Biomacromolecules 2008, 9, 2029–2035
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Preparation of a Class of Versatile, Chemoselective, and Amorphous Polyketoesters Devin G. Barrett and Muhammad N. Yousaf* Department of Chemistry and the Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290 Received March 12, 2008
A straightforward and versatile strategy for preparing a class of biodegradable and amorphous polyketoesters is reported. A series of ketone-containing diesters and diacids were combined with di(ethylene glycol) through condensation polymerization, achieving values of up to 10.1 × 103 g/mol. Glass transition temperatures ranged from -41 to -6 °C, rendering all of the materials liquid at room temperature. By including ketone groups in the repeat unit, facile postpolymerization modifications were possible by reaction with oxyamine-tethered ligands through the formation of an oxime linkage. Upon reaction with molecules that contain oxyamines, under mild conditions, these polymers can easily have a diverse set of side chains appended without coreagents or catalysts. The chemoselective oxime-forming coupling strategy is compatible with physiological conditions and can be done in the presence of a wide range of functional groups and biomolecules, including proteins and nucleic acids. We demonstrate the utility of this strategy by immobilizing a cell adhesive peptide (H2NO-RGD) to polyketoester films, creating cell adhesive elastomers. This immobilization strategy is synthetically flexible for designing and tailoring polymers for targeted biological applications.
Introduction Polyesters have proved to be practical and important materials for a range of biological and medical applications ranging from drug delivery and tissue engineering to surgically implantable devices.1 At present, the major synthetic focus in generating this class of polymers is based on ring-opening polymerizations (ROP) to produce poly(glycolic acid) (PGA), poly(L-lactic acid) (PLA), or poly(ε-caprolactone) (PCL). Although, these wellstudied polymers have many useful applications, there remain several key features that limit their utility for biological applications. For example, PGA, PLA, and PCL do not degrade uniformly due to the crystallinity and hydrophobicity of the polymers. In addition, all lack reactive functional groups capable of chemoselective polymer modifications. While these polyesters have had some success in the biological and medical fields, the introduction of functionality in the polymer backbone would allow for the selective tailoring of the polyester, which could dramatically increase their potential applications. There recently have been several reports to functionalize PGA, PLA, and PCL. Modified lactones and lactides have been synthesized to create polyesters that contain carboxylates,2,3 amines,3–5 azides,6,7 hydroxyl groups,3,8 as well as others.9–11 However, the complex multistep syntheses of new monomers may lead to degradation of polyester chains due to postpolymerization deprotection reactions and, therefore, may limit the utility of these polymers. There are also few strategies for conjugating a wide variety of molecules onto polyesters.9,10,12 One popular example, click chemistry,6,7,13,14 involves the 1,3dipolar cycloaddition of alkynes and azides. However, the use of both a base and a copper catalyst as coreagents may limit the application of this method in physiological conditions, as well as produce undesirable cytotoxic responses. Another strategy, less commonly employed, is based on polyketoesters.9,15 * To whom correspondence should be addressed. E-mail: mnyousaf@ email.unc.edu.
While these particular polyesters are not commonly studied, a major feature is even less explored: ketone-specific reactions. The coupling reaction between ketones and oxyamines to generate oximes is a very powerful conjugation strategy and is chemoselective, rapid, and hydrolytically stable.16–18 Combining polyketoesters with oxyamine-tethered molecules can allow for the postpolymerization addition of side chains or the design of graft copolymers. As an alternative synthetic strategy to ROP, materials synthesized using condensation polymerization can have their macromolecular properties adjusted quickly and easily.19,20 By substituting either the diol or the diacid, polymer properties associated with thermal, solubility, and mechanical characteristics can be tuned to fit the requirements of a specific application. Also, by adjusting monomer feed ratios, molecular weights and end-group functionality can be controlled. While it is difficult to synthesize materials with the large molecular weights of ROP (>105 g/mol) using condensation polymerization, the ability to easily control polymer properties offers distinct advantages. Herein, we report the generation of a series of biodegradable polyketoesters capable of chemoselective immobilization of a wide range of functional groups. Our strategy is based on the coupling reaction between polymers presenting ketone groups and oxyamine-tethered functional groups and ligands. By starting with monomers that contain ketones, a functional handle capable of conjugating ligands is present in each repeat unit of the polymer. We demonstrate this strategy for generating cell scaffolds by immobilizing a cell adhesive RGD-oxyamine peptide chemoselectively to polyketoester films. In addition, a strategy to create methacrylate-terminated polyketoester chains under extremely mild conditions is described.
