Nanoparticles Based on Novel Carbohydrate-Functionalized Polymers
Round 1
Reviewer 1 Report
This manuscript describes the preparation of functionalized PLGA and PEG with coumarin and carbohydrate moieties following various synthetic routes. Subsequently, nanoparticles based on these derivatives were prepared using an oil-in-water emulsion method. This work may be publishable in Molecules after major revisions, since at several points should be reconsidered before acceptance to this journal.
Specifically:
- The results and discussion section should be rewritten presenting not only details about the followed synthetic routes but also proofs for the successful preparation of the products based on the characterization data (NMR, FTIR, MS). Full assignment of the NMR and FTIR peaks and discussion should be added.
- The authors mentioned that the PEG derivatives 20, 24 and 25 can form nanoparticles with sizes ranging from 33 to 60 nm or 19 to 54 nm, which are spherical with a smooth surface and also after drying, can form films. But from Micrograph 1 cannot be concluded something like that. Only agglomerates/precipitations are observed. DLS results and z-potential measurements should be added as in case of PLGA derivatives.
- In the title, the authors stated that these functionalized polymers could be used for targeted therapies but they did not present any experiment to justify this suggestion. If they want to keep this title at least in vitro experiment should be done otherwise the title should be modified.
- Minor comments:
- There are several type- errors that should be corrected
- Scheme 2, R2 and R4 of compound 1 are CH3
- A CH3 group is missing in the position 4 of compounds 1 and 29
- Scheme 7, in the cycloaddition reaction, the compound 10 was used not the compound 18 as was written.
- Correct (translate in English) the titles of the axis in figure 1.
Author Response
Dear reviewer,
First of all, I would like to thank you for all your suggestions.
All changes made are indicated below and duly marked.
Reviewer 1
This manuscript describes the preparation of functionalized PLGA and PEG with coumarin and carbohydrate moieties following various synthetic routes. Subsequently, nanoparticles based on these derivatives were prepared using an oil-in-water emulsion method. This work may be publishable in Molecules after major revisions, since at several points should be reconsidered before acceptance to this journal.
Specifically:
- “The results and discussion section should be rewritten presenting not only details about the followed synthetic routes but also proofs for the successful preparation of the products based on the characterization data (NMR, FTIR, MS). Full assignment of the NMR and FTIR peaks and discussion should be added.”
Revised:
Spectra discussion has been added.
Pages 2 and 3; lines 84 – 93
Page 3; lines 111 – 121
Page 5; lines 151 – 177
Page 5 and 6; lines 180 – 200
Page 6; lines 203 – 219
Page 7; lines 237
Page 7 and 8; lines 242 – 252
Page 8; lines 258 – 271
All the assignments were made to the compounds description, in section 3 (Materials and Methods).
Page 11; lines 337 – 343
Page 12; lines 351 – 356
Page 12; lines 362 – 368
Page 12; lines 377 – 383
Pages 12 and 13; lines 392 – 398
Page 13; lines 406 – 411
Page 13; lines 420 – 422
Page 13; lines 428 – 433
Page 14; lines 450 – 454
Page 14; lines 461 – 464
Page 14; lines 469 – 474
Page 14; lines 480 – 486
Page 15; lines 500 – 506
Page 15; lines 517 – 522
Page 15; lines 531 – 536
Page 16; lines 542 – 548
Page 16; lines 555 – 560
Page 16; lines 568 – 574
Page 16; lines 580 – 584
Page 17; lines 592 – 593
Page 17; lines 601 – 608
Page 17; lines 618 – 624
Page 18; lines 634 – 640
Page 18; lines 648 – 655
Page 18; lines 661 – 670
- “The authors mentioned that the PEG derivatives 20, 24 and 25 can form nanoparticles with sizes ranging from 33 to 60 nm or 19 to 54 nm, which are spherical with a smooth surface and also after drying, can form films. But from Micrograph 1 cannot be concluded something like that. Only agglomerates/precipitations are observed. DLS results and z-potential measurements should be added as in case of PLGA derivatives.”
