Chemodrug-gated mesoporous nanoplatform for new near-infrared light controlled drug release and synergistic chemophotothermal therapy of tumours

Controlled drug release and synergistic therapies have an important impact on improving therapeutic efficacy in cancer theranostics. Herein, a new near-infrared (NIR) light-controlled multi-functional nanoplatform (GNR@mSiO2-DOX/PFP@PDA) was developed for synergistic chemo-photothermal therapy (PTT) of tumours. In this nano-system, doxorubicin hydrochloride (DOX) and perfluoro-n-pentane (PFP) were loaded into the channels of mesoporous SiO2 simultaneously as a first step. A polydopamine (PDA) layer as the gatekeeper was coated on their surface to reduce premature release of drugs at physiological temperature. Upon 808 nm NIR irradiation, the gold nanorods (GNR) in the core of the nanoplatform show high photothermal conversion efficiency, which not only can provide the heat for PTT, but also can decompose the polymer PDA to allow DOX release from the channels of mesoporous SiO2. Most importantly, the photothermal conversion of GNR can also lead the liquid–gas phase transition of PFP to generate bubbles to accelerate the release of DOX, which can realize the chemotherapy of tumours. The subsequent synergistic chemo-PTT (contributed by the DOX and GNR) shows good anti-cancer activity. This work shows that the NIR-triggered multi-functional nanoplatform is of capital significance for future potential applications in drug delivery and cancer treatment.


2.
To evaluate the in vitro cellular cytotoxicity, it is suggested that the cell viability in normal cells should also be investigated, and the irradiation power of NIR in Figure 5b should also be mentioned.

3.
For in vivo study of tumor growth curves in figure 8d, statistical analysis should be added.

4.
The manuscript contains some grammar errors and inconsistent formats in references section, please check them carefully. 5.
There are some writing mistakes which should be carefully examined and revised. For example, in Figure 3d "R2 = 0.998" should be "R2 =0.998".

Decision letter (RSOS-211004.R0)
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Title: Chemodrug-gated mesoporous nanoplatform for NIR light controlled drug release and synergistic chemophotothermal therapy of tumors Manuscript ID: RSOS-211004 Thank you for your submission to Royal Society Open Science. The chemistry content of Royal Society Open Science is published in collaboration with the Royal Society of Chemistry.
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Once again, thank you for submitting your manuscript to Royal Society Open Science and I look forward to receiving your revision. If you have any questions at all, please do not hesitate to get in touch. ********************************************** Reviewers' Comments to Author: Reviewer: 1 Comments to the Author(s) In this manuscript, the authors developed a multifunctional nanoplatform (GNR@mSiO2-DOX/PFP@PDA) based on gold nanorods (GNR) coated with mesoporous silica (mSiO2) for synergistic chemo-photothermal therapy of tumors. Doxorubicin hydrochloride (DOX) and perfluoro-n-pentane (PFP) were loaded into the pores of mSiO2. A polydopamine (PDA) layer as the gatekeeper of pores was coated on their surface. The whole nano-system is too complex, and the novelty of this work is very poor. There are a lot of similar published works, this manuscript is not suitable for publication on Royal Society Open Science. 1. What is the function of PFP in this nano-system? 2. In Figure 3a and b, one cannot see the difference within different concentrations of GNR solutions and GNR@mSiO2 solutions. These experiments should redo. 3. What is the purpose of microbubbles generation of GNR@mSiO2-PFP? 4. The error bars are missing in Figure 4d. 5. The in vivo chemo-photothermal therapeutic effect is very poor, but the authors claimed that 'the tumor could be basically completely eliminated after 8 ~ 10 days (Figure 8b).' The results are inconsistent with Figure 8c.
Reviewer: 2 Comments to the Author(s) The present study provides a NIR light controlled multifunctional nanoplatform based on gold nanorods coated with mesoporous silica for synergistic chemo-photothermal therapy of tumors. The manuscript is well managed and the work is interesting. However, further work should be done and the paper should be minor revised according to the following points before its acceptance.
1. The authors claimed that the photothermal conversion of GNR can also lead the liquid-gas phase transition of PFP to generate the bubbles to accelerate the release of DOX. For this reason, the control group without NIR in Figure 4c should be added. 2. To evaluate the in vitro cellular cytotoxicity, it is suggested that the cell viability in normal cells should also be investigated, and the irradiation power of NIR in Figure 5b should also be mentioned.

Comments to the Author(s)
The manuscript has been revised mostly according to the comments and suggestions of the reviewers, I recommend the acceptance of the manuscript for publication in Royal Society Open Science.

Do you have any ethical concerns with this paper? No
Have you any concerns about statistical analyses in this paper? Yes

Recommendation?
Accept with minor revision (please list in comments)

Comments to the Author(s)
The authors have addressed all my questions except the statistical analysis in figure 8b. After adding the statistical analysis, this work could be published in Royal Society Open Science.

