Toward biodegradable nanogel star polymers via organocatalytic ROP

Article abstract of DOI:10.1039/c2cc31406a

Organocatalytic ring opening polymerization (OROP) is used to effect the rapid, scalable, room temperature formation of size-controlled, highly uniform, polyvalent, nanogel star polymer nanoparticles of biodegradable composition.

Full text of DOI:10.1039/c2cc31406a

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Toward biodegradable nanogel star polymers via organocatalytic ROPw
Eric A. Appel,a Victor Y. Lee,a Timothy T. Nguyen,b Melanie McNeil,b Frederik Nederberg,a
James L. Hedrick,a William C. Swope,a Jullia E. Rice,a Robert D. Miller*a and Joseph Sly*a
Received 24th February 2012, Accepted 5th April 2012
DOI: 10.1039/c2cc31406a
Organocatalytic ring opening polymerization (OROP) is used
to effect the rapid, scalable, room temperature formation of
size-controlled, highly uniform, polyvalent, nanogel star polymer
nanoparticles of biodegradable composition.
Nanogel star polymers (unimolecular, globular, nanoscale
architectures comprised of a high local density of polymeric
arms emanating from a nanogel core1a) are currently under
widespread development as an organic nanoparticle platform.1,2
Driving this development is the advancement and application of
living polymerization methodologies that can generate these
complex structures with improved control over size, uniformity,
chemical structure and synthetic scale. Nanogel star polymers
of biocompatible compositions, in particular, are beginning to
emerge and are now being auditioned for a growing range of
biomedical applications.3
Scheme 1 The use of organocatalyst TBD 3 to effect the rapid, room
temperature, one pot/two step OROP synthesis of polyester nanogel
star polymer 6 with addressable core and peripheral functionalities.
Among the most attractive methods for affording polymers
of biocompatible composition are the ring opening polymeri-
zations (ROP) of cyclic esters, cyclic carbonates and epoxides.4
The Sn(II) catalyzed ROP of cyclic esters, in particular, is
among the most widely used, traditional, method for accessing
polyesters.5 Sn(II) is, however, notoriously difficult to remove
post-polymerization owing to its oxophilic nature, with residual
tin levels for linear polyesters often exceeding 1000 ppm.6
However, owing to its high toxicity, the United States Food
and Drug Administration (FDA) has set the limit for Sn(II) in
commercially used biomedical polymer materials at 20 ppm.7
As an alternative to metal catalysts, organocatalyic ROP
(OROP), i.e. effecting ROP using organic molecules, is a
rapidly maturing field applicable to a wide variety of cyclic
monomers.8 This approach to living polymerizations has been
recently applied to a range of polymer architectures and
compositions of biomedical relevance but has yet to be applied
to the creation of nanogel star polymers. Consequently, we
report herein the development of OROP as a highly efficacious
approach to uniform nanogel star polymers of biodgradable
composition9 and polyvalent functionality.
In this work, we chose to use the arm first approach1a for
nanogel star polymer formation (Scheme 1). d-Valerolactone 2
was chosen as the monomer for arm formation due to its
demonstrated rapid and controlled room temperature OROP with
organic catalysts including 1,5,7-triaza-bicyclo[4.4.0]dec-5-ene
3 (TBD).10 Benzyl alcohol 1 was used as the initiator owing to
the potential for further peripheral synthetic transformations
after star polymer formation. 5–50-Bis(oxepanyl-2-one) 5 (BOP)
was used as the crosslinking agent based on its demonstrated
utility in previous methodologies.11
In our initial approach, ‘‘living’’ poly(d-valerolactone) arms
4 of mass (Mn) = 3 kDa (degree of polymerization B30) and
polydispersity index (PDI) = 1.06 were first synthesized in
anhydrous toluene at room temperature over 15 min using a
relative molar ratio (1 : 2 : 3) equal to 0.03 : 1 : 0.005. After this
time, BOP 5 and a second quantity of TBD 3 were added to
the solution of living macroinitiator 4 in the ratio of 5 : 0.15 : 1
respectively. Analysis by gel permeation chromatography
(GPC) of the crude product formed after 4 h showed the
formation of a single, high molecular weight species with
PDI = 1.28 (Fig. 1) and little trace of any residual arms. After
quenching with benzoic acid, the crude product was isolated
by precipitation from methanol and purified by a single
solvent fractionation process. The viscous oil isolated was
re-precipitated into methanol to afford polyester nanogel star
polymer 6a with a high molecular weight and low PDI = 1.24
(Fig. 1) as a white, amorphous, free flowing powder in 50%
yield on a 10 g scale.
a IBM Almaden Research Center, 650 Harry Road, San Jose,
CA 95120, USA. E-mail: joesly@us.ibm.com;
Fax: +1 408 9273310; Tel: +1 408 927 1657
b Department of Chemical and Materials Engineering,
San Jose State University, San Jose, CA 95192, USA
w Electronic supplementary information (ESI) available: Synthetic
procedures and additional characterization data. See DOI: 10.1039/
c2cc31406a
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6163–6165 6163

