Connections between Metallic Nanoparticles and Chlorin e6—An Overview of Physicochemical and Biological Properties and Prospective Medical Applications

Round 1

Reviewer 1 Report

Please see attached comments.

Comments for author File: Comments.pdf

Author Response

Dear Reviewer,

Thank you very much for reviewing the manuscript and for your comments. Our responses to your comments are below.

1.) Please see comments in the document itself.

The manuscript was corrected following the Reviewer’s suggestions.

2.) Some references are outdated. Please search the literature for recent updates.

The references were updated – we have reviewed seven recent papers mainly from 2021 to 2023.

3.) Light dose is an essential element in PDT. Please explain why the light doses used in cell culture vary significantly from 1.8-1200 J/cm2 to get the desired decrease in cell viability.

We have checked the manuscript carefully and noticed that the light dose values of 1.8 and 1200 J/cm2 were an error. All values (light doses/light power) were carefully checked and listed in additional tables at the end of each section. The maximum light dose for in vitro PDT studies was 90 J/cm2, which is typical for those studies.

4.) Please include in the table light dosage and % viability.

Following your suggestions, the proper tables at the end of each section were added, including the size of nanoparticles, synthesis methods, light dosages/light powers (if specified), and cell liabilities.

Regards,

Authors

Reviewer 2 Report

Dear Ms. Paweesinee Chatkunakasem,

Thank you for giving me the opportunity to review the manuscript “Connections between metallic nanoparticles and chlorins – An overview of physicochemical, biological properties and prospective medical applications”. In this review, a variety of chlorins ─ metal nanoparticle conjugates is considered, they benefits for application in theranostics are discussed. A list of major comments has to be addressed by the authors before the manuscript can be considered further.

 

Major comments:

1. The introduction contains many repetitive phrases.

2. The manuscript is too narrative and lack of generalizations which have to be presented in Review. For example, it would be helpful to provide data of relative distribution of papers devoted to conjugates of chlorin 6 with various types of metal NPs.

3. The manuscript lacks sufficient details about nanoparticles used in each discussed paper (morphology, size, a method of synthesis).

4. The part addressed to biosafety and metabolism of chlorins ─ metal nanoparticle conjugates has to be added in the manuscript as this topic is very important for their potential iv-vivo applications.

5. Representation of nanoparticles in the Figures 2-4 is too simple and not plausible. Are the particles really so polydisperse? All Figures are too simple and big. In the caption to Figure 3, the numbers in Fe3O4 must be moved to indexes.

6. Summarizings of the part 2.1 and general conclusions are too obvious.

7. There are only 10 references to the papers from the last three years, more number of recent works should be considered.

Comments for author File: Comments.doc

Author Response

Dear Reviewer,

Thank you very much for reviewing the manuscript and for your comments. Our responses to your comments are below.

1. The introduction contains many repetitive phrases.

Following your comment, we have revised the Introduction section to erase repetitive phrases.

2. The manuscript is too narrative and lack of generalizations which have to be presented in Review. For example, it would be helpful to provide data of relative distribution of papers devoted to conjugates of chlorin 6 with various types of metal NPs.

We have emphasized the generalizations as a bullet-points at the end of each section. The information about the reviewed information timescale (2010-2023) was added at the end of the Introduction section.

3. The manuscript lacks sufficient details about nanoparticles used in each discussed paper (morphology, size, a method of synthesis).

Following your suggestions, the proper tables at the end of each section were added, including the size of nanoparticles, synthesis methods, light dosages/light powers (if specified), and cell viabilities.

4. The part addressed to biosafety and metabolism of chlorins ─ metal nanoparticle conjugates has to be added in the manuscript as this topic is very important for their potential iv-vivo applications.

