Letter pubs.acs.org/macroletters
Glucose-Sensitivity of Boronic Acid Block Copolymers at Physiological pH Debashish Roy and Brent S. Sumerlin* Department of Chemistry and Center for Drug Discovery, Design, and Delivery, Southern Methodist University, 3215 Daniel Avenue, Dallas, Texas 75275-0314, United States S Supporting Information *
ABSTRACT: Well-defined boronic acid block copolymers were demonstrated to exhibit glucose-responsive disassembly at physiological pH. A boronic acid-containing acrylamide monomer with an electron-withdrawing substituent on the pendant phenylboronic acid moiety was polymerized by reversible addition−fragmentation chain transfer (RAFT) polymerization to yield a polymer with a boronic acid pKa = 8.2. Below this value, a block copolymer of this monomer with poly(N,N-dimethylacrylamide) self-assembled into aggregates. Addition of base to yield a pH > pKa or addition of glucose at pH = 7.4 resulted in aggregate dissociation that may prove promising for controlled delivery applications under physiological relevant conditions.
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(co)polymers that exhibit unique glucose responsive solution behavior. Glucose-responsive polymers hold promise for the treatment of diseases such as diabetes.4,20 For biomedical applications, it is highly desirable that glucose-sensitive systems respond under physiological conditions.2125 Glucose-responsive hydrogels and statistical copolymers that operate at physiological pH have been reported by several groups.22,23 However, boronic acid containing block copolymers that respond at physiological pH are rare, with only van Hest and co-workers having reported such a system in which the responsive block was derived from a Wulff-type boronic acid monomer that responded at pH 7.4.18 Herein, we report the RAFT copolymerization of a low-pKa boronic acid monomer with a hydrophilic monomer. The resulting block copolymers self-assemble/dissociate in response to changes in the concentration of glucose in the surrounding medium at physiological pH. The ability to respond within pH ranges present in vivo strengthen the potential for these polymers to be employed for glucose-responsive delivery applications. The desired boronic acid-containing monomer22 was prepared by a novel synthetic route (Scheme 1, Supporting Information), which led to an electron withdrawing amide carbonyl on the phenylboronic acid moiety that served to reduce the pKa of the monomer and its resulting (co)polymers. Briefly, an excess of 1,2-diaminoethane was reacted with di-tertbutyldicarbonate to obtain tert-butyl-N-(2-aminoethyl)carbonate (89% yield). Subsequent reaction with acryloyl chloride resulted in N-tert-butyloxycarbonyl-N′-acryl-1,2-diami-
rganoboron (co)polymers have potential applications as electrolyte materials, blue emissive polymers, self-healing materials, flame-retardants, and precursors for functional polyolefins.1,2 Prospective biomedical applications for watersoluble boronic acid-containing polymers include glucose sensing, diabetes treatment, and supramolecular materials applications.1,3,4 Many of these fields can benefit from organoboron polymers with controlled topology, molecular weight, and composition. Radical polymerization is the most common route to synthesize polymers with pendant boronic acid functionality because of a relative lack of significant side reactions during polymerization.5 However, the synthesis of boronic acidcontaining polymers by conventional radical polymerization typically results in ill-defined random copolymers or crosslinked gels.6 Controlled radical polymerization (CRP) facilitates the preparation of polymers with predetermined molecular weights, narrow molecular weight distributions, and a high-degree of chain-end functionalization. Jäkle et al. have reported the efficient synthesis of organoboron vinyl (co)polymers via atom