Molecular Theranostic Agents for Photodynamic Therapy (PDT) and Magnetic Resonance Imaging (MRI)
Round 1
Reviewer 1 Report
The manuscript proposed by S. Jenni and A. Sour for publication in Organics, is entitled “Molecular theranostic agents for PDT and MRI” In this review, the authors describe studies on the combination at the molecular level of MRI and PDT which could lead to a real-time monitoring of the PhotoDynamic (PDT) treatment and could bring significant information via Magnetic Resonance Imaging. As said in the manuscript, the theranostic agents based on Nano-PARTICLES belong to another promising and active field. They have been reviewed in Chem. Rev. 2015, 115, 10907-10937; Chem. Rev. 2016, 116, 2826-2885 and ACS Nano 2017, 11, 9594-9613. The more particular nanoparticle approaches for MRI and PDT applications have also attracted increasing attention during the past decade (well described in these reviews J. Controlled Release 2015, 198, 35-54 and Chem. Soc. Rev. 2015, 44, 6670-6683 given tin the manuscript). Clinical translation has not yet been developed. The molecular theranostic agents for PDT and MRI have been studied to a lesser extent; however, interesting results have been obtained (small or medium‑size molecular agents, high reproducibility, stability, purity and quite good biocompatibility); To further improve the imaging efficiency of the theranostic agent, the local rigidity and the stability are two important parameters also to take into account. In addition to the MR imaging, the fluorescence properties of the tetrapyrrolic core have also been explored in some cases in a bi-modal imaging approach involving more or less sensitive phenomena.
This review is very interesting and exhaustive. Nevertheless, I would just suggest (to be complete and perfectly honest) to add a short description of the main drawbacks (and related advantages of the nanoparticle approach) of these molecular theranostic agents: more difficult and elaborated organic synthesis – expensive- AND, more difficult to adapt the sensitivity of the imaging agent to the sensitivity of the photosensitizer (in the case of PDT treatments).
This review is of great interest in a very actual research field; it is quite complete and deserve (from my point of view) for a publication in Inorganics.
Author Response
Response to reviewer 1:
The reviewer suggests adding a short description of the main drawbacks of the molecular theranostic agents.
Page 3 line 102 : we added a short description to describe the main drawbacks of molecular theranostic agents : “particularly due to the more elaborated and time-‐consuming synthesis.”
The reviewer also suggested to precise that it is more difficult with molecular systems to adapt the sensitivity of the imaging agent to the sensitivity of the PS.
We thank the reviewer for this remark. We think that this point of view can be discussed. It is partially included in the added sentence precising that molecular theranostic agents are more difficult to synthesize.
Then, on one hand, we agree that it is not possible to easily vary the number of Gd(III) complexes around the PS. On the other hand, when dealing with some nanoparticles, it is possible to easily vary the ratio between the two components but the reproducibility is sometimes a challenge difficult to resolve.
Furthermore, with the work done by Pandey and coworkers (page 4), we can see that with only 3 Gd(III) complexes attached to one photosensitizer, and without an exceptional relaxivity value per Gd, it is possible to obtain a good contrast in mice and to perform MR imaging and PDT treatment at a concentration that is low (10 µmol/kg) and harmless. This work suggests that it might be possible that a ratio of 3 Gd complexes to 1 PS is good to obtain a good image, and the synthesis of other theranostic agents with different ratios could later be avoided.
Taking into account this remark, we added the following sentence:
Page 4 line 150-‐152, we added the following sentence:
“This important result shows that, with the presence of three Gd(III) complexes appended to one photosensitizer, it is possible to perform MR imaging and PDT treatment at the same low concentration”.
Reviewer 2 Report
This review by Jenni et al gives a comprehensive overview of molecular theranostic agents combing MRI and photodynamic therapy (PTD) applications. The review is very well structured, introducing strengths and limitations of PDT treatment and the concept of MRI guidance of PDT, and highlighting the main approaches towards obtaining molecular theranostic agents.
The language is clear and after adjusting some minor linguistic errors (e.g. "information"should be used instead of "informations") it can be accepted in present form.
Author Response
Response to reviewer 2
Page 1, line 10 and 22: Informations has been replaced by information.
Page 2, line 80: Informations has been replaced by information.
Page 3, line 88 and 90: Informations has been replaced by information.
Reviewer 3 Report
This manuscript given an overview on molecular theranostic agents based PDT and MRI. In my opinion, the manuscript was well written and the overview on molecular theranostic agents could be attractive to the readers. The manuscript can be accepted to publish after a minor revision.
1. The authors should give a definition on molecular theranostic agents. (What is the difference between molecular theranostic agents and other theranostic agents? Molecular weight or something else?)
2. The readers would be interested in Porphyrin‑Gd‑complexes conjugates with potential MRI and PDT applications in subtitle 2, since few works had been done on molecular theranostic agents that act as photosensitizers as well as MRI contrast agents. The authors could add more sentences to introduce this section.
3. Do the molecular theranostic agents include supramolecular contrast agents? Some supramolecular contrast agents (Molecular imaging, 2007, 6, 7290-2007; Chemical Science, 2016, 7. 4230-4236; Coordination Chemistry Reviews, 2017, 333: 82-107.) and their applications (Biomaterials, 2018, 182: 269-278) in photodynamic therapy should be mentioned.
4. The subtitle 4 was missing.
Author Response
Dear Editor,
Thank you for your message of January 2nd. We would also like to thank the reviewers for their constructive comments and advice. We have taken into account their remarks and we also improved other sentences in our manuscript.
Response to reviewer 3:
1. Page 1, line 27: We added a sentence to define molecular theranostic agents: “These multifunctional molecules can be described as low and medium molecular weight compounds that don’t self-‐assemble into bigger systems.“
We thank the reviewer for this advice. We consider that the molecules are small or medium-‐sized compounds, that do not self-‐assemble into bigger systems. Although the molecular weights of the theranostic agents presented in this review are in the range between 960 and 4000 g/mol, we prefer not to precise the weight, as this can still evolve in the future.
2. Page 3, line 110-‐113: We slightly developed the introduction of this paragraph and transformed the first sentence into the two following sentences.
“Several porphyrin analogues have been associated to Gd(III) complexes and their ability to accumulate in cancer cells and/or their relaxivity have been studied. Although their ability to behave as PDT PSs has not been explored, these compounds are potential bifunctional compounds for MRI and PDT applications”.
3. The molecular theranostic agents do not include supramolecular contrast agents. We consider that supramolecular agents, that are defined as micelles and liposomes see Morelli Coord Chem Rev 2009 p 2193) with their size close to the one of nanoparticules, belong rather to the family of nanoparticules.
We could not find the first proposed article in Molecular imaging 2007. The second proposed article only concerns MRI contrast agents, with no therapeutic treatment. The same remark can be made with the 3rd proposed review, although some theranostic agents are presented. The 4th proposed article presents an example of a theranostic nanoparticle.
In our review we focus on molecular theranostic agents for MRI and PDT. We choose not to add these references: they concern only or principally MRI contrast agents and the last article is an example of nanoparticular theranostic agent and we prefer to mention the latest reviews concerning this field. We hope the reviewer agrees with our choice.
4. Page 9 line 307: 5. Conclusions has been replaced by “4. Conclusions”
