Predicting Monomers for Use in Polymerization-Induced Self-Assembly

Article abstract of DOI:10.1002/anie.201809614

We report an in silico method to predict monomers suitable for use in polymerization-induced self-assembly (PISA). By calculating the dependence of LogP_oct /surface area (SA) on the length of the growing polymer chain, the change in hydrophobicity during polymerization was determined. This allowed for evaluation of the capability of a monomer to polymerize to form self-assembled structures during chain extension. Using this method, we identified five new monomers for use in aqueous PISA via reversible addition-fragmentation chain transfer (RAFT) polymerization, and confirmed that these all successfully underwent PISA to produce nanostructures of various morphologies. The results obtained using this method correlated well with and predicted the differences in morphology obtained from the PISA of block copolymers of similar molecular weight but different chemical structures. Thus, we propose this method can be utilized for the discovery of new monomers for PISA and also the prediction of their self-assembly behavior.

Full text of DOI:10.1002/anie.201809614

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Predicting Monomers for use in Polymerization Induced Self-
Assembly
Authors: Jeffrey Foster, Spyridon Varlas, Benoit Couturaud, Joseph
Jones, Robert Keogh, Robert Mathers, and Rachel Kerry
O'Reilly
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809614
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10.1002/anie.201809614
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Predicting Monomers for use in Polymerization Induced Self-
Assembly
Jeffrey C. Foster,[a] Spyridon Varlas,†[a] Benoit Couturaud,†[a] Joseph R. Jones,[a] Robert Keogh,[b]
Robert T. Mathers,*[c] and Rachel K. O’Reilly*[a]
Abstract: We report an in silico method to predict monomers suitable
for use in polymerization-induced self-assembly (PISA). By
calculating the dependence of LogPoct/surface area (SA) on the length
of the growing polymer chain, the change in hydrophobicity during
polymerization was determined. This allowed for evaluation of the
capability of a monomer to polymerize to form self-assembled
structures during chain extension. Using this method, we identified
five new monomers for use in aqueous PISA via reversible addition-
fragmentation chain transfer (RAFT) polymerization, and confirmed
that these all successfully underwent PISA to produce nanostructures
of various morphologies. The results obtained using this method
correlated well with and predicted the differences in morphology
obtained from the PISA of block copolymers of similar molecular
weight but different chemical structures. Thus, we propose this
method can be utilized for the discovery of new monomers for PISA
and also the prediction of their self-assembly behavior.
Polymerization-induced self-assembly (PISA) has revolutionized
the preparation of soft nanoparticles.[1] Unlike traditional self-
assembly strategies, in which a block copolymer is synthesized
separately and transitioned into aqueous milieu,[2] PISA occurs in
situ as the polymerization progresses. During aqueous PISA, a
water-soluble homopolymer is chain-extended with a second,
water-miscible monomer.[3] As the polymerization proceeds, the
second block becomes gradually insoluble in the reaction media,
driving self-assembly.[4] A variety of self-assembled morphologies
can be readily accessed by tuning polymerization conditions.[5] In
addition to its simplicity, PISA is advantageous as it can be
conducted at high solids content (typically 10-30 w/w%) to
quantitative or near quantitative conversion of monomer.
[a]
Dr. J. C. Foster, S. Varlas, Dr. B. Couturaud, Dr. J. R. Jones, Prof.
R. K. O’Reilly
School of Chemistry, University of Birmingham
Edgbaston, Birmingham, B15 2TT (UK)
E-mail: r.oreilly@bham.ac.uk
Figure 1. Schematic illustration of the aqueous RAFT PISA process, A) Core-
forming monomers identified in the literature for use in RAFT PISA in aqueous
milieu and B) predicted core-forming monomers.
[b]
[c]
R. Keogh
Department of Chemistry, University of Warwick
Gibbet Hill Road, Coventry, CV4 7AL (UK)
Prof. R. T. Mathers
Department of Chemistry, Pennsylvania State University
New Kensington, PA 15068 (USA)
E-mail: rtm11@psu.edu
Polymer nanoparticles obtained from PISA have applications in
nanomedicine and drug delivery,[6] especially in the case of worm
or vesicle morphologies, which have specific advantages over
Supporting information for this article is given via a link at the end of
the document.
