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Hydrolytic Degradation of Poly(ethylene oxide)-block-Polycaprolactone

Worm Micelles

Yan Geng and Dennis E. Discher*

Department of Chemical and Biomolecular Engineering, UniVersity of PennsylVania,

Philadelphia, PennsylVania 19104

Received June 13, 2005; E-mail: abqjv4@r.postjobfree.com

Degradable polymers are foundational to a number of fields from

environmental chemistry to biomedical devices.1 While degradable

homopolymers and random copolymers are commonly used in bulk

materials, micro/nanoparticles, and films/ monolayers,2 degradable

self-assemblies of block copolymer amphiphiles are also emerg-

ing.3,4 Attention has thus far been limited to spherical micelles

assembled from copolymers of hydrophobic degradable polyesters, Figure 1. OCL worm micelles spontaneously shorten with time to spherical

micelles in water, visualized by FM and cryo-TEM (inset, scale ) 100

typically polylactide or polycaprolactone, plus a hydrophilic,

nm). Shown are 0.2 mg/mL OCL3 worm micelles at 37 C.

biocompatible block such as poly(ethylene oxide).4 However,

degradation has subtle if detectable effects on spherical morphol-

ogies, and degradation mechanisms and kinetics in such assemblies

are not clearly distinguished in time scales or pathway(s) from

degradation in bulk or film preparations.4,5 Here, we report novel

giant and flexible worm micelles prepared from degradable poly-

(ethylene oxide)-b-poly( -caprolactone) copolymers (PEO-PCL,

denoted OCL). The OCL worm micelles spontaneously shorten to

generate spherical micelles due, we show, to chain-end hydrolysis

of the PCL. Kinetics as well as mechanism are elucidated via

Arrhenius fits to key activating conditions of temperature, pH, and

copolymer molecular weight, providing novel insight into this

Figure 2. (a) Cumulative production of PCL hydrolysis monomer,

microphase transition. 6-hydroxycaproic acid, 6-HPA (inset: GPC chromatograms) with (b) the

The dominant morphology of amphiphilic copolymer aggregates decay of OCL worm micelle mean contour length L (37 C, pH 5 buffer).

in water is generally dictated by average block proportions.6 Giant

and flexible worm micelles were prepared from two OCL copoly- NMR (Figure S4). The analytical results thus demonstrate that PCL

mers with weight fractions of PEO (fEO ) 0.42) that favor worm in these copolymers hydrolyzes from the end by chain-end

micelle formation,6 OCL1 (Mn ) 4770) and OCL3 (Mn ) 11 500), cleavage rather than by a process of random scission 9 that would

using a cosolvent/evaporation method (see Supporting Information). yield various degradation products and broaden the polydispersity

Fluorescence microscopy (FM) was used to then visualize dye- of the polymer far more than found here.

labeled worm micelles (Figure 1) and track how the contour lengths End hydrolysis of PCL increases fEO and consequently shifts the

change with time.7 The mean contour length (L) of freshly made preferred morphology toward a higher curvature structure, namely,

OCL worm micelles is more than 10 m (Figure S1), and their from a cylinder to a sphere.6 By the time worms have disappeared,

PCL chains have, on average, lost 30% of their length by

flexibility, expressed as the persistence length, lP, is 0.5 m for

OCL1 micelles and 5 m for the larger diameter OCL3 micelles hydrolysis (Figure 2), which corresponds to increases in fEO from

(Figure S2). Core diameters of d ) 11 and 29 nm, respectively, 0.42 to 0.55. Such slight asymmetry, with fEO above 0.5, favors

were measured from cryo-TEM images.8 Values of lp and d prove spherical micelle formation.6 This simple estimation highlights the

to be very similar to those for PEO-polybutadiene worm micelles reason worm micelles are so susceptible to morphological trans-

of similar copolymer Mn and, likewise, fit well to the scaling relation formation: only an extremely narrow range of fEO favors the worm

lp d2.8 that indicates a fluid rather than glassy or crystalline micelle structure, whereas spherical micelles are found with a much

aggregate.7 broader range of fEO and are thus less sensitive to hydrolysis.6

On time scales of days, these giant OCL worm micelles shorten The worm-to-sphere transition occurs with bulb formation at the

spontaneously to spherical micelles, as seen in FM and cryo-TEM end of the worm, consistent with release of spherical micelles from

the end10 (Figure S5). Conservation of mass allows one to show

(Figure 1), as well as DLS (not shown). The predominant new

species generated was found by GPC to be 6-hydroxycaproic acid that the hydrolysis kinetics is the rate-limiting step in worm