Experimental Section Materials. All materials were purchased from Sigma-Aldrich (Milwaukee, WI) and used without further purification unless otherwise
10.1021/bm800271f CCC: $40.75 2008 American Chemical Society Published on Web 05/27/2008
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noted. Diethyl ketomalonate (monomer 1), diethyl 3-oxoglutarate (monomer 3), and di(ethylene glycol) (DEG) were distilled prior to use. R-Ketoglutaric acid (monomer 2), 4-oxoheptanedioic acid (monomer 4), and 5-oxononanedioic acid (monomer 5) were recrystallized in ethyl acetate. Polyketoester Synthesis. NoVozyme-435 Catalyzed.19,21 Monomers were combined in a 10 mL round-bottom flask in a 1:1 molar ratio. The reagents were then heated to 90 °C and stirred until a homogeneous melt was produced, followed by the addition of Novozyme-435 (10 wt %). The polymerization continued for 2 h, after which time the flask was sealed and the pressure was reduced to 35 torr for the final 46 h of the reaction. Upon completion, the mixture was diluted with methylene chloride and the enzyme was removed by filtration. Following rotary evaporation, polymers were precipitated in -78 °C methanol and dried under vacuum. Metal Catalyzed.20 Monomers were combined in a 10-mL roundbottom flask in a 1:1 mol ratio. The flask was evacuated, followed by the creation of an inert environment with argon gas. The reagents were then heated to either 140 or 150 °C and stirred until a homogeneous melt was produced. After adding the catalyst, 0.01 mol % tin(II) 2-ethylhexanoate (Sn(oct)2), the reaction continued for 2 h, at which time the pressure was reduced to 15 Torr for the final 22 h of the reaction. The mixture was then diluted with methylene chloride to reduce the viscosity, followed by precipitation in -78 °C methanol. The polymers were dried under vacuum. Characterization. 1H and 13C NMR spectra were acquired on either a Bruker 400 MHz AVANCE or a Bruker 500 MHz DRX spectrometer in deuterated chloroform. Molecular weights were measured, compared to polystyrene standards, on a Waters GPC system, with detection based on refractive index values. The measurements were taken at 40 °C, with tetrahydrofuran as the mobile phase, on three columns in series (Waters Styragel HR2, HR4, and HR5). Using a Seiko 220C DSC, glass transition temperatures were measured during the second heating cycle (10 °C/min). Infrared spectra were recorded on an ASI ReactIR 1000. Functionalization. Polymers and ligands were combined in a solvent (methanol, methylene chloride, or THF) to create an oxyamine-to-ketone mole ratio of 3:2. After the reaction had stirred for 5 h at room temperature, the solution was concentrated by rotary evaporation and redissolved in chloroform. Several milliliters of diethyl ether were added to the polymer solution. After this mixture was filtered, the process was repeated to ensure the removal of all the nonimmobilized ligand. The polymer was again concentrated by rotary evaporation, precipitated in -78 °C methanol, and dried under vacuum. End-Capping. Monomer 4 was combined with DEG (molar ratio 1:1.15) to form polyester chains terminating in hydroxyl groups. Following purification (as described above), this polyketoester and 4 mol equiv of vinyl methacrylate were dissolved in chloroform. After adding Novozyme-435 (10 wt %), the reaction mixture was stirred and refluxed at 65 °C for 48 h. Upon completion, the enzyme was removed by filtration. The polymer was then concentrated by rotary evaporation, precipitated in -78 °C methanol, and dried under vacuum. Cross-Linking. To facilitate cross-linking, a photoinitiator, R,Rdiethoxyacetophenone, was added (0.1% w/w) to methacrylateterminated polyketoesters. The mixture was manually stirred and applied to a glass coverslip and patterned with a polydimethylsiloxane (PDMS) stamp, fabricated using soft lithography. To set the material, irradiation with 365 nm light for 10 min in an Electro-Cure-500 UV curing chamber (Electro-Lite Coporation, Bethel, CT) was performed. The PDMS was then removed, resulting in a patterned polymer surface. To cure the polymer for use in cytotoxicity studies, the above procedure was followed without the use of PDMS, resulting in discs. Cytotoxicity Testing. Polyketoester films were soaked in methylene chloride for 12 h, to remove the soluble portion of the material, and then dried for 5 h in a vacuum chamber at room temperature to remove all solvent. Cytotoxicity was then examined by two methods. First, small fragments of the materials were added to a confluent layer of