†These authors contributed equally to this work.
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10.1002/anie.201809614
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spherical micelles. In particular, these morphologies often have
higher loading capacities than spherical micelles and different in
vivo cell adsorption and internalization behavior.[7] In the case of
polymeric vesicles, both hydrophobic and hydrophilic payloads
can be encapsulated due to the fact that they possess both a
vesicle membrane and an aqueous interior.[8]
In principle, PISA can be carried out using any type of
controlled/living polymerization; however, the vast majority of
examples in the literature concern the use of reversible addition-
fragmentation chain transfer (RAFT) polymerization. RAFT is
well-suited for PISA due to its wide monomer scope and tolerance
towards most conventional reaction media including polar- and
non-polar organic solvents, ionic liquids, and most importantly,
water.[9] To date, a number of vinyl monomers have been
identified that undergo PISA via RAFT in aqueous milieu (Figure
1A); for example, acrylates (MEA),[10] methacrylates (HPMA,
11]
HBMA, DEGMA),[5,
and acrylamides (DAAm, DEAm,
Figure 2. Evolution of oligomer hydrophobicity as a function of the length of the
oligomer. LogPoct values (ALogP98 method) normalized by Connolly surface
area (SA). Blue region indicates corona-forming blocks and red region indicates
core-forming blocks in aqueous PISA.
NIPAM)[12] have all been utilized successfully. In light of the
diversity of these monomer examples, there exists no clear
principle to identify whether a certain monomer can be utilized to
conduct PISA in a given solvent. Indeed, most of the monomers
found to undergo PISA appear to have been identified empirically.
In other words, the capability of a monomer to undergo PISA is
most often recognized during polymerization, indicated by an
onset of turbidity within the polymerization solution.
In this contribution, we report a generalized in silico method to
predict whether a given monomer will undergo PISA in water. This
method evaluates the variance in polymer hydrophobicity with
increasing chain length, which is hypothesized to be a key feature
in determining if the monomer is capable of behaving as a core-
forming monomer for PISA. Application to monomers known to
undergo PISA resulted in the emergence of a trend through which
additional PISA monomers could be predicted. Then, this method
was utilized to identify proposed new PISA monomers (Figure 1B).
Validation of these new monomers via RAFT polymerization in
water confirmed the capability of our method to predict new
monomers for PISA.
The underlying methodology for predicting PISA behavior
involves calculating the hydrophobicity of oligomeric models using
octanol-water partition coefficients (LogPoct). For several decades,
this metric has served as a key predictor of drug solubility for the
pharmaceutical industry.[13] Although it has only recently adapted
for polymer science, the versatility of LogPoct values has facilitated
assessment of condensation polymerizations,[14] UV-cured
post-polymerization
and crystallization-driven
(CDSA).[18] During initial efforts to switch the focus from small,
drug-like molecules to larger polymeric structures, normalizing
LogPoct values with surface area (SA) minimized end-group
effects and molecular weight differences.[15]
and indeed they demonstrated an opposite trend. This analysis
was further applied to a wide range of previously reported
monomers, as shown in Figure S1. Based on this analysis, the
magnitude of LogPoct/SA and corresponding slope predicts
whether a unimer will achieve increasing hydrophobicity during
propagation and thus enable its utilization as a core-forming
monomer in PISA. While the slope and magnitude in Figure 2 will
be influenced by experimental parameters (i.e., temperature,
solvent, and pH), computational predictions of hydrophobicity
appear to accommodate a wide variety of functional groups found
in polymer science. As such, the trends observed in LogPoct/SA
for neutral polymers at pH ~7 appear to be universal and provide
an insight into the upper and lower limits of hydrophobicity for
core-forming PISA monomers.