transfer radical polymerization (ATRP)7 either from silylated precursors that were subsequently borylated8 or from polymerization of organoboron monomers.9 Recently, Hoogenboom and co-workers reported the nitroxidemediated polymerization of a boronic acid monomer.10 We are primarily interested in the synthesis and aqueous solution behavior of amphiphilic organoboron block copolymers, especially those with acrylamido hydrophilic blocks. Reversible addition−fragmentation chain transfer (RAFT) polymerization11 has proven excellent for the polymerization of acrylamido monomers.12,13 RAFT is readily conducted under mild conditions to yield well-defined complex macromolecular topologies.14 Our group15−17 and others18,19 have demonstrated the promise of RAFT for the synthesis of boronic acid © 2012 American Chemical Society
Received: January 26, 2012 Accepted: April 2, 2012 Published: April 9, 2012 529
dx.doi.org/10.1021/mz300047c | ACS Macro Lett. 2012, 1, 529−532
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Scheme 1. Synthesis of Boronic Ester and Boronic Acid (Co)polymers
noethane (77% yield). Boc-group deprotection with trifluoroacetic acid (TFA) yielded the TFA salt of N-(2-aminoethyl)acrylamide. Subsequent base treatment with triethylamine led to N-(2-aminoethyl)acrylamide. 4-Carboxyphenylboronic acid was treated with an excess of pinacol to form its pinacol ester (48% yield). After treatment with oxalyl chloride, the resulting compound was reacted with N-(2-aminoethyl)acrylamide to yield the targeted monomer, N-(2-acryloylamino-ethyl)-4(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (59% yield). Additional experimental details and characterization results are described in the Supporting Information. RAFT polymerization was chosen for the polymerization of the boronic ester monomer because of its functional group tolerance and suitability for the synthesis of well-defined acrylamido polymers.12,24 Thus, N-(2-acryloylamino-ethyl)-4(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1) was polymerized with 2-dodecylsulfanylthiocarbonyl-sulfanyl2-methylpropionic acid (2) as the chain transfer agent (CTA) and 2,2′-azobisisobutyronitrile (AIBN) as the initiator at 70 °C in DMF (Scheme 1). The molar ratio of [monomer]/[CTA]/ [initiator] was [100]/[1]/[0.5]. After a brief inhibition period ( pKa), the polymer is essentially a fully soluble polyanion even in the absence of sugar. Thus, the highest degree of sugar sensitivity involves a boronic acid-containing polymer at a pH just below its pKa, such that addition of sugar leads to a dramatic swing in the ionization equilibrium from the neutral/hydrophobic boronic acid groups to the anionic/hydrophilic boronate ester groups. 531
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(4) Cambre, J. N.; Sumerlin, B. S. Polymer 2011, 52, 4631−4643. (5) Letsinger, R. L.; Hamilton, S. B. J. Am. Chem. Soc. 1959, 81, 3009. Lennarz, W. J.; Snyder, H. R. J. Am. Chem. Soc. 1960, 82, 2169. Pellon, J.; Deichert, W. G.; Thomas, W. M. J. Polym. Sci. 1961, 55, 153. (6) Kataoka, K.; Miyazaki, H.; Bunya, M.; Okano, T.; Sakurai, Y. J. Am. Chem. Soc. 1998, 120, 12694. Kataoka, K.; Miyazaki, H.; Okano, T.; Sakurai, Y. Macromolecules 1994, 27, 1061−1062. Ge, H.; Ding, Y.; Ma, C.; Zhang, G. J. Phys. Chem. B 2006, 110, 20635−20639. (7) Wang, J. S.; Matyjaszewski, K. J. Am. Chem. Soc. 1995, 117, 5614. Kato, M.; Kamigaito, M.; Sawamoto, M.; Higashimura, T. Macromolecules 1995, 28, 1721. (8) Yang, Q.; Guanglou, C.; Anand, S.; Jäkle, F. J. Am. Chem. Soc. 2002, 124, 12672. Qin, Y.; Cheng, G.; Achara, O.; Parab, K.; Jäkle, F. Macromolecules 2004, 37, 7123. (9) Qin, Y.; Sukul, V.; Pagakos, D.; Cui, C.; Jäkle, F. Macromolecules 2005, 38, 8987. (10) Vancoillie, G.; Pelz, S.; Holder, E.; Hoogenboom, R. Polym. Chem. 2012, DOI: 10.1039/C1PY00380A. (11) Chiefari, J.; Chong, Y. K.; Ercole, F.; Krstina, J.; Jeffery, J.; Le, T. P. T; Mayadunne, R. T. A.; Meijs, G. F.; Moad, C. L.; Rizzardo, E.; Thang, S. H. Macromolecules 1998, 31, 5559. Handbook of RAFT Polymerization; Barner-Kowollik, C., Ed.; Wiley-VCH: Weinheim, 2008. (12) Lowe, A. B.; McCormick, C. L. Prog. Polym. Sci. 2007, 32, 283. McCormick, C. L.; Lowe, A. B. Acc. Chem. Res. 2004, 37, 312. (13) Girard, E.; Tassaing, T.; Marty, J.