pose, respectively. On the other hand, the results in 6h in the two groups were conducted by using another two mice. We guarantee the results are reproducible and reliable and thanks for your comments again. , 
 #2 Thank you for presenting a possible explanation. On social media others pointed out that I missed one repeated mouse: u201c6h Free DiR is the same as those in the red boxes.u201d I have added an additional red box. In this case, your previous explanation would seem inapplicable. Update: Perhaps the authors could post high-resolution original images here to reassure readers. ***  , 
 #2 Another reader pointed out a problem with your initial explanation: u201cno change in position for 12h might suggest fluid supplementation w saline to prevent hypothermia wasnu2019t given (ethics issue?).u201d Could the authors comment on whether saline was provided during this 12 hour period? If so, how would this be possible without moving the position of the mice. If not, could the authors point to the ethics approval for this animal treatment? I was unable to locate this myself. , 
 #5  WARD of PTX - is this wide-angle XRD? More often abbreviated as WAXD or WAXS or WAXRD. , 
 Another reader pointed out an additional concern: two plots in Figure 2D appear to be unexpectedly similar. For a better illustration see https: twitter.com science_surf status 1242141288574513152?s=20 ***  *** Full figure and caption  , 
 We are investigating this. , 
 #8 Apparently the mice did not even breath during their 12 hours of anaesthesia. Are the authors sure that results obtained from mice maintained in deep anaesthesia for the duration of the experiment are relevant to the metabolisms of mice in a normal state? , 
 #3 When superimposing the inverted images over the highly similar ones, they are almost a perfect match, with a tiny bit scaling up or down. (http: i.imgur.com GhesXve.jpg) , 
 Correction Pages 1752-1753 | Published online: 13 Apr 2020 DOI: 10.1080 10717544.2019.1709919 When this article was first published online there were errors in Figures 2 and 7 as detailed below: 1. The WAXRD of PTX and PTXu2009+u2009HA-TOS in Figure 2(D) was misused and the caption of Figure 2(D) should be the WAXRD instead of WARD. The correct Figure 2 and caption are shown below. Figure 2. (A) TEM image of the HA-ss-TOS-PTX micelles. (B) TEM image of the HA-TOS-PTX micelles. (C) DSC curves of PTX, HA-ss-TOS, the physical mixture of PTX and HA-ss-TOS, and HA-ss-TOS-PTX. (D) WAXRD of PTX, the physical mixture of PTX and HA-ss-TOS, HA-ss-TOS-PTX, the physical mixture of PTX and HA-TOS, HA-TOS-PTX. (E) Fluorescence intensity of pyrene in the presence of different concentrations of GSH: (a) HA-ss-TOS without GSH; (b) HA-ss-TOS with 10u2009mM GSH; (c) HA-ss-TOS with 20u2009mM GSH; and (d) HA-TOS with 20u2009mM GSH. 2. Some mistakes were found in the in vivo imaging in Figure 7(A). The correct Figure 7 is presented below. These figures have been updated in the online article.   , 
 #10 It appears that the author s explanation at #2 was made up, and the repeated use of the same mouse images in Fig 1 (with different flurorescence images superimposed) was an error rather than a result of mouse immobility. We are still left wondering, how did the error arise? How did the researchers find themselves with three copies of one visible-light image of one mouse, and two copies of another image, but superimposed with different fluorescence patterns from different files? ,