The magnitude of the LogPoct/SA values shown in Figure 2
conveys meaningful insight into the overall hydrophobicity of the
growing polymer chain. For example, oligomers prepared from 2-
HPMA possess LogPoct/SA values that are ca. 0.004 Å-2 greater
than those of MEA across all chain lengths. Because the
hydrophobicity of the growing polymer chain affects its partitioning
between water and organic phases, relative comparisons of the
magnitude of LogPoct/SA could potentially predict both the length
of the chain required to induce micellization and the predominate
morphology for a given oligomer length. We consider PEG-b-
PHPMA and PEG-b-PMEA block copolymers reported by Armes
films,[15]
electrolytes,[17]
modifications,[16]
self-assembly
polymer
and
Meada,
respectively.[19]
For
PEG113-b-PHPMA300,
unimolecular vesicles are obtained at 10 wt% solids, while
spherical micelles are reported for PEG113-b-PMEA300 at the same
concentration. This difference in morphology between polymers
of similar molecular weight can be rationalized in terms of their
relative hydrophobicities. As our model predicts via the magnitude
of the LogPoct/SA value, polymers of 2-HPMA are more
hydrophobic than those of MEA. Thus, higher-order morphologies
are obtained for 2-HPMA than for MEA at the same degree of
polymerization (DP) and concentration.
When molecules experience a two-phase environment, such as
octanol and water, positive LogPoct values indicate the molecule
is hydrophobic and mostly partitions into the octanol phase. In
contrast, negative LogPoct values confirm a preference for
solubility in the aqueous phase. In Figure 2, four previously
reported core-forming polymers (as shown in Figure 1A) were
calculated to exhibit positive LogPoct/SA values (for short
oligomers, 6-mers) and positive slopes upon increasing the block
length to 24. As a comparison, we performed the same calculation
for three well-established water-soluble oligomers and polymers
Using our predictive model, seven further vinyl monomers were
selected based on either their commercial availability or their
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similarity to monomers that have been previously reported to
undergo PISA (Figure 1B). For example, THFA and iBuOMAm
can be purchased from commercial vendors, while 3-HPMA is a
structural isomer of 2-HPMA. 2-HPMA is perhaps the most
commonly utilized core-forming monomer in PISA, which is most
often obtained as a mixture of isomers. Because the LogPoct/SA
values of 3-HPMA are less than those of 2-HPMA by almost a
factor of two, the behavior of commercial isomeric monomer
mixtures during PISA is expected to depend on their respective
molar ratios. We also chose to compare the LogPoct/SA values
and self-assembly behavior of 4-HBA and 2-HBA, another pair of
structural isomers. These monomer pairs would, we envisioned,
yield
meaningful
insight
into
structure/hydrophobicity
relationships. Toward this end, LogPoct/SA values were calculated
for these monomers at various oligomer lengths as shown in
Figure 2 and Figure S1.
Interestingly, all seven of the predicted monomers were found to
reside in the hydrophobic region of the LogPoct/SA vs n-mer plot
shown in Figure 2 and Figure S1 and possessed positive slopes.
This suggested that all of the monomers shown in Figure 1B were
predicted to be suitable as core-forming monomers in PISA. It
should be noted that the acrylamides HPEAm and MeOBzAm
were solids at room temperature and could not be dissolved in
H2O at concentrations relevant for PISA (i.e., ≥ 10 wt%).
Therefore, this approach for identifying potential PISA monomers
is limited by the fact that it does not give direct information about
the solubility of the monomer itself in H2O. The remaining five
monomers each appeared to be miscible with H2O at
concentrations as high as 25 wt%.
We then evaluated the capability of the five water-miscible
monomers—3-HPMA, 4-HBA, THFA, 2-HBA, and iBuOMAm—to
undergo PISA in aqueous media. A series of polymerizations
were carried out for these monomers via RAFT using a PEGylated
chain transfer agent (macro-CTA, Mn ~ 5 kDa). For these
experiments, the concentration of monomer was held constant at
25 w/w%, the [macro-CTA]/[initiator] ratio was maintained at 1 :
0.1, and the [monomer]/[ macro-CTA] ratio was varied to target
different degrees of polymerization. The polymerizations were
Figure 3. Evaluation of RAFT PISA using THFA as a core-forming block. A)
Schematic of THFA aqueous PISA. B) Kinetic plots of polymerization targeting
DP = 100. The inset shows the semilogarithmic plot. C) SEC RI traces of four
different polymerizations targeting DPs of 50 (black trace and circle), 75 (green
trace and circle), 100 (red trace and circle), and 200 (blue trace and circle). The
inset shows the variance in Mn with DP. D-F) Cryo-TEM images after
polymerization showing the evolution of morphology upon increasing DP. The
size of the inset of F is 1 µm2.