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units into the nanogel core for every linear arm 4 incorporated
into the structure of 6a. This implies that the molecular weight
of star polymer 6a is comprised of ca. 35% BOP- 5 based core
and 65% linear polyester arms. This corresponds to 6a having
approx. 72 arms per macromolecule. Differential scanning
calorimetry (DSC) indicated a melting temperature (Tm) of
47 1C and a glass transition temperature (Tg) of ꢀ34 1C, for
6a, both lower than for the constituent linear arms 4 (50 1C and
ꢀ24 1C, respectively).
The 1H-NMR analysis of nanogel star polymer 6a also
showed that the signal from the methylene adjacent to the
hydroxyl terminus of the linear arm 4 is retained in the
spectrum of the star polymer 6a, although broadened (Fig. 2).
This is attributed to the residual alcohol groups from the
‘‘living’’ polymerization being now located within the core of
the star polymer structure, with approx. one hydroxyl existing
for every arm incorporated into the star polymer structure.
These core hydroxyl groups of 6a could be quantiatively
acetylated using the TBD 3 catalyzed reaction with acetic
Fig. 1 GPC traces of (A) linear poly(d-valerolactone) 4 and the
corresponding polyester nanogel star polymer 6a as highly uniform
polymers of increasing molecular weight (B) crude polyester nanogel
star polymers 6a and 16, formed from TBD 3 and Sn(II) catalysts
respectively, showing the increased product uniformity afforded by 3.
Dynamic Light Scattering (DLS) analysis of nanogel star
polymer 6a indicated a hydrodynamic radius (Rh) = 5.0 nm
(THF) with a PDI = 1.21 and Mn = 333 kDa. 1H-NMR
(400 MHz, CDCl3) analysis of the linear arm 4 and the nanogel
star polymer 6a showed the integration of the individual signals
of the ester moieties (B4.1, 2.8, and 1.7 ppm) increased from
60, 60 and 120 to approx. 88, 88, and 198, respectively (Fig. 2).
This is attributed to the inclusion of an average of 7 BOP 5
1
anhydride10 as confirmed by H-NMR analysis (Fig. 2) of the
resulting product 7 without noticeable change to the Rh, Mn or
PDI of 7 as compared to 6a. The synthetic accessibility of the
core hydroxyl groups of 6a was also confirmed by quantitative
tosylation to the corresponding core-tosylated nanogel star
polymer 8. The ability of the tosylate groups of 8 to undergo
nucleophilic displacement reactions to form higher core-
functional systems is now under evaluation.
The introduction of peripheral functionality to the polyester
nanogel star polymer structure was then studied. The removal
of the benzyl groups of nanogel star polymer 6a was not
readily achieved in a quantitative fashion. Consequently,
1-tert-butyldimethylsiloxy-propan-3-ol was used as an initiator
to produce star polymer 9 with size, arm number and BOP 5
incorporation similar to nanogel star polymer 6a. After
acetylation of the core hydroxyl groups (to preclude over-
lapping hydroxyl signals) the peripheral protecting groups of
nanogel star polymer 9 were removed with TBAF to produce
the peripherally hydroxy-functional nanogel star polymer 10
(Fig. 2) which was then transformed into the peripherally
tosylated form 11. This ability to manipulate both core and
peripheral functionality orthogonally now provides a viable
route to the formation of biodegradable nanogel star polymer
systems with tandem ‘‘dual-mode’’ functionality.1a
In the course of this work, it was found that catalyst purity
was critical in promoting a controlled polymerization to
nanogel star polymer systems (Table 1). The initial use of
Table 1 The effect of varying catalyst 3 purity, reaction temperature
and reaction time in OROP polyester nanogel star polymer formation
Reaction Reaction Mna Crudea Sn(II)
Entry Catalyst time (h)
temp. (1C) (kDa) PDI
content
1 (6a) TBCc
2 (6b) TBDb
3 (6c) TBDc
4 (6d) TBDc
5 (6e) TBDc
6 (16) Sn(II)d
4
16
16
4
16
48
RTe
RTe
RTe
40
40
110
340 1.21
333 1.31
1126 1.84
1200 1.51
1804 2.20
o 2 ppm
Fig. 2 Partial 1H NMR (400 MHz, CDCl3) spectra of (A) linear
poly(d-valerolactone) 4 (B) polyester nanogel star polymer 6 formed from
4 showing the increased integral values of the ester signals arising from
the incorporation of the core-forming BOP 5 units and the methylene
signal adjacent to the hydroxyl terminus from the nanogel core region (C)
the quantative acetylation of the core hydroxyl groups of 6 to form core
