The Advantages of Polymeric Hydrogels in Calcineurin Inhibitor Delivery
Round 1
Reviewer 1 Report
The article entitled “Being for the Benefit of Polymeric Hydrogels in 2 Calcineurin Inhibitors Delivery" has been carefully reviewed. This is not very novel review in view of polymeric hydrogels in biomedical applications. In recent years there were published few of the, e.g.
Sosnik A, Seremeta KP. Polymeric Hydrogels as Technology Platform for Drug Delivery Applications. Gels. 2017;3(3):25. Published 2017 Jul 3. doi:10.3390/gels3030025.
Susheel Kalia. Polymeric Hydrogels as Smart Biomaterials. Springer Series on Polymer and Composite Materials. 2016.doi:10.1007/978-3-319-25322-0.
Aswathy SH, Narendrakumar U, Manjubala I. Commercial hydrogels for biomedical applications. Heliyon. 2020;6(4):e03719. Published 2020 Apr 7. doi:10.1016/j.heliyon.2020.e03719.
The novel part is usage the polymeric hydrogels to deliver very concrete group of substances. All kinds of polymeric hydrogels were well characterized. The most popular drug delivery materials, such as alginate, chitosan and CMC, were also described.
As we all known the success of kidney transplantation is attributable to the calcineurin inhibitors, which well also presented. However, toxicity of these inhibitors were confirmed. Authors shows an alternative way to still use cyclosporine and tacrolimus, but you haven’t mentioned about to reduce or remove calcineurin inhibitors by use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept. Present the superiority of your solution over the use of the above-mentioned substances.
There is no explanation for the acronym: PolyHy – it should be explained in first place, where is used – line 35.
Author Response
Reviewer 1
Comments and Suggestions for Authors
As we all known the success of kidney transplantation is attributable to the calcineurin inhibitors, which well also presented. However, toxicity of these inhibitors were confirmed. Authors shows an alternative way to still use cyclosporine and tacrolimus, but you haven’t mentioned about to reduce or remove calcineurin inhibitors by use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept. Present the superiority of your solution over the use of the above-mentioned substances.
Answer: The majority of the maintenance treatment are based on a combination of three immunosuppressive drugs, which have different mechanism of action. Calcineurin inhibitors (CNIs) still are the main part of this combination. This is a known strategy to minimize morbidity and mortality, and to achieve additive efficacy, although adverse drug effects could be frequent. The selection of the regimens depends on patient’s comorbidity and clinical conditions, transplant center, availability of medicines and, mainly, on evidence-based medicine [1]. Calcineurin inhibitors are the cornerstone of the maintenance treatment. Both Cyclosporine A (CsA) and Tacrolimus still are the most used immunosuppressors worldwide (Evidence 2D for tacrolimus and 2B for CsA) [2]. Although there are other immunosuppressors as was mentioned by the Reviewer 1, it is important to consider that a new proposal to improve the pharmacological profile of CNIs could be a first step of treatment optimization, instead to just changing to another more expensive drug options. Modification of pharmaceutical formulation to improve oral bioavailability by extended-release tablets has been used since many years ago, demonstrating the necessity of keep using CNIs in the first line of treatments. That is why new uses like hydrogels is in the same direction. Any cost saving alternative that do not compromise the demonstrated patient’s safety are beneficial [2], especially in a long-term therapy like immunosuppressors with CNIs.
In this sense, the Kidney Disease: Improving Global Outcomes (KDIGO) guideline indicates “The earlier that therapeutic blood levels of a CNIs can be attained, the more effective the CNIs will be in preventing acute rejection” [2], supporting that an he CNIs are in the first line of use. We have mentioned a part of this argument in the conclusion of the new version of the manuscript (line 449).
- Kaplan, B.; Barr, M.L.; O’Grady, J.; Berezan, D.; Hughes, G.; Becker, B.; Blumberg, E.; Bradley, J.A.; Brennan, D.; Briscoe, D.M.; et al. KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Am. J. Transplant. 2009, 9, 168.
- Kaplan, B.; Barr, M.L.; O’Grady, J.; Berezan, D.; Hughes, G.; Becker, B.; Blumberg, E.; Bradley, J.A.; Brennan, D.; Briscoe, D.M.; et al. EDITOR-IN-CHIEF Philip F. Halloran, Canada DEPUTY EDITORS Jonathan S. Bromberg, USA Robert L. Fairchild, USA Sandy Feng, USA. 168.
There is no explanation for the acronym: PolyHy – it should be explained in first place, where is used – line 35.
Answer: Thank you for comment. We have corrected this in the new version of manuscript.
Reviewer 2 Report
Overall, the manuscript is well written and of interest to the reader. However, there are some comments that should be addressed before publication:
- You should state what you are referring by PolyHy (polymeric hydrogels) but this should be clear in the text.
- The different types of classification are confusing, as they are mixed among each other. Maybe you should try to find another way to group the different classes.
- The manuscript is really lacking tables. Authors should condense the information in tables, it would be interesting if you separate the functionality of the PolyHy, I mean some increases oral bioavailability, other reduces degradation, and so on...
- In the tables, it would be interesting also how the particles are formed. There is little information on that in the text.
- Include also some schematics on how the manufacturing of the polyHy and particles takes place
Author Response
Reviewer 2
Comments and Suggestions for Authors
Overall, the manuscript is well written and of interest to the reader. However, there are some comments that should be addressed before publication:
1. You should state what you are referring by PolyHy (polymeric hydrogels) but this should be clear in the text.
Answer: Thank you for comment. We have corrected it in the new version of manuscript.
2. The different types of classification are confusing, as they are mixed among each other. Maybe you should try to find another way to group the different classes.
Answer: We corrected the title in 1.1 to “Family of Hydrogels”, in order to avoid the initial confusion. In addition, we added a table with PolyHy examples that permit us to represent in a better way how we have classified the Hydrogels (page 5 in the new version). We hope that this new information, with additional references, may permit a better understanding of this section.
3. The manuscript is really lacking tables. Authors should condense the information in tables, it would be interesting if you separate the functionality of the PolyHy, I mean some increases oral bioavailability, other reduces degradation, and so on...
4. In the tables, it would be interesting also how the particles are formed. There is little information on that in the text.
5. Include also some schematics on how the manufacturing of the polyHy and particles takes place
Answer for 3, 4 and 5: Considering the main focus of our manuscript, we assayed the opportunities, previous experiences, and current challenges for calcineurin inhibitors drug delivering. We believe that topics proposed by the reviewer (functionality, formation and manufacturing of PolyHy), not only could be discussed in a different chapter also may look away the main focus of our work.