light scattering (SLS) by comparison with a theoretical form factor
for disperse random coils in the case of the DP=75 sample and
from a measured Rg/Rh ratio of 0.995 for the DP=200 sample
which is consistent with hollow spheroids (Figure S22). Similar
trends were observed for the other new monomers (SEC traces
found in Figures S8-S10; TEM images in Figures S11-S15);
however, a significant difference in the morphology of the self-
assemblies was observed that depended on the monomer utilized,
implying a correlation between the chemical nature of the
monomer and the morphology of the resulting nanoparticles. It
should be noted that some of the monomers utilized (THFA, 2-
and 4-HBA) produced polymers with Tg values below room
temperature. As such, the morphologies present immediately
following polymerization may not be directly reflected by TEM
images or SLS data, which are conducted at lower temperatures.
The success of our evaluation of PISAs using the five predicted
monomers validated prediction of new core-forming monomers
using LogPoct/SA calculations. In addition to predictive data, we
wondered whether this quantitative treatment, which gives
information about the relative hydrophobicity of polymer
microstructures, could be correlated to other aspects of PISA. It
is well understood that assembly morphology depends on factors
such as the degree of stretching of the core-forming chains, the
interfacial tension between the hydrophobic cores and their
external environment, and repulsion between corona chains.[2]
These parameters are most often tuned by varying the relative
volume fraction of the hydrophobic and hydrophilic blocks.[20] In
contrast, there has been little study into how the chemistry of the
initiated
using
2,2'-azobis(2-methylpropionamidine)
dihydrochloride (V-50), which is water-soluble, and were heated
at 50 °C for 2-6 h until the monomer conversions had reached ≥
90%. The polymerization samples were then analyzed by size-
exclusion chromatography (SEC) and transmission electron
microscopy (TEM).
In all cases, RAFT PISA using the five monomers resulted in the
formation of self-assembled morphologies, regardless of the
targeted DP. Molecular weight distributions were generally narrow,
with experimentally measured MWs that agreed well with
expected values. PISA using THFA is highlighted in Figure 3. As
shown in Figure 3B, RAFT polymerization followed pseudo-first-
order kinetics, with a change in rate at ca. 10 min that
corresponded to the onset of self-assembly. MW values
increased linearly with increasing targeted DP (Figure 3B, inset),
and dispersity values remained low for the polymerizations
targeting DPs of 50, 75, and 100 (ƉM ≤ 1.3), but was higher for
the DP 200 sample (ƉM = 1.56). In addition, the self-assembled
morphologies evolved from worms to a mixed morphology
containing worms and vesicles to pure vesicles as the DP of the
core block increased from 75 to 100 to 200, respectively (Figures
3D-3F). These morphologies were further confirmed using static
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Figure 4. Morphological prediction and rationalization using LogPoct/SA method. A) Semi-logarithmic kinetic plots for RAFT PISA using DAAm, 2-HBA, and HBMA
targeting DP = 100. B) Plot of the DP at the onset of assembly as a function of LogPoct/SA. C) SEC RI traces of the RAFT PISAs using DAAm, 3-HPMA, 2-HPMA,
2-HBA, and HBMA. D) Dry-state (DAAm, 3-HPMA, 2-HPMA, and HBMA) or cryo-TEM (2-HBA) images of RAFT PISAs using these five monomers after
polymerization. The insets show an increase in turbidity of the polymerization solutions with increasing polymer hydrophobicity.
core-forming chains affects self-assembly. As the interfacial
tension between the cores of the self-assembled aggregates and
their solvent environment depends principally on the
hydrophobicity of the polymer chains located at that interface, we
envisioned that our LogPoct/SA analysis could enable
morphological prediction. Therefore, we hypothesized that for
block copolymers with identical corona and core block lengths,
changes in LogPoct/SA of the hydrophobic block could be related
to the morphology of the self-assembled particles.
assemblies accelerates polymerization rate, leading to high local
monomer concentration. Indeed, these transitions are apparent in
Figure 4A (additional kinetic data provided in Figures S17-S21),
with the onset of assembly dependent upon the monomer utilized.
