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by
  • Mihai Adrian Socaciu 1,†,
  • Remus Moldovan 2,† and
  • Simona Clichici 2
  • et al.

Reviewer 1: Anonymous Reviewer 2: Anonymous Reviewer 3: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Animal ethical approval number is required to mention.

More work is required to mention.

Write the background behind the study. Mention the rationale behind it

Comments on the Quality of English Language

Simplify the English

Author Response

Answers are attached as an additional file.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled Delivery and Metabolic Fate of Doxorubicin and Betulins’ Nanoformulations in Vivo: A Metabolomics Approach, presents an interesting and relevant study that investigates the in vivo behavior and metabolic fate of doxorubicin and betulin-based nanoformulations using a metabolomics approach. However, several aspects require improvement and clarification to enhance the manuscript’s scientific depth, interpretive clarity, and overall presentation quality.

Suggestions

  • All figures should be accompanied by concise explanatory captions that summarize the key findings rather than only describing the methods or abbreviations. The discussion in the text should also explicitly refer to the main insights derived from each figure. In Figure 1, the representation of microbubbles within the L/NLC formulations is unclear.
  • The analytical depth of the study can be improved by adding one additional comparative or quantitative parameter from the existing data.
  • Provide a clearer justification for the selection of the Wistar rat model and the Walker 256 tumor type, explaining their suitability for metabolomic profiling and translational relevance. Confirm full compliance with ARRIVE 2.0 guidelines by specifying the randomization process, blinding, inclusion/exclusion criteria.
  • Include details on the number of technical replicates used in UHPLC-QTOF-ESI+MS analyses, QC parameters (RSD%, calibration linearity), and statistical validation for metabolite identification (mass accuracy, fragmentation confirmation, and database matching). A description of non-sonoporated nanoformulation control groups would help distinguish effects attributed specifically to sonoporation.
  • The discussion and conclusion section should be substantially expanded to interpret the mechanistic relationship between the observed metabolic fate and the pharmacokinetic or toxicological outcomes. Elaborate on how specific metabolites (e.g., p-cresyl sulfate, DMA, creatinine) relate to hepatic or renal stress, and discuss the biological relevance of these findings.
  • The abstract should concisely summarize the main quantitative outcomes, such as percentage changes in bioavailability or toxicity. The introduction can be shortened by reducing general background information and emphasizing the specific knowledge gaps addressed.



Comments on the Quality of English Language

Minor grammatical and stylistic revisions are needed throughout the manuscript.



 

 

 

Author Response

Answers are attached as an additional file.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors
  1. Line 44-49; The First sentence appeared to be complex for the reader to understand. Hence, the authors are encouraged to clarify in like 2 sentences.
  2. Line 55-57; What is the dosage considered for GRAS with low side effects?
  3. Line 56-57; What are the low side effects? Please clarify for the readers.
  4. Line 75; The authors should describe how PEGylated liposomes improved AB and B in vitro.
  5. Line 87; What do the authors mean by “PEGylated Liposomal Doxo”? Is it Doxo encapsulated PEGylated liposomes? Please clarify.
  6. Line 201; Polydispersity is one word.
  7. Line 320; The use of a proper degree symbol is required in “-20⁰ C”.
  8. Line 326; The use of a proper degree symbol is required in “-20⁰ C”. Avoid double spacing between the sentences.
  9. Line 482; The authors are encouraged to provide an explanation for the high release in Urine and equal distribution in T and P.
  10. Line 538-548; The authors are suggested to explain Figure 8 in detail.

 

Comments on the Quality of English Language

It can be improved by the authors. The authors can try to avoid long and complex sentences for readability. 

Author Response

Answers are attached as an additional file.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Author has revised the content and now manuscript is in acceptable in present form

Comments on the Quality of English Language

Manauscript can be accepted , English is improved.

Author Response

Dear reviewer,

Thank you again for the comments and suggestions.

We are happy that the manuscript can be accepted!

Reviewer 2 Report

Comments and Suggestions for Authors

With reference to the manuscript entitled “Delivery and Metabolic Fate of Doxorubicin and Betulin’s Nanoformulations In Vivo: A Metabolomics Approach,” the authors have incorporated the suggested revisions. However, the following points need to be addressed before acceptance:

  1. Figure 1 is not clearly visible and should be improved for better clarity and resolution.

  2. The future perspectives section in the conclusion can be refined and presented more clearly.

Comments on the Quality of English Language

 

 

 

 

Author Response

Attached as separate file

Author Response File: Author Response.docx