Peptide-Based Drug-Delivery Systems in Biotechnological Applications: Recent Advances and Perspectives

Round 1

Reviewer 1 Report

The authors summarized recent advances of peptide-based DDS especially using assembled nanostructure the authors have dealt with. Based on the accumulated experiences, the history was precisely summarized. Thus, this reviewer recommends the paper for publication as a review article as it stands.

 Some comment and typographical error were found as follows:

 1)  Page 9-10: As the abbreviation of cell penetrating peptide, “CCP” is sometimes written, should be “CPP”.

 2)  Tumor homing peptides have been developed and applied. This reviewer recommends that the authors discuss this point in the manuscript [e.g. Nat. Commun., 3, 951 (2012); Research on Chemical Intermediates, 44, 4685 (2018)].

Author Response

 1)  Page 9-10: As the abbreviation of cell penetrating peptide, “CCP” is sometimes written, should be “CPP”.

Response:   We have approveded and changed this term.

 2)  Tumor homing peptides have been developed and applied. This reviewer recommends that the authors discuss this point in the manuscript [e.g. Nat. Commun., 3, 951 (2012); Research on Chemical Intermediates, 44, 4685 (2018)].

Response: Our target is not limited to CPP system and we consider both suggest references too specific and not properly to the our review topic. Sorry but we not able to insert our suggestions.

Reviewer 2 Report

The manuscript molecules-419203 covers a very interesting topic, describing the use of peptides in peptide-based drug delivery systems. Mainly, authors focused on the properties and properties that make aggregation of peptides in nanostructures possible. The manuscript is well structured and provides readers with a sequential information.

Overall, the information presented in this review is comprehensive, of interest to the scientific community. However, my main concern is with the overall grammar, writing style. The manuscript needs to be majorly revised or rewritten prior to publication.

Major comments:

The introduction is poor. Contains repeated sentences from abstract and it’s not an appropriate setting for the reviewed information in the manuscript. The conclusion is it too not carefully prepared. The authors should pay more attention to these two sections.

The authors should also pay to other sections for instance section 3.1 and 3.2. Section 3.1 mainly considers TAT peptide, but the title suggests that the authors will present other peptides – CPPs and smart sequences. More information should be added to this section, the authors could even review CPPs  able to cross the Blood-brain barrier. In the literature authors can easily find works of Giralt or Castanho related to the translocation of the BBB. Trans-BBB peptides or BBB shuttles are being studied as peptide-based drug delivery systems into the brain. These CPPs could appear in a table, together with sequence, mechanism and therapeutic application. Again for section 3.2 the authors could present the different peptide-receptor interactions in a table.  It would be easier to follow and compare.

Minor comments/corrections:

Overall, the manuscript is not well written and contains many sentence fragments, choppy sentences, awkward grammar, nonparallel sentence structure, making difficult to read. The reviewer recommends carefully rewriting/revising the manuscript.

1.       INTRODUCTION

The authors report the production of peptides by chemical synthesis but miss the production through DNA recombinant, which is one of the most applied techniques to obtain peptides..

2.       Peptide self-assembled nanostructure

2.1   a-helical and b-sheet peptides

This section is confusing

First, it is not formatted properly. Then, an introduction for each secondary structure is missing.

2.2   Linear peptides

In this section, authors mention the different nanoparticles that can be obtained by peptides self assemble. It is an exhaustive collection of information with good examples. It is well structured and comprehensible. However, expressions such as, “particular fascinating”, “excellent”, “impressive”, “intelligent”, “contest”, among others are inappropriate…

2.3   Cyclic peptides

Only a few examples are presented in this section in comparison to the last one. It is well-organized but the mechanisms and some explanations are missing.

2.4   Amphiphilic peptides

The section is not well written. It does not have a rational… It lacks explanations, mechanisms, and the presentation of the examples is confused. Some have a lot of information and other only a few words.

3.       Self-assembling PAs for targeting in nanostructures

In this section, authors present several examples of peptides capable of forming nanostructures. This nanostructures are then applied in nanotargetting, increase peptide properties,… The examples presented are good and cover a broad line of research. Nevertheless, they are too extensive or only have few comments. In addition, they lack the reason why, mechanisms of action, authors explanations for some evidence. It is a review! In my point of view must not be just a collection of examples. Authors should comment the most interesting evidence, and try to come out with good explanations for some features. The English is difficult to follow…

The authors begin start the section with “In the previous paragraph” if this is a new section it does not make sense to refer to the last paragraph.

3.1   Cell penetrating peptides (CPPs) and smart sequences

Is not clear why the authors add to the title smart sequences, there was something else to had to this section? Other CPPs either than TAT? CPPs for specific tissues, like brain?

3.2   Peptide able to interact with overexpressed receptors

As mention previously the different receptors could appear in a table.

3.2.1         Peptide target for integrins reeptors

Integrins are one of the most important receptors that can be used in active targeting delivery. It is a family composed of many receptors. Thus, in the beginning I think that authors should put a reference to that. Then, they can just focus on the most important ones.

The examples presented are good but it is messy. Example after example after example the reader will be lost… Lack of explanations for some important features is also a problem.

3.2.2         GPR Target peptide

GPR are important receptors. They are a family with very different receptors. The authors mention 5 saying that are the most important ones. Why do they talk just about these 5? In the following sections they only specify three. In this brief introduction, I think that the authors should talk a little bit more about the reason why they selected just these three.

3.2.2.1    Somastatin receptors

A number of examples with few comments, information… They are lacking something because I think that the reader does not understand their value.

3.2.2.2    Bombesin receptors

3.2.2.3    CCK receptors

4.       Conclusions

The conclusions are not well written… I think that being the paper a review, authors should highlight challenges, enumerate advantages, talk a little bit about what is to come, give a personal comment on what has been done. The last paragraph is poor and “in our guess” is not a proper way to finish such exhaustive paper.

Author Response

Thanks for your comments. Please see the attachment.

Author Response File: Author Response.pdf