We agree with the Reviewer's opinion that the safety of using metallic nanoparticles is an important issue from the point of view of the possibility of later use of conjugates with photosensitizers in anticancer therapy. However, the positive therapeutic impact of PDT may be limited due to many factors that accompany the therapy, including poor tumor specificity and low solubilities of photosensitizers, which restrict their effective administration and blood circulation. Therefore, nanocarrier systems that modulate PS pharmacokinetics (PK) and pharmacodynamics (PD) constitute a promising approach allowing to bypass these limitations. Up to 2020, several clinical trials were performed where numerous different nanoparticles were studied for PS delivery, such as liposomes, dendrimers, gold nanoparticles, silver nanoparticles, and polymersomes. These studies concerned several subjects and allowed to increase the concentration of PS in the cancer area, as well as diminish their phototoxic properties. Various studies revealed that photosensitizers with the passive absorption of NPs could cause acute hypersensitivity in healthy cells since they cannot distinguish only cancerous cells [Calixto, G.M.F.; Bernegossi, J.; De Freitas, L.M.; Fontana, C.R.; Chorilli, M. Molecules 2016, 21, 342]. For this reason, it is a need to develop conjugated delivery systems consisting of photosensitizers, nanoparticles, and targeting moieties to avoid undesirable phototoxic effects.

Following your suggestion, we added to the Conclusion section the paragraph dealing with some safety matters connected with porphyrinoids-NPs conjugates.

5. Representation of nanoparticles in the Figures 2-4 is too simple and not plausible. Are the particles really so polydisperse? All Figures are too simple and big. In the caption to Figure 3, the numbers in Fe3O4 must be moved to indexes.

All figures were corrected concerning their sizes and details.

6. Summarizings of the part 2.1 and general conclusions are too obvious.

The summaries and conclusion section were revised, and more detailed information was added.

7. There are only 10 references to the papers from the last three years, more number of recent works should be considered.

The references were updated – we have reviewed seven recent papers mainly from 2021 to 2023.

Regards,

Authors

Reviewer 3 Report

The study titled “ Connections between metallic nanoparticles and chlorins-An overview of physiochemical, biological properties and prospective medical applications” is interesting and well written. The review article is structured well and is informative. However, there are few suggestions that the authors would have to consider to improve the quality of the current manuscript.

1.      The title of the manuscript is quite misleading. A major part of the review (more than 90%) concentrates on a specific chlorin: Chlorin-E6. Therefore, I suggest that the title of the review be changed to be more specific to chlorin-E6.

2.      What is PTT? Expand at first instance.

3.      Line 99: “The following chapter….” Change it to “The following review….”

4.      Line 114: “It was conducted that the ………” Sentence grammatically incorrect.

5.      Provide the light wavelength and dose for all the nanoparticles in all the sections.

6.      All the figures look very primitive. It is suggested that the authors improve the quality of the figures with better representation of the nanoparticles and structures.

7.      The colour of each entity in the figure should be mentioned in the figure legend.

8.      The size of the nanoparticles should be mentioned in each of the section. This is missing in some of the sections and therefore needs to be added.

9.      Figure 3: the iron oxide mentioned in the figure is not visible. The authors should address the comment with respect to comment 6.

10.   Figure 3: Fe3O4 should be mentioned in subscript.

11.   Line 168: “ who….” The study is by a team and should be plural.

12.   The whole study has the confusion on mentioning chlorin E6. The authors should either mention it as chlorin E6 and Ce6 throughout the manuscript uniformly.

13.   Line 218: “ weighted….” This sentence is not clear.

14.   The authors should make a paragraph on Ce6 in the introduction of the review. Properties of the chlorin, wavelength and other thermal properties should be mentioned.

15.   Line 259: “AuNPs..” expand at first instance.

16.   Line 275: “ The authors studied the photothermal ……” sentence grammatically incorrect.

17.   Line 289: “…bearing a tin chlorin e6….” The meaning is incomplete.

18.   Line 291: “ Staphylococcus aureus ….” Italicize the organism’s name.

19.   Line 323: “ This protocol enabled to …..” sentence is grammatically incorrect.

20.   Line 344: “….the amount of 92.5%.....” sentence is grammatically incorrect.

21.   The authors need to add a table at the end of each section rather than at the end. The table should contain information on nanoparticle size, radiation, wavelength, dose, cell line used for viability and % of death. This need to be done mandatorily to make the review more readable.

