Thermoresponsive Polymers with Functional Groups Selected for

Chapter 14

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Thermoresponsive Polymers with Functional Groups Selected for Pharmaceutical and Biomedical Applications Naohiko Shimada and Atsushi Maruyama* Institute for Materials Chemistry and Engineering, Kyushu University, Motooka 744-CE11, Nishi-ku, Fukuoka, Japan, 819-0395 *E-mail: [email protected].

Thermoresponsive polymers can be employed in design of smart devices for pharmaceutical and biomedical applications. For these purposes, the thermoresponsive polymers are modified with functional groups that allow control of stimuli-responsiveness and manipulating interactions with biocomponents. This review focuses on design and characteristics of thermoresponsive polymers. Firstly, we highlight some examples of ‘lower critical solution temperature’ LCST polymers with functional groups selected for pharmaceutical and biomedical applications. Next, we introduce ‘upper critical solution temperature’ UCST polymers. Although there are only a few examples of polymers that exhibit UCST-type phase behavior in an aqueous media, recent efforts to engineer the phase behavior and interactions with biocomponents by chemical modifications are discussed.

Introduction Polymers that change physicochemical properties in response to external stimuli, such as temperature, pH, light and/or magnetic field, have received attention in broad research areas including those related to microfluidics (1), textiles (2), and sensors (3). Polymers with non-linear changes (i.e., phase transitions) in solubility have been extensively explored. Thermoresponsive © 2013 American Chemical Society In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


polymers that undergo phase transitions in response to modest temperature changes are best characterized of the stimulus-responsive polymers. Various types of smart or intelligent devices using thermoresponsive polymers have been proposed. Thermoresponsive polymers are classified into two categories: One includes polymers that become insoluble upon heating above a lower critical solution temperature (LCST). The other category includes those that are insoluble below an upper critical solution temperature (UCST). Polymers having UCSTs or LCSTs near physiological temperature under physiological buffer conditions enable us to design smart devices for pharmaceutical and biomedical applications. Modification of the polymers with appropriate functional groups allows modulation of the polymer interactions with biocomponents such as proteins, nucleic acids, lipids, and cells. This review focuses on thermoresponsive polymers with functional groups that have been designed for pharmaceutical and biomedical applications.

Figure 1. Schematic illustration of temperature-responsive affinity control of the binding between integrin receptors on a cell and a dish coated with a thermoresponsive polymer modified with cell adhesion peptide. Reprinted with permission from (11), copyright (2007) Elsevier.

LCST-Type Polymers with Functional Groups The LCST-type phase transition behavior is due to hydrophilic/hydrophobic property changes. Poly(N-isopropylacrylamide) (poly(NIPAm)) is one of the most useful LCST-type polymers for bio-related applications because its LCST is close to body temperature (32 °C) under physiological conditions. Okano and his colleagues have reported that cells cultured on a dish grafted with poly(NIPAm) can be detached as a cell sheet by cooling process (4), and the cell sheet has been clinically tested in repair of impaired heart function and of esophageal lesions (5–7). The same groups also synthesized 2-carboxyisopropylacrylamide (CIPAm), a derivative of NIPAm containing carboxylic groups. Cells were grown on dishes coated with poly(NIPAm-co-CIPAm) could be more rapidly detached 236 In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


than those grown on poly(NIPAm) homopolymer, because the carboxylic groups of the polymer accelerate surface hydration of the dish (8). The carboxylic groups of the copolymers have also been utilized as site for modification of the polymer with peptides. Coating of the growth surface with copolymer modified with cell adhesion peptide (RGDS) facilitates the spreading of human umbilical vein endothelial cells without serum at temperatures above LCST; the cells detach at temperatures below LCST after cultivation (Figure 1) (9). The surface of chitosan, a polysaccharide with amino groups, copolymerizes with poly(NIPAm), and cells adhere to the copolymer and rapidly detach below LCST (10). There are also many reports of use of LCST-type thermoresponsive polymers in drug delivery systems. Qin et al. reported that the anticancer drug, doxorubicin, entrapped by the thermosensitive block copolymer poly(ethylene oxide-b-NIPAm), is released upon cooling to below the LCST (12). Copolymers of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and NIPAm form a complex with DNA and have a size of around 200 nm; these complexes have the potential to be taken up by cells (13). The LCSTs of polymers can be tuned over wide range by copolymerization with hydrophobic or hydrophilic monomers. LCSTs of copolymers with ionic groups can be varied by alterations in the charged state of the groups. Based on this property, conversion of thermoresponsiveness to pH responsiveness by introduction of pH-sensitive ionic groups to LCST polymers was demonstrated. Poly(NIPAm-co-butylmethacrylate-co-acrylic acid) was used as delivery carrier for human calcitonin, which is a peptide hormone, in an oral drug delivery system (14). Calcitonin is not released from the complex with copolymer at low pH, but the calcitonin can be released at neutral pH at 37 °C because deprotonation of carboxylic acid induces an increase in LCST to above 37 °C at neutral pH. Soppimath et al. synthesized self-assembling, amphiphilic polymers, poly(NIPAm-co-N,N-dimethylacrylamide-co-10-undecenoic acid). Drugs encapsulated in nanoparticles assembled from this copolymer are released in acidic conditions at 37 °C, whereas the particles are stable at pH 7.4 (15). As mentioned above, rational design concepts of smart polymers based on LCST-type polymers have been established. Sophisticated bio-devices tailored for pharmaceutical and biomedical applications were created by employing these polymers. LCST-type phase change was basically driven by considerable dehydration and hydrophilicity change. Thermoresponsive polymers that do not change hydrophilicity upon phase change would be interesting, because these polymer would not cause denaturation and damages of biocomponents owing to excess hydrophobic interactions.

