Mesoporous Silica Nanoparticles for pH-Responsive Delivery of Iridium Metallotherapeutics and Treatment of Glioblastoma Multiforme
Round 1
Reviewer 1 Report
The manuscript entitled "Mesoporous Silica Nanoparticles for pH-responsive delivery of Iridium Metallotherapeutics and Treatment of Glioblastoma Multiforme" describes the synthesis of Ir (III) complex functionalized mesoporous silica nanoparticles in order to be used in cancer therapy. Generally, the manuscript is well written but I have some suggestions and comments:
1. A schematic representation of coordination reaction between Ir(III) prodrug and ligands must be introduced in Results and Discussion section.
2. The release studies were discussed superficially. Generally, the release profile is represented as % biologically active species released or % amount of biologically active species released vs. time. Please replace the Figure 4a with one in which the Y axis represents %Ir (III) complex released.
3. What is the difference between the system used in this manuscript and other systems designed for similar purposes?
4. Do the authors have any idea about the accumulation of nanoparticles in different part of the body after administration of the system?
Author Response
Responses to Reviewers comments:
The authors are thankful to the reviewers for their comments and suggestions, which significantly contributed toward improving the quality of the manuscript.
Reviewer #1:
The manuscript entitled "Mesoporous Silica Nanoparticles for pH-responsive delivery of Iridium Metallotherapeutics and Treatment of Glioblastoma Multiforme" describes the synthesis of Ir (III) complex functionalized mesoporous silica nanoparticles in order to be used in cancer therapy. Generally, the manuscript is well written but I have some suggestions and comments:
- A schematic representation of coordination reaction between Ir(III) prodrug and ligands must be introduced in Results and Discussion section.
Our reply: The new schematic is now introduced as suggested, as Scheme 1.
- The release studies were discussed superficially. Generally, the release profile is represented as % biologically active species released or % amount of biologically active species released vs. time. Please replace the Figure 4a with one in which the Y axis represents %Ir (III) complex released.
Our reply: The Figure is now corrected as suggested (please note it is now Figure 5a). We also corrected the Figure 5b and added the following sentence to further discuss the release studies: “In comparison to the highest release at pH 5, the maximum of the released % observed after 48 h for both materials lowered to approximately 60% in case of pH 6 and to 30% in case of pH 7.4. “
- What is the difference between the system used in this manuscript and other systems designed for similar purposes?
Our reply: We included information about other systems in the introduction section:
“Different types of drug delivery systems have been developed recently, including ionically crosslinked gels [18], Janus nanofibrous membranes [19], mesoporous silica [20], and other inorganic nanoparticles [21].
…
Recent advances have shown the applicability of different types of nanoparticles for the delivery of Ir(III)-based therapeutics for cancer treatment [28- 30]. On the other hand, only one report was published very recently on incorporation of Ir(III) within MSN for application in therapy of cancer [31]”
- Do the authors have any idea about the accumulation of nanoparticles in different part of the body after administration of the system?
Our reply: In the introduction section we included the following information about the toxicity and biodistribution of MSN:
“Studies on in vivo toxicity and biodistribution of MSN-based materials evidence their high biocompatibility and capabilities for preferential accumulation in tumor tissues [15], though their biodistribution profiles can be affected by the shape [16], as well as by the size and functionalization of the particles [17].”
Along with the new references:
- Lu, J.; Liong, M.; Li, Z.; Zink, J. I.; Tamanoi, F., Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small 2010, 6 (16), 1794-1805.
- Shao, D.; Lu, M.-m.; Zhao, Y.-w.; Zhang, F.; Tan, Y.-f.; Zheng, X.; Pan, Y.; Xiao, X.-a.; Wang, Z.; Dong, W.-f.; Li, J.; Chen, L., The shape effect of magnetic mesoporous silica nanoparticles on endocytosis, biocompatibility and biodistribution. Acta Biomaterialia 2017, 49, 531-540.