Barrett and Yousaf Table 1. Ketone-Containing Monomers for Preparation of Polyketoesters
monomer
name
m
n
R1
1 2 3 4 5
diethyl ketomalonate R-ketoglutaric acid diethyl 3-oxoglutarate 4-oxoheptanedioic acid 5-oxononanedioic acid
0 0 1 2 3
0 2 1 2 3
Et H Et H H
3T3 Swiss Albino mouse fibroblasts. After 48 h, cells were examined by light microscopy, and cytotoxicity was determined based on cell morphology, monolayer confluence, and the biological functions of subsequent generations of cells. Second, small fragments of the polyketoester films were extracted in serum-containing medium for 48 h. A confluent layer of 3T3 Swiss Albino mouse fibroblasts was then exposed to the medium. After 48 h, cells were examined by light microscopy, and cytotoxicity was determined based on the previously described criteria. Peptide Immobilization, Cell Culture, and Microscopy. To functionalize the surface of the polyketoester films, ∼100 µL of a solution of the adhesive peptide H2NO-GRGDS (10 mM) was added directly to the top of the film and allowed to react for 5 h. After rinsing the films in a phosphate-buffered saline solution (PBS), 3T3 Swiss Albino mouse fibroblasts were seeded onto the RGD-presenting thermosets and incubated in Dulbecco’s modified Eagle’s medium (Sigma, St. Louis, MO) with 10% bovine calf serum and 1% penicillin/ streptomycin at 37 °C with 5% CO2. The cells were added at a density of 80000 cells/mL. Phase-contrast images were taken using a Nikon Eclipse TE2000-E inverted microscope (Nikon USA, Inc., Melville, NY).
Results and Discussion A series of ketone-containing diacids and diesters were combined with DEG to synthesize a family of amorphous polyketoesters. Designing polyesters that contain ketones in the repeat units allows for mild and chemoselective postpolymerization modifications by reacting these groups within the polymer with soluble oxyamine-tethered ligands. Through the oxime-forming reaction, a wide variety of functionality can be appended onto biodegradable polymers. Monomers. Five monomers were studied in an attempt to incorporate ketones into polyesters: diethyl ketomalonate (monomer 1), R-ketoglutaric acid (monomer 2), diethyl 3-oxoglutarate (monomer 3), 4-oxoheptanedioic acid (monomer 4), and 5-oxononanedioic acid (monomer 5). These diesters and diacids ranged in size from three carbons to nine carbons in their backbone (Table 1). While diacids were preferred due to autocatalysis of ester bond formation, two diesters were used as well. Monomer 1 was only commercially available as the diester, while the diacid of monomer 3 underwent decarboxylation when heated. DEG was used as the diol to ensure that all resulting polymers would be completely amorphous at physiological temperature (37 °C).19 Polyketoester Synthesis and Characterization. Initially, all polymers were to be synthesized using Sn(oct)2 as the catalyst (Scheme 1). However, not all monomers were compatible with this reaction strategy. Only monomers 3, 4, and 5 polymerized with DEG without cross-linking when catalyzed by Sn(oct)2. Using these monomers, polyketoesters 3-5 were synthesized under identical reaction conditions except for the reaction temperature. To obtain the highest possible molecular weights while maintaining relatively low polydispersity indices (PDI),
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Scheme 1. Synthesis and Functionalization of Polyketoesters
Table 2. Characterization of Polyketoesters polyketoester monomers 1d 2d 3e 4e 5e 6e d
1 2 3 4 5 4
and and and and and and
DEG DEG DEG DEG DEG DEG
Trxn % ratio (°C)a yield (g/mol)b PDIb Tg °C)c 1:1 1:1 1:1 1:1 1:1 1:1.15
90 90 140 150 150 150
96 55 89 92 91 88
600 900 5100 10100 6200 3500
1.4 1.6 1.7 1.7 1.7 1.4
-40.8 -6.3 -23.2 -22.3 -34.4 -30.1
a Reaction temperature. b Determined by GPC. c Determined by DSC. Enzyme-catalyzed polymerization. e Metal-catalyzed polymerization.