A plot of the DP of the core block at which the onset of self-
assembly occurred vs the LogPoct/SA value of the oligomeric
species of the corresponding polymer yielded a linear relationship.
Unsurprisingly, the length of the core-forming block required to
induce self-assembly decreased with increasing oligomer
hydrophobicity. More significantly, the morphologies of the
resulting assemblies, which arose via self-assembly of block
copolymers of approximately equal molecular weight (Figure 4C)
also varied dramatically with LogPoct/SA. As shown in Figure 4D,
the least hydrophobic polymers prepared from DAAm and 3-
HPMA, self-assembled into small, spherical micelles. 2-HPMA
and 2-HBA, forming polymers of intermediate hydrophobicity,
produced worm-like micelles. Finally, the most hydrophobic
polymers, formed of HBMA, produced a mixed morphology which
contained worm-like micelles and polymeric vesicles.
To evaluate this hypothesis, we conducted five polymerizations
using DAAm, 3-HPMA, 2-HPMA, 2-HBA, and HBMA under
otherwise
identical
experimental
conditions.
Separate
polymerizations were conducted targeting DP = 100 in the
hydrophobic block using each monomer. Our analysis of
polymerization kinetics, as well as SEC traces of the resulting
block copolymers and TEM images of the nanoparticles after
polymerization are summarized in Figure 4.
For PISA, a change in slope is expected in the semi-logarithmic
plot which corresponds to the onset of assembly. This inflection
originates as sequestration of monomer within the cores of the
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In summary, we report an in silico method that predicts monomers
that can be utilized in aqueous PISA. By calculating the variance
in LogPoct/SA with increasing oligomer length, the change in
hydrophobicity can be evaluated and related to the capability of
the monomer to form self-assembled structures during
polymerization. Using this method, we identified five new
monomers for use in RAFT PISA, and these were found to
successfully undergo PISA to produce various nano-object
morphologies such as spheres, worms, and vesicles. Interestingly,
this method was also leveraged to gain insight into both the onset
of self-assembly during PISA and the resulting morphology. As
the hydrophobicity of the monomers and their oligomers
increased, the onset of assembly occurred at lower DPs.
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monomer for PISA. Since novel monomers are often designed
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provide information about their polymerization-dependent
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Acknowledgements
This work was supported by the ERC (615142). B. Couturaud
acknowledges funding from the European Union’s Horizon 2020
research and innovation programme under the Marie
Sklodowska-Curie
grant
agreement
No
703934,
FluoroDendriNostic project. Advanced BioImaging Research
Technology Platform, BBSRC ALERT14 award BB/M01228X/1 is
thanked for supporting cryo-TEM analysis, and Dr. S. Bakker,
University of Warwick, is thanked for assistance.
Keywords: PISA, RAFT polymerization, nanoparticles,
structure-property relationships, polymer hydrophobicity
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COMMUNICATION
We report
a
method to predict
Jeffrey C. Foster,[a] Spyridon Varlas,†[a]
Benoit Couturaud,† [a] Joseph R. Jones,
[a] Robert Keogh,[b] Robert T. Mathers,*[c]
and Rachel K. O’Reilly*[a]
monomers suitable for use in PISA,
which calculates the dependence of
LogPoct/SA on the length of the growing
polymer chain. Using this method, we
identified five new monomers for use in
aqueous
PISA
via
RAFT
Page No. – Page No.
polymerization, and confirmed that
they all successfully underwent PISA
to produce nanostructures of various
morphologies. Our method also
explains trends observed between
polymer hydrophobicity and its self-
assembled morphology.
Predicting Monomers for use in
Polymerization Induced Self-
Assembly
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