- He, Q.; Zhang, Z.; Gao, F.; Li, Y.; Shi, J. In vivo Biodistribution and Urinary Excretion of Mesoporous Silica Nanoparticles: Effects of Particle Size and PEGylation. Small 2011, 7, 271–280.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The paper needs a major revision before accept
-the abstract doesn’t provide the goal of the study properly and needs to be revised
-please add mesoporous silica NPs to the keywords
-it is suggested to discuss some related papers and compare different nanocarriers with yours, for example https://0-doi-org.brum.beds.ac.uk/10.1016/j.apsusc.2022.155290, https://0-www-sciencedirect-com.brum.beds.ac.uk/science/article/abs/pii/S0022286022005919, https://0-doi-org.brum.beds.ac.uk/10.1002/advs.202003535, https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12080725
-the style of refs in the text is wrong, please correct
-how samples were prepared for SEM analysis
-I have some concerns about using inorganic NPs for drug delivery, what about their cytotoxicity? Please address this in the conclusion part
-Figure 3 has low resolution
-it needs to add a graphical abstract to present your novelty
Author Response
Responses to Reviewers comments:
The authors are thankful to the reviewers for their comments and suggestions, which significantly contributed toward improving the quality of the manuscript.
Reviewer #2:
The paper needs a major revision before accept
- the abstract doesn’t provide the goal of the study properly and needs to be revised
Our reply: We included additional sentence in the abstract: “Hence, the aim is set forth at constructing novel mesoporous silica nanoparticle (MSN)-based acidification-responsive drug delivery systems for targeted cancer therapy.”
- please add mesoporous silica NPs to the keywords
Our reply: We added the keyword as suggested
- it is suggested to discuss some related papers and compare different nanocarriers with yours, for example https://0-doi-org.brum.beds.ac.uk/10.1016/j.apsusc.2022.155290, https://0-www-sciencedirect-com.brum.beds.ac.uk/science/article/abs/pii/S0022286022005919, https://0-doi-org.brum.beds.ac.uk/10.1002/advs.202003535, https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12080725
Our reply: We included these papers in the introduction section on page 2 as follows:
“Different types of drug delivery systems have been developed recently, including ionically crosslinked gels [18], Janus nanofibrous membranes [19], mesoporous silica [20], and other inorganic nanoparticles [21].”
Furthermore, we discussed additional related studies:
Recent advances have shown the applicability of different types of nanoparticles for the delivery of Ir(III)-based therapeutics for cancer treatment [28- 30]. On the other hand, only one report was published very recently on incorporation of Ir(III) within MSN for application in therapy of cancer [31]
- the style of refs in the text is wrong, please correct
Our reply: We corrected as suggested.
- how samples were prepared for SEM analysis
Our reply: We added the sentence in the methodology section about the SEM measurements:
“The morphology of nanoparticles was characterized by scanning electron microscopy (SEM) on a Tescan Vega3 Phenom (Tescan, Brno, the Czech Republic). The samples were prepared by placing them on a conductive carbon adhesive tape and sputtered with gold to increase conductivity.”
- I have some concerns about using inorganic NPs for drug delivery, what about their cytotoxicity? Please address this in the conclusion part
Our reply: We included in the conclusion section the following sentence:
“All materials showed low toxicity against healthy MRC-5 cells.”
We also included a section about cytotoxicity and biodistribution of MSN in the introduction section:
“Studies on in vivo toxicity and biodistribution of MSN-based materials evidence their high biocompatibility and capabilities for preferential accumulation in tumor tissues [15], though their biodistribution profiles can be affected by the shape [16], as well as by the size and functionalization of the particles [17].”
Along with the new references:
- Lu, J.; Liong, M.; Li, Z.; Zink, J. I.; Tamanoi, F., Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small 2010, 6 (16), 1794-1805.
- Shao, D.; Lu, M.-m.; Zhao, Y.-w.; Zhang, F.; Tan, Y.-f.; Zheng, X.; Pan, Y.; Xiao, X.-a.; Wang, Z.; Dong, W.-f.; Li, J.; Chen, L., The shape effect of magnetic mesoporous silica nanoparticles on endocytosis, biocompatibility and biodistribution. Acta Biomaterialia 2017, 49, 531-540.