the polymerization temperature is critical to avoid thermal degradation. With these criteria, we determined 140 °C to be an ideal reaction temperature for monomer 3, while 150 °C was better suited for monomers 4 and 5. In this manner, all three polymers achieved molecular weights of at least 5.0 × 103 g/mol, with PDIs of 1.7 (Table 2). We found the metal-catalyzed polymerization strategy unsuccessful for monomers 1 and 2. When catalyzed by Sn(oct)2, polyesters synthesized from DEG and either monomer 1 or 2 produced insoluble, completely cross-linked materials. This result was unexpected due to the fact that each monomer was bifunctional in terms of ester bond formation (acids, esters, or alcohols). If the polymerizations had proceeded as expected, linear polymers should have been the product, as opposed to cross-linked materials. We believe, based upon this observation, that monomers containing a ketone located adjacent to an acid/ ester would produce unwanted branching when polymerized with the tin catalyst. Therefore, to polymerize these two materials, a different catalyst was needed. The enzyme Novozyme-435, composed of immobilized lipase B from Candida antarctica, has been shown to be specific for coupling acids and primary alcohols.22 To polymerize monomers 1 and 2, we combined them (equal stoichiometry) with DEG and 10 wt % Novozyme-435 at 90 °C. While polymerization did occur, only low molecular weight materials were possible (Table 2). Compared to the other polymers in the series, the low molecular weights observed are also associated with the R-position of the ketone groups in the monomers. However, the overall syntheses of polyketoesters 1-5 were very efficient, as four of the polymerizations had yields of 88% or greater (Table 3). Polyketoester 2, with a yield of 55%, was the lone material to react inefficiently. While monomers 1 and 2 only led to the formation of oligomers, important observations were noted. The choice of
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Table 3. Functionalization of Polyketoesters with Oxyamines poly(ester oxime)
polyketoester
oxyamine
Trxn (°C)
% yield
1 2 3 4
1 2 3 4
1 2 3 4
25 25 25 25
95 98 99 99
catalysts in the synthesis of polyesters is not based solely on thermal conditions, time, and the presence of certain functional moieties. Both Sn(oct)2 and Novozyme-435 were unsuccessful in polymerizing high molecular weight materials from monomers with ketones adjacent to acids/esters. The critical observation is that the location of the functional group is equally as important in the choice of catalyst as the more commonly considered factors (time, heat, and functional groups present). Simply considering what functional groups are present is insufficient; one must also consider the position of the functional groups relative to each other. Functionalization. The design rationale for the polyketoester family was based on a biodegradable, noncytotoxic, and moldable material that can be chemoselectively functionalized under mild conditions. A key feature of the material is the incorporation of a ketone into the repeat unit of the polyester, which would allow for a variety of ligands that contain oxyamines to be subsequently covalently immobilized. The reaction between ketones and oxyamines is chemoselective and mild, resulting in postpolymerization modifications that do not degrade the material (Supporting Information, Figure 1). To demonstrate the functionalization potential of this strategy, five model oxyamines were chosen: O-allylhydroxylamine (oxyamine 1), O-methylhydroxylamine (oxyamine 2), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (oxyamine 3), aminooxyacetic acid (oxyamine 4), and a cell attachment peptide H2NORGD (oxyamine 5) (Chart 1). These materials were chosen as model compounds because they are commercially available and represent a diverse set of functional groups. This synthetic strategy may be extended to generate a range of oxyaminetethered molecules to tailor the polymer for specific applications. For the functionalization studies, polyketoester 1 was combined with oxyamine 1 to make poly(ester oxime) 1, polyketoester 2 was combined with oxyamine 2 to make poly(ester oxime) 2, and so on. However, polyketoester 5 was not functionalized with an oxyamine-containing molecule; it was synthesized only as a proof-of-principle and not pursued further due to the price of monomer 5. The oxyamine was added in a 50% excess relative to the concentration of the ketones to ensure complete reaction. After reacting for 5 h at room temperature, complete Chart 1.