Revised
PEG SEM analysis was altered according to Reviewer 1 advice, in a way that only agglomerates and films were observed. DLS results for these derivatives were added and discussed.
Page 8; lines 273 – 275
- “In the title, the authors stated that these functionalized polymers could be used for targeted therapies but they did not present any experiments to justify this suggestion. If they want to keep this title at least in vitro experiment should be done otherwise the title should be modified.”
Revised
We have changed the title because at the moment it is not possible to present the results of biological tests. This work is done by another research group, which, due to the global health situation, was forced to interrupt the work in progress for an indefinite time. It is our intention in the future, when possible, to invest in this scientific aspect.
In view of this reality, we opted to publish the synthetic part, as we consider that methods of synthesis of various versatile compounds are described, which could have application in several areas, thus being a useful chemical tool in different areas.
New title:
Nanoparticles based on novel carbohydrate-functionalized polymers
Page 1 – lines 2 and 3
- Minor comments:
- “There are several type- errors that should be corrected”
Revised
The typing errors have been corrected throughout the manuscript.
Page 1 – line 5
Page 1 – line 7
Page 1 – line 12
Page 1 – line 41
Page 2 – line 51
Page 2 – line 55
Page 2 – line 58
Page 2 – line 77
Page 3 – line 102
Page 3 – line 108
Page 4 – line 132
Page 4 – line 133
Page 11 – line 308
Page 11 – line 327
Page 11 – line 308
Page 11 – line 335
Page 11 – line 308
Page 11 – line 336
Page 11 – line 349
Page 12 – line 350
Page 12 – line 361
Page 12 – line 386
Page 12 – line 392
Page 13 – line 403
Page 13 – line 404
Page 14 – line 461
Page 14 – line 477
Page 15 – line 496
Page 15 – line 499
Page 15 – line 508
Page 15 – line 513
Page 15 – line 524
Page 16 – line 538
Page 16 – line 551
Page 16 – line 576
Page 18 – line 644
Page 18 – line 645
Page 18 – line 676
- Scheme 2, R2and R4of compound 1 are CH3
Revised
Scheme 2 was corrected according to the reviewer’s suggestion, and also for the product 2 was added R2,R4=CH3.
Page 3; Scheme 2
- “A CH3 group is missing in the position 4 of compounds 1 and 29”
Corrected
We apologize for the mistake made in scheme 3 (it is not reagent 1, but 6), which created confusion in the interpretation of the structures of compounds 1 and 29, which are correct.
Page 3; line 102
Page 3; Scheme 3
- “Scheme 7, in the cycloaddition reaction, the compound 10 was used not the compound 18 as was written.”
Corrected.
Page 4; Scheme 5
- Correct (translate in English) the titles of the axis in figure 1.”
Corrected
Both the X and Y axes in figure 1 were translated into English.
Page 10; Figure 2
Reviewer 2 Report
This manuscript reported that poly(ethylene glycol) (PEG) and poly(lactic-co-glycolic acid) (PLGA) were functionalized with coumarin and carbohydrate moieties such as thymidine, glucose, galactose, xylose and mannose that have high biological specificities via CuAAC “click” reaction. These functionalized polymers were used to obtain drug delivery agents, either por-drugs or nanoparticles for drug encapsulation. The synthetic work is huge and many products are obtained. I think this article can be accepted after fully addressing the following major issues:
- Although the authors demonstrate that those particles can load a variety of drugs on the surface, no biological evaluation data was provided. I think the authors should provide at least one bio-related result in the paper.
- The chapter number of the paper should be re-checked again.
- Perhaps a schematic illustration of ester hydrolysis of 2 to afford 3 should be given in the article?
- In this paper, there is no analysis of the MALDI MS spectra results, maybe the characteristic mass-charge ratio peak can be explained?