Decision letter (RSOS-211004.R1)
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Dear Dr Liu: Title: Chemodrug-gated mesoporous nanoplatform for NIR light controlled drug release and synergistic chemophotothermal therapy of tumors Manuscript ID: RSOS-211004.R1 Thank you for submitting the above manuscript to Royal Society Open Science. On behalf of the Editors and the Royal Society of Chemistry, I am pleased to inform you that your manuscript will be accepted for publication in Royal Society Open Science subject to minor revision in accordance with the referee suggestions. Please find the reviewers' comments at the end of this email.
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• Data accessibility It is a condition of publication that you make available the data and research materials supporting the results in the article. Datasets should be deposited in an appropriate publicly available repository and details of the associated accession number, link or DOI to the datasets must be included in the Data Accessibility section of the article (https://royalsocietypublishing.org/rsos/for-authors#question17). Reference(s) to datasets should also be included in the reference list of the article with DOIs (where available).
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• Authors' contributions
Please include an Authors' Contributions section at the end of your main text detailing the contribution of each author. All authors should have read and approved the manuscript before submission and this should be stated in the Authors' Contributions section.
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All contributors who do not meet all of these criteria should be included in the acknowledgements.
We suggest the following format: AB carried out the molecular lab work, participated in data analysis, carried out sequence alignments, participated in the design of the study and drafted the manuscript; CD carried out the statistical analyses; EF collected field data; GH conceived of the study, designed the study, coordinated the study and helped draft the manuscript. All authors gave final approval for publication.
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We thank you very much for serving as editor of our manuscript and also thanks very much for the referees' comments and suggestions. The professional comments are all valuable and helpful for revising and improving our manuscript, as well as have important guiding significance to our researches. Now we have carefully addressed the comments and made the revision accordingly (red marked in the revision). We hope that you and the referee will now deem our manuscript suitable for publication in Royal Society Open Science. We have addressed the reviewer's comments one by one behind this letter (blue marked).

Response to Editors and Reviewers' Comments
Reviewers' comments:
Doxorubicin hydrochloride (DOX) and perfluoro-n-pentane (PFP) were loaded into the pores of mSiO2. A polydopamine (PDA) layer as the gatekeeper of pores was coated on their surface. The whole nano-system is too complex, and the novelty of this work is very poor. There are a lot of similar published works, this manuscript is not suitable for publication on Royal Society Open Science.
Authors＇response: Thanks for your comments. In drug delivery research, the use of stimulation-responsive drug delivery to achieve more accurate and efficient release of drugs is widely favored. However, the release rate of pH, photothermal and other stimulating drug release methods still cannot achieve the desired effect. The nano-system we designed can use the bubbles generated by the phase change agent under the photothermal action to promote and accelerate the drug release together with the photothermal and pH action. We believe the work here does do contributions to the field of accelerating drug release and shortening treatment time. 1. What is the function of PFP in this nano-system? Authors＇response: Thanks for your questions. PFP is perfluoro-pentane, which can be gasified to generate bubbles when heated to high temperature. The original boiling point of PFP is 29 °C, however, it will rise to 40-50 °C due to the blood pressure after intravenous injection. [1] It makes use of the heat produced by the photothermal effect of gold nanorods in the nano-system to realize phase change and generate bubbles, which further accelerate the release of drugs from the pores of the nano-system. Figure 3a    Authors＇response: Thank you for your question, and we have revised the discussion section of in vivo chemo-photothermal therapy. We have deleted the description "the tumor could be basically completely eliminated after 8 ~ 10 days", because the tumor volume is decreased but not disappeared. Compared with the control group (PBS), the tumor inhibitory ratio in GNR@mSiO2-DOX/PFP@PDA + NIR group is estimated to be about 79%. In Figure 8c, the typical photographs of excised tumors also indicate that the treated mouse has the lowest tumor size.

Reviewer #2:
The present study provides a NIR light controlled multifunctional nanoplatform based on gold nanorods coated with mesoporous silica for synergistic chemo-photothermal therapy of tumors. The manuscript is well managed and the work is interesting.
However, further work should be done and the paper should be minor revised according to the following points before its acceptance.

Authors＇response:
We appreciate the reviewer's comments.
1. The authors claimed that the photothermal conversion of GNR can also lead the liquid-gas phase transition of PFP to generate the bubbles to accelerate the release of DOX. For this reason, the control group without NIR in Figure 4c should be added.  2. To evaluate the in vitro cellular cytotoxicity, it is suggested that the cell viability in normal cells should also be investigated, and the irradiation power of NIR in Figure   5b should also be mentioned. We are submitting our revised manuscript entitled "Chemodrug-gated mesoporous nanoplatform for NIR light controlled drug release and synergistic chemophotothermal therapy of tumors" to be considered for publication in Royal Society Open Science.

Authors
We thank you very much for serving as editor of our manuscript and also thanks very much for the referees' comments and suggestions. The professional comments are all valuable and helpful for revising and improving our manuscript, as well as have important guiding significance to our researches. Now we have carefully addressed the comments and made the revision accordingly (red marked in the revision). We hope that you and the referee will now deem our manuscript suitable for publication in Royal Society Open Science. We have addressed the reviewer's comments one by one behind this letter (blue marked).
Yours truly,