Model Oxyamine-Terminated Ligands
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Figure 1. 1H NMR spectra: (a) polyketoester 4; (b) poly(ester oxime) 4.
conversion of ketones to oximes was observed. However, by using longer reaction times (10 h), complete conversion to oximes can be achieved with a 1:1 molar ratio of oxyamines to ketones (data not shown). Figure 1 shows 1H NMR spectra for polyketoester 4 and poly(ester oxime) 4. Before functionalization, the peaks corresponding to the methylene groups alpha (position a) to the ketone and beta to the ketone (position b) are distinguishable from each other. However, after oxyamine 4 was conjugated to polyketoester 4, the peak associated with position a shifted upfield, resulting in a partial overlap with the peak representing position b. More direct evidence of oxime formation is presented in the 13C NMR spectra (Supporting Information, Figures 12 and 27). Before ligand immobilization, a signal at 208 ppm is present, representing the carbonyl-carbon of the ketone. After oxyamine 4 was coupled to the polymer backbone, the signal at 208 ppm was completely replaced by a signal at 160 ppm, corresponding to the carbon in the oxime bond. In addition, after functionalization, both the 1H NMR and 13C NMR spectra show new signals that correspond to the oxyamine-containing molecules. The flexibility and versatility of this family of polyesters makes them ideal for biological applications. One essential feature for biological studies is the inclusion of ether linkages throughout the polyester. Studies have concluded that these moieties aid in rendering materials inert to nonspecific adsorption of proteins and adhesion of cells.23–25 Also, previous work has shown that oxyamines can be easily incorporated into a range of biomolecules, such as natural therapeutic agents,26 fluorescent dyes,27 peptides,16 proteins,28 oligonucleotides,29 and phospholipid-like molecules.30 In addition, several examples of oxyamine-functionalized polymers have been demonstrated, which can lead to potential graft and block copolymers.9,31,32 Finally, although not demonstrated here, the oxime-forming reaction can occur rapidly and efficiently at physiological conditions.16,27 Due to the nature of this immobilization strategy, polyketoesters have the ability to allow one polymeric backbone to have many diverse applications by simply changing the identity of the oxyamine-containing ligand. Future work will investigate polyketoesters in biological applications, ranging from drug and gene delivery to tissue engineering. Cross-Linking. To extend the applications of polyketoesters, we pursued potential cross-linking methods. A common strategy for adding acrylates and methacrylates onto free hydroxyl groups of aliphatic polyesters is to deprotonate the hydroxyls with triethylamine, followed by the addition of acryloyl chloride or methacryloyl chloride.33,34 After the reaction is complete, the
Scheme 2. Methacrylate Addition by Heterogeneous, Enzymatic Catalyst
polymer is then extracted with various combinations of acid, base, and salt solutions. Our early attempts utilizing this endcapping method with the polyketoesters resulted in unwanted side-reactions, as indicated by changes in color throughout the reaction and workup. Ideally, an extremely mild and efficient method to add crosslinking sites into a polyester should be possible. This would make the reaction more compatible with ketones, as well as avoid potential polymer degradation by eliminating harsh conditions. Such an end-capping strategy was explored based on Novozyme-435, the enzyme already used to synthesize polyesters (Scheme 2). Monomer 4 was combined with DEG in an approximate ratio of 1:1.15, resulting in hydroxyl-terminated polyketoester chains with a molecular weight of 3500 g/mol (polyketoester 6, Figure 2). After purification, the prepolymer and an excess of vinyl methacrylate were dissolved in chloroform. After adding Novozyme-435 (10 wt %), the reaction continued for 48 h while refluxing at 65 °C. The enzyme, in addition to being specific for primary alcohols, is also a heterogeneous catalyst, allowing for facile separation following the reaction; Novozyme-435 was removed by filtration and the polymer was purified as described above. As shown in Figure 3, approximately 55% of polymer ends were converted to methacrylates. While complete conversion is not observed, there were enough cross-linking sites to enable
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Figure 2. 1H NMR spectra: polyketoester 6. After enzymatic end-capping with vinyl methacrylate, polyketoester 6 was converted to a polymer capable of photoinitiated cross-linking. Peaks that are labeled -CH2OH refer to hydroxyl end groups that were not converted to methacrylates. Inset: magnified section of 3.4-4.4 ppm.