- He, Q.; Zhang, Z.; Gao, F.; Li, Y.; Shi, J. In vivo Biodistribution and Urinary Excretion of Mesoporous Silica Nanoparticles: Effects of Particle Size and PEGylation. Small 2011, 7, 271–280.
- Figure 3 has low resolution
Our reply: We provided the figure with better resolution
- it needs to add a graphical abstract to present your novelty
Our reply: We provided the graphical abstract
Author Response File: Author Response.pdf
Reviewer 3 Report
The manuscript “Mesoporous Silica Nanoparticles for pH-responsive delivery of Iridium Metallotherapeutics and Treatment of Glioblastoma Multiforme” reports the fabrication of surface-functionalized mesoporous silica nanoparticles with a Ir(III)-based complex. The release of Ir(III)-complexes was studied by UV/VIS spectroscopy at the weakly acidic environments and at physiological conditions. Also, the authors presented the potential of these nanomaterials for efficient treatment of glioblastoma multiforme cells.
The work is well structured and the data are clearly discussed. I recommend the publication after some revisions. Below, I include some comments.
1. Could the authors add the FTIR spectra of MSN, MSN-H1, MSN-H2, and [Ir] in Figure 2a as well? It would be nice to compare the different stages of products.
2. Check the numbering of the sections. “Materials and Methods” should be numbered as 3 and not 4, and “Conclusions” as 4 and not 5.
3. The conclusions should be enriched with the authors’ findings. Please add some detail over the main results that have come up in this research.
Author Response
Responses to Reviewers comments:
The authors are thankful to the reviewers for their comments and suggestions, which significantly contributed toward improving the quality of the manuscript.
Reviewer #3:
The manuscript “Mesoporous Silica Nanoparticles for pH-responsive delivery of Iridium Metallotherapeutics and Treatment of Glioblastoma Multiforme” reports the fabrication of surface-functionalized mesoporous silica nanoparticles with a Ir(III)-based complex. The release of Ir(III)-complexes was studied by UV/VIS spectroscopy at the weakly acidic environments and at physiological conditions. Also, the authors presented the potential of these nanomaterials for efficient treatment of glioblastoma multiforme cells.
The work is well structured and the data are clearly discussed. I recommend the publication after some revisions. Below, I include some comments.
- Could the authors add the FTIR spectra of MSN, MSN-H1, MSN-H2, and [Ir] in Figure 2a as well? It would be nice to compare the different stages of products.
Our reply: The spectra of all materials are now added to the Figure as suggested.
- Check the numbering of the sections. “Materials and Methods” should be numbered as 3 and not 4, and “Conclusions” as 4 and not 5.
Our reply: Thank you for noticing. We corrected the manuscript.
- The conclusions should be enriched with the authors’ findings. Please add some detail over the main results that have come up in this research.
Our reply: We modified the conclusion as follows:
“Novel mesoporous silica nanoparticles are synthesized and characterized for pH-responsive delivery of surface-functionalized Ir(III) complexes. The materials demonstrated the capabilities for enhanced release of the surface-functionalized iridium(III)-complexes upon exposure to weakly acidic environment in comparison to the physiological pH. All materials showed low toxicity against healthy MRC-5 cells. The materials containing Ir(III) exhibited enhanced toxicity against glioblastoma multiforme cells. In case when the materials were exposed to buffers for 24 h prior to testing their activity, their toxicity against glioblastoma increased by an order of magnitude in comparison to their direct dispersion and testing from the cell media. The results of this study reveal the promising potential of the prepared materials for targeted cancer treatment in response to the weakly acidic environment.“
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
accept
Reviewer 3 Report
I thank the authors for reviewing their manuscript according to the reviewers comments. All my points were taken into account and the text has been modified accordingly. I recommend publication in its present form.