UCST-Type Polymers with Functional Groups UCST polymers exhibit thermoresponsiveness on the basis of cohesive interactions, such as hydrogen bonding or electrostatic interactions, among polymer chains. The cohesive interactions are stabilized in low polarity solvents. There have been relatively few reports describing polymers with UCST-type behavior in an aqueous media, because both hydrogen bonds and 237 In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


electrostatic interactions among polymer chains are destabilized by water and salts. Strong cohesive interactions between polymer chains is required to provide UCST behavior in an aqueous media. Poly(sulfobetaine)s (16, 17), poly(N,N-dimethylaminoethyl methacrylate) in the presence of a multivalent anion such as [Co(CN)6]3- (18), and poly(vinyl ether)s with pendant imidazolium salts (19) exhibit UCST-type phase transition behavior induced by electrostatic interactions among the polymer chains. Hydrogen bonding is also important in the UCST-type phase transition. One of the most familiar examples of a UCST-type polymer is poly(acrylic acid) (poly(AAc)) (20). Poly(AAc) and poly(acrylamide)(poly(AAm)) form a complex at low pH, because protonated carboxylic groups hydrogen bond with amide moieties of polyAAm (21). Katono et al. demonstrated release of drug incorporated in interpenetrating polymer network gels composed of poly(AAc) and poly(AAm-co-butylmethacrylate) in distilled water; release occurred as the temperature was increased above UCST (22). Few polymers that exhibit UCST-type behavior under physiological buffer conditions are known. Recently, it was reported that polymers with multiple amide groups, including poly(N-acryloylglycineamide) and its derivatives, exhibit UCST-type behavior in a phosphate buffer at physiological pH (23–25). The utility of these polymers in pharmaceutical and biomedical applications will be restricted because the phase separation temperatures (Tps) are less than 30 °C. As introduction of ionic and hydrophilic groups into the polymers usually results in a considerable decrease in Tp, these polymers are not good candidates for functionalization. Introduction of trace amounts of ionic groups into poly(N-acryloylglycineamide) actually reduces or prevents the UCST-type behavior (26).

Figure 2. Structural formula of poly(allylurea) derivatives (a) and poly(L-citrulline-co- L-ornithine).

To exhibit UCST-type behavior in aqueous media, polymers must have groups with the ability to hydrogen bond and should have few ionizable groups. This hypothesis is supported by data on recently synthesized poly(acrylamide-co-acrylonitrile) and poly(methacrylamide) polymers. These non-ionic polymers have Tps above 37 °C (27) and are thus candidates for 238 In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


introduction of functional groups. Polymers with ureido groups, poly(allylurea) (PU) and poly(L-citrulline) (Figure 2), show UCST-type behavior under physiologically relevant pH and salt conditions (28). A UCST polymer with Tp greater than 60 °C was obtained by controlling ureido content and molecular weight. Ionic amino groups (> 20 mol %) were introduced without reducing Tp below the physiological range. The Tp of poly(allylurea-co-allylamine) (PU-Am) can be regulated over the temperature range from 8 °C to 65 °C by changing amino group content (Figure 3). PUs having succinyl (PU-Su) or acetyl groups (PU-Ac) have also been obtained (29) and exhibit UCST behavior under physiological relevant conditions. The Tps of the polymers with ionic groups change when the pH of the solution is changed. Furthermore, selective protein capture and separation is possible using PUs with different ionic groups (29). Poly(L-citrulline) derivatives , poly(L-citrulline-co-L-ornithine), also show UCST-type behavior (28). Because these derivatives are composed of naturally occurring amino acids, these polymers are biocompatible and biodegradable and hold promise for pharmaceutical and biomedical applications.

Figure 3. UCST-type transmittance curves of PU-Ams at pH 7.5 in buffer containing 150 mM NaCl. The numbers indicate mol% of amino groups of PU-Am. Reprint with permission from (28), Copyright (2011) American Chemical Society.

Conclusion Pharmaceutical and biomedical utilities of thermoresponsive polymers have been expanded by introduction of functional groups to the polymers. Bioconjugation, conversion of stimuli-responsiveness and manipulation of biocomponents were achieved by functionalizing thermoresponsive polymers. 239 In Tailored Polymer Architectures for Pharmaceutical and Biomedical Applications; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Moreover, recent advances in UCST-type thermoresponsive polymers are particularly notable because these polymers would give us new strategies for material design that could not be achieved with LCST-type polymers.

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Thermoresponsive Polymers with Functional Groups Selected for

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