Drug-Induced Phase Separation in Polyelectrolyte Microgels
Round 1
Reviewer 1 Report
This paper studies the volume phase transition undergone by polyelectrolyte microgels upon loading and release of amphiphilic molecules.
The study places special emphasis on the generation of the outermost gel layers and the formation of a core-shell structure. The main hypothesis of the authors is that the core-shell boundary is stabilized by thermodynamic factors, and consequently that collapsed and swollen phases should be able to coexist also at equilibrium.
I think that the ideas behind these experiments could be of interest to the soft matter science community.
I would recommend that this manuscript be accepted for publication after the authors address the following comments:
1) The authors found that collapsed, AMT-rich, and swollen, AMT-lean phases coexist “in equilibrium” or as “long-lived metastable states” at intermediate drug loading levels. It seems that the authors are not able to discriminate the thermodynamic state of the system. The stable equilibrium state is "truly unchanging", whereas the metastable state may be changing, but too slowly to be observed. For example, polyelectrolyte layer-by-layer assemblies are metastable systems, but due to the fact that changes are too slow, these assemblies are employed in different applications.
2) I agree with authors that the system is dominated by thermodynamic factors. But, what are the actual molecular interactions lying behind these thermodynamic factors? For example, pi-pi interactions might be playing a role in AMT-AMT associations within the polymer matrix. Please describe the molecular interactions governing this system in as much detail as possible.
Author Response
Please see the attachment
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The manuscript by Al-Tikriti and Hansson presents the experimental study of PA micro gels interacting with cationic amphiphilic drug AMT at two ionic strengths in buffer solution (I = 10 mM and 155 mM). As expected, an increase in AMT load causes swelling–to-collapse transition in micro gel with formation of the collapsed AMT-rich and swollen AMT-lean phases. At I = 10 mM, AMT-rich phase in micro gels was located closer to the micro gel boundary in the form of separate domains. At physiological ionic strength (I = 155 mM) AMT-rich phase constituted the collapsed core while AMT-depleted phase gave rise to swollen shell. The authors check their hypothesis that the boundary between the collapsed core and swollen shell could be stabilized by thermodynamic factors, and thus the two phases could coexist at equilibrium or, at least, as long-living metastable states.
I think that the study is interesting, and the authors provide reasonable experimental arguments to support their claims. However, it would be helpful to general readership of the journal to get more specifics/insights about the system investigated.
Below are my questions/comments to be addressed prior publication of the manuscript in Gels:
- One could naively expect that association of AMT micelles (envisioned as cationic polyvalent species) with the periphery of weakly crosslinked PA micro gel would follow the same trends as complexation of branched (e.g., star-like) ionic polymers with oppositely charged oligomers. Star-like polyions are known to experience disproportionation of the branches upon complexation with oppositely charged oligomers (see, e.g., Langmuir 2009, 25 (4), 1915). That is, part of the branches collapses forming the central core compensating oligomer charge while the rest of the branches constitute swollen shell of star-like polymer.
Could similar phenomenon happen in PA micro gel at low ionic strength, i.e., when the electrostatic interactions are strong, and AMT micelles give rise to domains mostly in the peripheral region of micro gels? Could the internal structure of these domains be somehow specified?
- The binding ratio b should be defined when it first arrives on p. 3 in the text. Although the authors explain on p. 14 how they experimentally measure b, physical definition of b should be placed in the text earlier to improve clarity of presentation. In particular, I did not understand how b is related to ratio of bare charges on PA micro gel and AMT load?
- It would be also helpful to know the aggregation number (bare charge) in AMT micelles, the average length of PA spacers between crosslinks, the degree of PA ionization, etc.
To summarize: I recommend publication of the manuscript in the Gels after minor revision addressing my comments.
Author Response
Please see the attachment
Author Response File: Author Response.pdf
