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..
Line | Comment |
42 | The reference is old. Currently, there are more recent works reporting the applications of peptides. |
43 | These advantages depend on the strategy applied to produce peptides. |
44 | “easily synthetized”. The authors are mostly focused on synthetic peptides. It is true that they are and that this is one of the major advantages of peptides over other biological agents, such as antibodies. However, they must emphasize that it is a feature of the synthetic peptides. |
46 | Next, they mention the degradation. It is true. But, it is true for all peptides. This needs to be clarify. |
47 | “several chemical approaches” and in the next sentence they mention some examples. One is the introduction of specific coded or un-coded amino acids… This is not a chemical modification. It is obtained by DNA recombinant technology. |
54 | Needs a reference. |
65 | “ingredients” ?? |
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.
Line | Comment |
94 | “bring into play”??? |
109 | “take the key role”??? |
113 | “are decisive” – strong statement |
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…
Line | Comment |
119 | Can you clarify what is a short and ultra-short peptide? |
120 | “particular fascinating”… |
131 | “impressive”… |
133 | “they strongly affected” – not correct |
153 | “biological marker” – replace with dye or fluorophore |
154 | The study was performed in vivo to extrapolate that these carriers to deliver at constant rates in the body? |
155 | Very high thermal and metabolic stability. The sentence shown does not make sense |
165 | Cut materials |
166 | “This excellent”… |
220 | “They” |
223 | Very recent… Recently… |
229 | “They” |
230 | So research is a contest? |
233 | Very recently… Recently… |
256 | Very recently… Recently… |
256 | “unexpected” – the authors are to bias |
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.
Line | Comment |
281 | “This way” is not correct |
284 | Which is the mechanism behind the self-assembling of L and D peptides? |
292 | Rephrase the sentence. And why are cyclic peptides not suitable as drug delivery systems? |
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.
Line | Comment |
301 | Philosophical but does not add nothing to the text |
306 | The amino acids are well presented and a person that work with them quickly understand why they self-assemble. However, I think that the authors must have a few words concerning the properties of these amino acids. |
308 | Physical and chemical properties, which are… |
309 | Rephrase |
312 | In details. I thought that the authors would explore the self-assemble properties. However, the detail is an example of the applicability. |
324 | Rephrase |
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.
Line | Comment |
376 | “what was preloaded” – terrible way to talk about the cargoes, drugs, … Rephrase |
376 | “PAs” comprises an amino acid sequence “ – well it is a peptide… “which performs” – the sequence does not perform nothing! The sequence of amino acid residues is responsible for the targeting and delivery of drugs due to… |
378 | Not just pathological… and the diagnosis? |
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?
Line | Comment |
380 | Title has a typo CCPs instead of CPPs |
381 | “The first among the tasks”… |
382 | The reference is from 2002! Since 2002 a lot of CPPs were discovered and studied |
383 | If they are cationic they have positive charge – redundant |
386 | And new ones. One very recent has the following doi: 10.1016/J.abb.2018.11.010 – I suggest that the authors read the review and reference it. |
387 | All the CPPs lack cancer specificity? In the literature, cannot be found any work reporting CPPs specificity towards cancer cells? |
390 | Thermal stimuli, light, ultra-sound, enzymes, pH. There are more ways of stimuli the release of a drug. pH and enzymatic are just two examples. |
390 | Considered as smart is not an accurate expression in my opinion…. |
393-402 | Very good explanation and strategy presentation |
404 | Mices showed |
406 | Than in controls |
3.2 Peptide able to interact with overexpressed receptors
As mention previously the different receptors could appear in a table.
Line | Comment |
418 | Could allow the intracellular delivery |
419 | Of the payload |
423 | Kept the conformation |
427 | Conjugation to proteins, lipids, nanoparticles… |
430 | New peptide sequences can act – New and old! That always depend on the purpose of the peptide and on the applications that you give to the strategy applied |
432 | 1. They do not act |
433 | 2. The present |
434 | The rational design… |
441 | EPR consists in a phenome where some molecules are retained in the tumor site due to increase of capillary permeability. Here you are saying that they increase the blood circulation and that this feature is due to PEGylation? |
445 | The spacer allows the maintenance of molecule flexibility, mobility and increase solubility is some cases |
449 | Figure 3 (left panel) shows and… |
461 | Use of enzymes, copper-free chemistry, … |
464 | Do you think that these are the only receptors overexpressed or the only ones that researchers can tackle? |
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.
Line | Comment |
474-479 | Make a better introduction of the integrin family |
477 | Literature data… No! |
490 | In the most cases? |
501-508 | Confused |
516 | The authors talk about the three RGD analogues but then they do not refer specifically to each of them. |
517 | Compared to other two analogue sequences. Which analogues? |
532-543 | Extremely confusing… |
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.
Line | Comment |
550 | I did not understood the sentence |
552 | Rearrange the sentence |
555 | “Reported in figure 4b” – This is not correct. Shown in Figure 4b is more accurate |
557 | “This cyclic peptide is able to cross the cell membrane via endocytosis (…)” |
567 | Every single formulation must be full characterized. Moreover, every single molecule must be full characterized. |
572 | Good explanations |
574 | The reason why this does not happen |
3.2.2.2 Bombesin receptors
Line | Comment |
649 | The four receptor-subtytes which are… |
653 | The authors do not report nothing in figures… |
660 | Just to increase hydrophilicity? Researchers add PEG to increase other properties rather than solubility |
663 | Lack fundamentation |
672 | “Interesting probe” Why? |
682 | Explain the reasons why authors performed the substitutions |
3.2.2.3 CCK receptors
Line | Comment |
698 | Rephrase… |
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