- The authors could add the following references which would again increase the interest to general “click” chemistry readers:Journal of Controlled Release 2018，273, 160-179; Polymer, 2017, 125, 303-329; Polym. Chem., 2019,10, 3806-3821; Coordination Chemistry Reviews, 2019, 380, 484-518.
Author Response
Dear reviewer,
First of all, I would like to thank you for all your suggestions.
All the changes made are indicated below and duly marked.
Reviewer 2
This manuscript reported that poly(ethylene glycol) (PEG) and poly(lactic-co-glycolic acid) (PLGA) were functionalized with coumarin and carbohydrate moieties such as thymidine, glucose, galactose, xylose and mannose that have high biological specificities via CuAAC “click” reaction. These functionalized polymers were used to obtain drug delivery agents, either por-drugs or nanoparticles for drug encapsulation. The synthetic work is huge and many products are obtained. I think this article can be accepted after fully addressing the following major issues:
- “Although the authors demonstrate that those particles can load a variety of drugs on the surface, no biological evaluation data was provided. I think the authors should provide at least one bio-related result in the paper.”
We changed the title because at the moment it is not possible to present the results of biological tests. This work is done by another research group, which, due to the global health situation, was forced to interrupt the work in progress for an indefinite time. It is our intention in the future, when possible, to invest in this scientific aspect.
In view of this reality, we opted to publish the synthetic part, as we consider that methods of synthesis of various versatile compounds are described, which could have application in several areas, thus being a useful chemical tool in different areas.
Page 1 – lines 2 and 3
- “The chapter number of the paper should be re-checked again.”
Corrected
The Section 3 was corrected with subsections (3.1, 3.2, etc.) and the Conclusion section was changed from 5 to 4.
Page 11; line 315
Page 11; line 326
Page 11; line 331
Page 11; line 332
Page 11; line 344
Page 12; line 357
Page 12; line 369
Page 12; line 384
Page 13; line 399
Page 13; line 412
Page 13; line 423
Page 13; line 434
Page 14; line 443
Page 14; line 455
Page 14; line 465
Page 14; line 475
Page 14; line 487
Page 15; line 494
Page 15; line 507
Page 15; line 523
Page 15; line 537
Page 16; line 549
Page 16; line 561
Page 16; line 575
Page 16; line 585
Page 17; line 594
Page 17; line 609
Page 17; line 625
Page 18; line 641
Page 18; line 656
Page 18; line 671
Page 19; line 677
Page 19; line 684
- “Perhaps a schematic illustration of ester hydrolysis of 2 to afford 3 should be given in the article? “
Revised
According the reviewer’s suggestion an explanatory note has been added at scheme 2.
Page 3; Scheme 2
- “In this paper, there is no analysis of the MALDI MS spectra results, maybe the characteristic mass-charge ratio peak can be explained?”
Revised
MALDI-TOF results of PEG derivatives were added and discussed.
Page 5; lines 176 – 177
Page 6; lines 198 – 200
Page 6; lines 217 – 219
Page 8; lines 249 – 250
- “The authors could add the following references which would again increase the interest to general “click” chemistry readers:Journal of Controlled Release 2018，273, 160-179; Polymer, 2017, 125, 303-329; Polym. Chem., 2019,10, 3806-3821; Coordination Chemistry Reviews, 2019, 380, 484-518.”
Revised
We appreciate the reviewer’s literature suggestions. We believe that this information contributes to the enrichment of our manuscript. We have included Journal of Controlled Release, 2018，273, 160-179 reference, due to the interesting review of the authors about cycloaddition reactions with polymers. In addition, Polym. Chem., 2019, 10, 3806-3821 was also added due to click chemistry with commercial available polymers. These articles are cited in section 1. Introduction.
Page 2; lines 66 – 68
Round 2
Reviewer 1 Report
The authors were taken under consideration all my suggestion and now I think that the manuscript is suitable for publication.
Reviewer 2 Report
I think the current revised version seems OK for me