functionalized nanogel star polymer 7 and (D) the core (acetylated) and
peripherally (alcohol) functionalized polyester nanogel star polymer 10.
—
—
—
—
290
—
1800 ppm
a
b
Determined by DLS. Used as received. Purified by sublimation.
c
d
e
Tin(II) 2-ethylhexanoate. Temperature of glove box ca. 30 1C.
c
6164 Chem. Commun., 2012, 48, 6163–6165
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commercial grade TBD 3 resulted in the reaction stalling
within 16 h, at which time a nanogel star polymer 6b had
formed (Entry 2). Using purified catalyst under the same
conditions produced nanogel star polymer 6c (Entry 3), larger
than 6b but with increased PDI. Reducing the reaction time to
4 h enabled the formation of the previously described 6a
(Entry 1). Increasing the reaction temperature to 40 1C formed
nanogel star polymer 6d in 4 h with a similar mass to 6c but
with lower PDI (Entry 4) and extending the reaction time to
16 h at 40 1C produced a very large nanogel star polymer 6e
(Entry 5) but again with increased PDI. The crude products
6b–e could be purified (as for 6a), with varying efficiency, to
produce uniform polyester nanogel star polymers of different
sizes and structural parameters.
BOP 5 and TBD 3 directly (Fig. 3). This suggests a potential
verstaility of this reaction platform for the formation of nanogel
star polymers of varying compositions by other alcohol termi-
nated polymers relevant to biomedical application such as
poly(alkylene oxides), polylactides and polyoxazolines.
In summary, we have described the first use of OROP as a
means for producing nanogel star polymers comprised of
biodegradable compositions. This process results in the rapid,
room temperature controlled formation of highly uniform, size
controlled nanoparticles which can be effectively functionalized,
either internally or peripherally in an orthogonal fashion. The
further development of OROP for nanogel star polymer
formation as a general platform using other polymers and
block co-polymers of biomedically relevant compositions is
ongoing and will be described in due course.
We next performed a comparative study of TBD 3 versus
Sn(II) catalysis for polyester nanogel star polymer formation.
In our hands, the Sn(II) catalysed reaction,11d after 48 h in
refluxing toluene, produced a crude nanogel star polymer 16 of
similar arm length and molecular weight to 6a (i.e. that formed
by TBD 3 in four hours at room temperature), although with a
much higher PDI (Fig. 1b, Table 1). ICP-MS analysis showed
16 had a Sn(II) content much higher than it’s constituent linear
polymer arm (1800 vs. 610 ppm respectively). The residual tin
content of 6a produced by TBD 3 catalysed OROP was o2 ppm,
below both detection limits and the current FDA limits of
20 ppm.7 One of the advantages of nanogel star polymer
architectures lies in the high local density of polyvalent
function. In the context of residual tin(II) catalyst sequestra-
tion however, this problem is exacerbated for these systems
when created through Sn(II) catalysis and stands to hinder
current Sn(II) removal techniques (which typically rely on
bi-dentate competitive ligation agents).7b,12 The ability of
OROP to rapidly produce tin-free polyester nanogel star poly-
mers is expected to help accelerate their biomedical application.
Finally, two other key features of the OROP formation of
nanogel star polymers were noted. First, the sequential addition
of monomer 1 and cross-linker 5 is unnecessary owing to the
relatively low solubility of 5 and the rapid polymerization of the 1.
Consequently, the reaction could be readily performed as a one
step, one pot reaction in which all reagents can be combined from
the outset, increasing the practicality of the reaction (Fig. 3).
More importantly, it was also determined that OROP nanogel
star polymer synthesis could also be accomplished using pre-
formed hydroxyl-terminated poly(d-valerolactone) arms using
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Fig. 3 The OROP formation of polyester nanogel star polymers as
either a one pot process (left) or a process using preformed alcohol-
terminated linear polymers 4 (right) and a photograph (middle) of the
result from a single large scale synthesis of 6.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6163–6165 6165