(6-HPA), that is, the monomer product of PCL hydrolysis (Figure shortening kinetics. The amount of monomer generated initially

from OCL1 and OCL3 worm micelles, 0.01 and 0.002 mM/h,

2a). For both block copolymers, accumulation of 6-HPA parallels

in form and time scales with the decays in mean contour length L respectively (Figure 2a), gives the volume of spherical micelles

of OCL worm micelles (Figure 2b). No other significant degradation generated from the worm micelles, based on the above changes in

fEO and PCL s volume density.11 The estimations yield respective

products were detected, and the polydispersity of the OCL

shortening rates of 1.0 and 0.1 m/h, as observed in FM (Figure

copolymer remained essentially the same (Figure S3). Loss of

caprolactone units from the OCL copolymer was confirmed by 2b). Such estimations apply equally well to the two copolymers

J. AM. CHEM. SOC. 2005, 127, 127**-*****

12780 10.1021/ja053902e CCC: $30.25 2005 American Chemical Society

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applications, in particular, for drug delivery. While polymeric

spherical micelles have already proven to be extremely useful for

therapeutic applications,17 worm micelles are just now emerging

as novel alternatives that provide larger core volume for drug

loading and an ability to flow readily through capillaries and pores

due to their cylindrical shape and flexibility.18 One novel strategy

for drug delivery would be to start with worm micelles and then

progressively degrade into spherical micelles as desired. Further-

more, strong effect of temperature, pH, and Mn on degradation rate

could also be used for controlled drug release.19

In summary, we show that worm micelles self-assemble from

Figure 3. Arrhenius plots of OCL worm micelle shortening rate constants,

k, with temperature (4, 25, and 37 C), R ) 8.314 kJ/mol. degradable PEO-b-PCL block copolymers and spontaneously

shorten to spherical micelles. Such morphological transition is

that differ in molecular weight and thus differ in molecular mobility

triggered by hydrolytic degradation of PCL, governed by an end-

within worms by far more than 2-fold.12 This suggests that the rate-

cleavage mechanism that is faster than that in bulk/film. Degradation

limiting process is indeed hydrolysis rather than chain diffusion

rate can be tuned by temperature, pH, and Mn, and quantitative

and segregation post-hydrolysis.

assessment appears to be consistent with the molecular explanation,

While the end-cleavage of PCL within worm micelles appears

whereby the hydroxyl end of the PCL chain localizes to the hydrated

to be consistent with both the chemical and the nanoscale physical

interface of the micelle.

changes, it is also considerably faster than the slow hydrolysis

reported for PCL homo/copolymer bulk, particle, or films,2 that is, Acknowledgment. We thank F.S. Bates group at University

on the time scale of months-years under the same condition. The Minnesota for TEM, Chemistry at Penn for NMR and lyophilizing

distinction arises with the specific effect of OCL worm micelles facilities, and L. Romsted at Rutgers University for discussions.

on PCL hydrolysis. As speculated from studies on spherical Support was provided by NSF-MRSEC, Penn-NTI, and NIH.

micelles,13 the terminal -OH of the hydrophobic PCL block is not

Supporting Information Available: Materials and Methods, OCL

strictly sequestered in the dry, hydrophobic core but will tend to

worm micelle contour length distribution and flexibility, GPC, NMR,

be drawn into the hydrated corona. A micellar catalysis effect14

transition intermediate, OCL-acetate worm micelles, and data of

involving interfacial water plus this likely participation of the shortening rate constants (PDF). This material is available free of charge

terminal hydroxyl group15 collectively fosters the attack by H2O via the Internet at http://pubs.acs.org.

of the end-ester group nearest the chain terminus. Following this

ester hydrolysis, a new -OH is generated to restart the process of References

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Degradable OCL worm micelles with such unique degradation

mechanism and kinetics are potentially useful for numerous JA053902E

J. AM. CHEM. SOC. VOL. 127, NO. 37, 2005 12781

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