22.   The authors have used @ symbol at several places. This needs to be changed and modified with a hyphen value.

23.   The mechanism of action od the upconverted nanoparticles should be given in a figure to make it easier for the readers to understand the mechanism.

24.   Line 486: “…..some other metallic….” Change to “….other metallic…”

25.   Line 499: “The authors observed…..” rephrase the sentence for better meaning.

26.   Line 531: “ …HeLung normal cells ….” What are HeLung cells?

27.   Line 551: “….whereas PTT and PDT…” meaning unclear.

28.   Line 554: “They linked with success…..” Sentence unclear.

29.   Line 583: “…and enhanced subsequently…..” Sentence unclear.

30.   Line 596: “…what is interesting upon light activation” sentence unclear.

31.   Line 600: use abbreviation for human umbilical vein endothelial cells.

32.   Line 621: “IC50” 50 should be in subscript.

33.   Line 628: “It is well-known that …” cite reference.

34.   Line 638: “H2O2” use proper scientific representation for chemical compounds.

35.   Line 639: The authors should mention hours as either “h” or “hrs” throughout the manuscript uniformly.

36.   Line 646: “carbon nanotubes” carbon nanotubes are not metals and therefore needs to be justified.

37.   Silica is not a metal and is a metalloid. The Si nanoparticles needs reconsideration.

38.   Line 654: OH radical representation is incorrect.

39.   Expand MOF at first instance.

40.   Line 682: Expand HaCaT at first instance.

41.   Line 728: expand DBBC at first instance

42.   Line 729: O2 radical representation is incorrect.

43.   Conclusion is incomplete and needs to contain information on the limitations of the metal conjugated Ce6 and future scopes/prospects of this review.

 

Author Response

Dear Reviewer,

Thank you very much for reviewing the manuscript and for your comments. Our responses to your comments are below.

1. The title of the manuscript is quite misleading. A major part of the review (more than 90%) concentrates on a specific chlorin: Chlorin-E6. Therefore, I suggest that the title of the review be changed to be more specific to chlorin-E6.

Following your suggestion, the title was changed.

2. What is PTT? Expand at first instance.

PTT – photothermal therapy. The abbreviation was expanded in the Introduction section.

3. Line 99: “The following chapter….” Change it to “The following review….”

Changed.

4. Line 114: “It was conducted that the ………” Sentence grammatically incorrect.

The sentence was rewritten.

5. Provide the light wavelength and dose for all the nanoparticles in all the sections.

Following your suggestions, the proper tables at the end of each section were added, including light dosages/light powers (if specified) and cell viabilities.

6. All the figures look very primitive. It is suggested that the authors improve the quality of the figures with better representation of the nanoparticles and structures.

All figures were corrected with their size and detail.

7. The colour of each entity in the figure should be mentioned in the figure legend.

We have corrected the figure’s captions following your suggestions.

8. The size of the nanoparticles should be mentioned in each of the section. This is missing in some of the sections and therefore needs to be added.

Following your suggestions, the proper tables at the end of each section were added, including the size of nanoparticles and synthesis methods.

9. Figure 3: the iron oxide mentioned in the figure is not visible. The authors should address the comment with respect to comment 6.

All figures were corrected with their size and detail.

10. Figure 3: Fe3O4 should be mentioned in subscript.

Corrected.

11. Line 168: “ who….” The study is by a team and should be plural.

Corrected.

12. The whole study has the confusion on mentioning chlorin E6. The authors should either mention it as chlorin E6 and Ce6 throughout the manuscript uniformly.

Corrected for Ce6.

13. Line 218: “ weighted….” This sentence is not clear.

Corrected with the word “increased”.

14. The authors should make a paragraph on Ce6 in the introduction of the review. Properties of the chlorin, wavelength and other thermal properties should be mentioned.

Thank you for the critical advice. Following your suggestion, we have added some information about the absorption properties of chlorin. We couldn’t find effective and quality information about the thermal properties of Chlorin. The first and second paragraphs have been extended and updated.

