Real-time 31P NMR reveals different gradient strengths in polyphosphoester copolymers as potential MRI-traceable nanomaterials

Polyphosphoesters (PPEs) are used in tissue engineering and drug delivery, as polyelectrolytes, and flame-retardants. Mostly polyphosphates have been investigated but copolymers involving different PPE subclasses have been rarely explored and the reactivity ratios of different cyclic phospholanes have not been reported. We synthesized binary and ternary PPE copolymers using cyclic comonomers, including side-chain phosphonates, phosphates, thiophosphate, and in-chain phosphonates, through organocatalyzed ring-opening copolymerization. Reactivity ratios were determined for all cases, including ternary PPE copolymers, using different nonterminal models. By combining different comonomers and organocatalysts, we created gradient copolymers with adjustable amphiphilicity and microstructure. Reactivity ratios ranging from 0.02 to 44 were observed for different comonomer sets. Statistical ring-opening copolymerization enabled the synthesis of amphiphilic gradient copolymers in a one-pot procedure, exhibiting tunable interfacial and magnetic resonance imaging (MRI) properties. These copolymers self-assembled in aqueous solutions, 31 P MRI imaging confirmed their potential as MRI-traceable nanostructures. This systematic study expands the possibilities of PPE-copolymers for drug delivery and theranostics.

Reviewer #1 (Remarks to the Author): The manuscript by Wurm and coworkers presented an interesting story about synthesis of polyphosphoesters in the presence of organic catalysts.The gradient copolymers with varying amphiphilicity and gradient strength were well produced by the combination of different comonomers and organocatalysts.Thses polymers have potential applications in drug and theranostics.Reactivity ratios were determined and simulated for different binary or/and trinary comonomers.Altogether, the scientific quality and the scholarly presentation of this manuscript are very good, thus the work is certainly of sufficient impact and novelty to warrant publication.
As a minor correction, I would suggest citing the following article on construction of polyphosphoesters with the main chain of rigid backbones and stereostructures via organocatalyzed ring-opening polymerization.Polym. Chem., 2020, 11, 3475-3480.Reviewer #2 (Remarks to the Author): This paper is excellently written, and the results are clearly and systematically rationalized and explained.This class of copolymers grants access to a wide variety of properties, owing to the different reactivities afforded by the organocatalysis.I would recommend it for publication, essentially as is, with a couple exceptions.Reviewer #3 (Remarks to the Author): The manuscript entitled "Real-time 31P NMR of organocatalytic ring-opening copolymerization reveals different gradient strengths in polyphosphoesters -a road to MRI-traceable nanostructures" describes precise analytical data for copolymerization of various cyclic phosphorus-containing monomers and newly MRI properties of the copolymers.Overall, this manuscript is well written and contains important basic information to understand polymerization manner of cyclic phosphorus-containing monomers.The findings of this manuscript will be of use for the design new polymeric materials based on polyphosphoesters.The referee would like to just ask authors to add MRI image of P(EtPPn-co-EEP) to better understand the effect of structure of polymers on MRI properties.

Communica ons chemistry
Reviewer #1 (Remarks to the Author): The manuscript by Wurm and coworkers presented an interes ng story about synthesis of polyphosphoesters in the presence of organic catalysts.The gradient copolymers with varying amphiphilicity and gradient strength were well produced by the combina on of different comonomers and organocatalysts.Thses polymers have poten al applica ons in drug and theranos cs.Reac vity ra os were determined and simulated for different binary or/and trinary comonomers.Altogether, the scien fic quality and the scholarly presenta on of this manuscript are very good, thus the work is certainly of sufficient impact and novelty to warrant publica on.
As a minor correc on, I would suggest ci ng the following ar cle on construc on of polyphosphoesters with the main chain of rigid backbones and stereostructures via organocatalyzed ring-opening polymeriza on.Polym. Chem., 2020, 11, 3475-3480.We thank the reviewer for reding our manuscript and giving sugges ons.We do not really see the connec on of this publica on (Zhen 2020) to our manuscript.Beside the fact that it discuss polyphosphoesters (PPE), no connec on is apparent.We le out the suggested cita on.
Reviewer #2 (Remarks to the Author): This paper is excellently wri en, and the results are clearly and systema cally ra onalized and explained.This class of copolymers grants access to a wide variety of proper es, owing to the different reac vi es afforded by the organocatalysis.I would recommend it for publica on, essen ally as is, with a couple excep ons.We thank the reviewer for reding our manuscript and giving construc ve input to improve our manuscript.Thanks for the remark, we increased the symbol size and changed the chape.The colors are adjusted as well.
Reviewer #3 (Remarks to the Author): The manuscript en tled "Real-me 31P NMR of organocataly c ring-opening copolymeriza on reveals different gradient strengths in polyphosphoesters -a road to MRI-traceable nanostructures" describes precise analy cal data for copolymeriza on of various cyclic phosphorus-containing monomers and newly MRI proper es of the copolymers.Overall, this manuscript is well wri en and contains important basic informa on to understand polymeriza on manner of cyclic phosphoruscontaining monomers.The findings of this manuscript will be of use for the design new polymeric materials based on polyphosphoesters.The referee would like to just ask authors to add MRI image of P(EtPPn-co-EEP) to be er understand the effect of structure of polymers on MRI proper es.
We thank the reviewer for reding our manuscript and giving construc ve input to improve our manuscript.
We agree on the sugges on, and added a MRI image of P(EtPPn-grad-EEP) in Figure 7.

Figure 2 .
Figure 2. Increase the font size of the axes.

Figure 6 :
Figure 6: It's a bit difficult to distinguish the colors.Consider (part c and d) making the symbols different and a bit larger size.

Figure 2 .
Figure 2. Increase the font size of the axes.Thanks a lot for the hint, we agree and changed the figure.

Figure 6 :
Figure 6: It's a bit difficult to dis nguish the colors.Consider (part c and d) making the symbols different and a bit larger size.