-D.; Destarac, M. Polym. Chem. 2011, 2, 2222−2230. (14) Williams, P. E.; Moughton, A. O.; Patterson, J. P.; Khodabakhsh, S.; O’Reilly, R. K. Polym. Chem. 2011, 2, 720−729. Willcock, H.; O’Reilly, R. K. Polym. Chem. 2010, 1, 149−157. Li, H.; Li, M.; Yu, X.; Bapat, A. P.; Sumerlin, B. S. Polym. Chem. 2011, 2, 1531−1535. Smith, D.; Holley, A. C.; McCormick, C. L. Polym. Chem. 2011, 2, 1428− 1441. Smith, A. E.; Xu, X.; Savin, D. A.; McCormick, C. L. Polym. Chem. 2010, 1, 628−630. (15) Cambre, J. N.; Roy, D.; Gondi, S. R.; Sumerlin, B. S. J. Am. Chem. Soc. 2007, 129, 10348−10349. (16) Roy, D.; Cambre, J. N.; Sumerlin, B. S. Chem. Commun. 2008, 2477−2479. Roy, D.; Cambre, J. N.; Sumerlin, B. S. Chem. Commun. 2009, 2106−2108. (17) De, P.; Gondi, S. R.; Roy, D.; Sumerlin, B. S. Macromolecules 2009, 42, 5614−5621. Bapat, A. P.; Roy, D.; Ray, J. G.; Savin, D. A.; Sumerlin, B. S. J. Am. Chem. Soc. 2011, 133, 19832−19838. (18) Kim, K. T.; Cornelissen, J. J. L. M.; Nolte, R. J. M.; van Hest, J. C. M. J. Am. Chem. Soc. 2009, 131, 13908−13909. (19) Cheng, F.; Jäkle, F. Chem. Commun. 2010, 46, 3717−3719. (20) You, L. C.; Lu, F. Z.; Li, Z. C.; Zhang, W.; Li, F. M. Macromolecules 2003, 36, 1−4. (21) Roy, D.; Cambre, J. N.; Sumerlin, B. S. Prog. Polym. Sci. 2010, 35, 278−301. (22) Matsumoto, A.; Ikeda, S.; Harada, A.; Kataoka, K. Biomacromolecules 2003, 4, 1410−1416. (23) Matsumoto, A.; Kurata, T.; Shiino, D.; Kataoka, K. Macromolecules 2004, 37, 1502−1510. Matsumoto, A.; Yamamoto, K.; Yoshida, R.; Kataoka, K.; Aoyagi, T.; Miyahara, Y. Chem. Commun. 2010, 46, 2203−2205. Zenkl, G.; Klimant, I. Microchim. Acta 2009, 166, 123−131. Matsumoto, A.; Yoshida, R.; Kataoka, K. Biomacromolecules 2004, 5, 1038−1045. (24) Vogt, A. P.; Sumerlin, B. S. Macromolecules 2008, 41, 7368− 7373. Vogt, A. P.; Sumerlin, B. S. Soft Matter 2009, 5, 2347−2351. (25) Kim, H.; Kang, Y. J.; Kang, S.; Kim, K. T. J. Am. Chem. Soc. 2012, 134, 4030−4033.
Figure 3. Glucose-responsive behavior of PDMA90-b-PAEBB31; aqueous hydrodynamic size determined by dynamic light scattering distributions at 25 °C.
disassembly of the aggregate to unimers. The effect of further lowering the concentration of glucose needed for dissociation is under investigation. In addition to the DLS results, dissociation was also apparent by visual inspection, as the slightly turbid and bluish aggregate solution of PDMA90-b-PAEBB31 immediately became transparent when glucose was introduced. This phenomenon was attributed to conversion of the mostly neutral/hydrophobic boronic acid groups in the aggregate cores being converted to anionic/hydrophilic cyclic boronates upon binding to glucose. These results demonstrate that PDMA-b-PAEBB boronic acid block copolymers with pKa values near physiologically relevant pH can self-assemble and dissociate in response to changes in solution pH or glucose concentration. Accordingly, these materials may hold promise in the areas of saccharide sensing and self-regulated sugar-induced delivery applications and may help address the limitations of other boronic acidbased systems.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures and selected 1H NMR spectra of synthesize and characterization of PAEBB and PDMA-bPAEBB. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This material is based on work supported by the National Science Foundation (CAREER DMR-0846792) and an Alfred P. Sloan Research Fellowship (BSS).
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REFERENCES
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