15. Line 259: “AuNPs..” expand at first instance.

Expanded.

16. Line 275: “ The authors studied the photothermal ……” sentence grammatically incorrect.

The sentence was corrected.

17. Line 289: “…bearing a tin chlorin e6….” The meaning is incomplete.

The sentence was corrected.

18. Line 291: “ Staphylococcus aureus ….” Italicize the organism’s name.

Corrected.

19. Line 323: “ This protocol enabled to …..” sentence is grammatically incorrect.

Corrected.

20. Line 344: “….the amount of 92.5%.....” sentence is grammatically incorrect.

Corrected.

21. The authors need to add a table at the end of each section rather than at the end. The table should contain information on nanoparticle size, radiation, wavelength, dose, cell line used for viability and % of death. This need to be done mandatorily to make the review more readable.

Following your suggestions, the proper tables at the end of each section were added, including nanoparticle size, light wavelength and dose (if specified), cell line, and cell viability.

22. The authors have used @ symbol at several places. This needs to be changed and modified with a hyphen value.

Corrected.

23. The mechanism of action of the upconverted nanoparticles should be given in a figure to make it easier for the readers to understand the mechanism.

The new figure 6, presenting the mechanism of action of the upconverted nanoparticles, was added.

24. Line 486: “…..some other metallic….” Change to “….other metallic…”

Corrected.

25. Line 499: “The authors observed…..” rephrase the sentence for better meaning.

The sentence was corrected.

26. Line 531: “ …HeLung normal cells ….” What are HeLung cells?

It should be “HeLa cells” – the phrase was corrected.

27. Line 551: “….whereas PTT and PDT…” meaning unclear.

The sentence was corrected.

28. Line 554: “They linked with success…..” Sentence unclear.

The sentence was corrected.

29. Line 583: “…and enhanced subsequently…..” Sentence unclear.

The sentence was corrected.

30. Line 596: “…what is interesting upon light activation” sentence unclear.

The sentence was corrected.

31. Line 600: use abbreviation for human umbilical vein endothelial cells.

HUVEC abbreviation was used.

32. Line 621: “IC50” 50 should be in subscript.

Corrected.

33. Line 628: “It is well-known that …” cite reference.

The proper reference was cited.

34. Line 638: “H2O2” use proper scientific representation for chemical compounds.

Changed.

35. Line 639: The authors should mention hours as either “h” or “hrs” throughout the manuscript uniformly.

Corrected.

36. Line 646: “carbon nanotubes” carbon nanotubes are not metals and therefore needs to be justified.

We have divided the subsection “2.4 Other metallic nanoparticles” and all carbon-based nanomaterials were described in separate subsection 2.5.

37. Silica is not a metal and is a metalloid. The Si nanoparticles needs reconsideration.

We have changed the subsection 2.4 title to “Other metallic and metalloid nanoparticles”.

38. Line 654: OH radical representation is incorrect.

Corrected.

39. Expand MOF at first instance.

It was expanded in the Introduction section.

40. Line 682: Expand HaCaT at first instance.

Expanded.

41. Line 728: expand DBBC at first instance

Expanded.

42. Line 729: O2 radical representation is incorrect.

Corrected.

43. Conclusion is incomplete and needs to contain information on the limitations of the metal conjugated Ce6 and future scopes/prospects of this review.

The information about the limitations of using metallic nanoparticles was added at the end of the Conclusion section as well as some future scopes.

Regards,

Authors

Round 2

Reviewer 1 Report

I did not run the manuscript through a software for plagiarism.

Comments for author File: Comments.pdf

Author Response

Dear Reviewer,

The manuscript was corrected following your suggestions. Also, other minor editing errors were corrected.

Kind regards,

Authors

Reviewer 2 Report

The manuscript can be accepted in current form.

Author Response

Dear Reviewer,

Thank you very much for your kind recommendation.

Kind regards,

Authors

Reviewer 3 Report

The authors have addressed all the comments satisfactorily.  

Author Response

Dear Reviewer,

Thank you very much for your kind recommendation.

Kind regards,

Authors