Figure 3. Micropatterned films from enzymatically end-capped polymers. After converting polyketoester 6 into a dimethacrylate, imprint lithography was used to create microarrays of various geometries. After UV exposure (10 min), patterns were transferred to the newly molded polymer film. Films were patterned with (A) 30 µm circles and (B) 50 µm squares with a depth of ∼40 µm.
the material to cure upon exposure to UV light (365 nm, 10 min.). To demonstrate the utility of this strategy, the dimethacrylate derived from polyketoester 6 was cross-linked in the presence of a PDMS stamp patterned by soft lithography.35 After removal of the stamp, patterns were transferred to the polymer, which was then cross-linked (Figure 3). Also, current studies support that the ketone groups are unmodified after cross-linking, allowing for postcuring film functionalization. We show in Figure 4 a molded polyketoester that has been subsequently reacted with rhodamine-oxyamine on the top face to demonstrate selective oxime conjugation (the wells in the patterned mold are unmodified and appear as black circles).16,27 The ease with which this strategy works will greatly add to the versatility and flexibility of polyketoesters. Biocompatibility. As future applications of these materials will be directed toward the medical and biological fields, cellular responses to these polyketoesters was investigated. Cytotoxicity was determined in two ways: cellular exposure to polyester films and cellular exposure to polyester degradation byproducts (oligomers, diacids, DEG, poly(acrylic acid)). Compared to a control sample of fibroblasts that were not exposed to any polyester or polyester byproduct, 48 h of exposure to polyketoesters 1-4 did not elicit a negative response from cells. Cell morphologies were identical to the control sample and monolayer confluence was unaffected. In fact, when exposed to
polyketoester degradation byproducts, cells were able to proliferate under standard cell culture conditions for the same amount of time as the control sample of cells. Based on these results, these materials can be considered for future biological and medical applications. In addition to general cytotoxicity, the biocompatibility of polyketoester films was determined by using them as cell scaffolds. After cross-linking polyketoesters 1-4, soluble portions were removed by soaking the films in methylene chloride for 12 h. After drying the materials for 5 h in a vacuum chamber at room temperature, a solution of an oxyamine-tethered peptide, RGD (oxyamine 5) was added to the surface and allowed to react. The RGD peptide is well known to bind to cell surface integrin receptors and mediates biospecific cell adhesion and migration.36 Cells were then seeded on the polyketoester films (Figure 5) and allowed to adhere, migrate, and proliferate. Cross-linked materials derived from polyketoesters 1-4 were all able to support cell attachment after immobilization of RGD, without negative cytotoxic effects. Furthermore, these materials are biologically inert, in that they are unable to support cell attachment without the functionalization with RGD. This could prove to be useful in the future as a method to spatially pattern cells on three-dimensional molded cell scaffolds.
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Figure 4. Patterned film functionalization. Cross-linked films were functionalized with an oxyamine-tethered rhodamine conjugate. Films were reacted on the top face with a 1 mM solution of rhodamine-oxyamine in methanol for 5 h. After rinsing in methanol and acetone, films were dried and visualized with (A) phase-contrast and (B) fluorescence microscopy. The scale bars represent 50 µm.
Figure 5. Polyketoester films as cell scaffolds. Polyketoesters 1-4 were able to biospecifically support cell attachment after a cross-linking reaction if RGD-oxyamine was immobilized to the elastomer surface. Images were taken of cells on nonfunctionalized polyketoester 2 (A) and polyketoester 2 functionalized with RGD at 2 weeks (B) and 10 weeks (C). The scale bars represent 100 µm.
These films were able to support cells for various durations, ranging from 3 weeks (polyketoester 1) to 4 months (polyketoester 4).
to explore this conjugation strategy to synthesize multiple functionalized polymers, as well as to achieve more complex polymer morphologies for cell scaffold and tissue engineering applications.
Conclusion
Acknowledgment. The authors thank Prof. Joe DeSimone’s laboratory for insightful discussions and for help with polymer characterization. This work was supported by the Carolina Center for Cancer Nanotechnology Excellence and the Burroughs Wellcome Foundation (Interface Career Award).
Condensation polymerization allowed for the facile synthesis of a family of amorphous polyketoesters capable of mild and chemoselective postpolymerization modifications. Several model oxyamines were conjugated to the polymers, demonstrating only a small fraction of the functional groups that can be appended through this immobilization strategy. Polymer degradation was not observed after functionalization due to the mild reaction conditions. With a wide range of glass transition temperatures (-41 to -6 °C), solubility properties, and hydrophilic content, this initial investigation on polyketoesters offers a number of potential biological and medical applications. However, two of the five materials produced were oligomers, achieving relatively low molecular weights (
