Introduction

Trimethylene carbonate (TMC) is a six-membered ring, and poly(TMC) (PTMC) is synthesized by ring-opening polymerization.1, 2, 3, 4 It is possible to obtain PTMC by anionic polymerization, cationic polymerization and enzyme polymerization. In 2007, Hedrick and coworkers5 reported TMC polymerization with an organic compound as a catalyst. When PTMC is to be used as a biocompatible material, a polymerization system employing organic compounds is ideal. PTMC has been used in biomedical applications because of its biodegradable properties,6, 7 which result from a hydrolysis reaction on the polymer main chain. It is noteworthy that no acidic organic compounds are generated from hydrolysis, which is suitable for biomedical applications. The softness of PTMC is due to its low glass transition temperature. Furthermore, its reaction rate is different from that of polyester, and this property is frequently used in biomedical applications. The physical properties of PTMC are also important as they enable a wide variety of biomedical uses. To vary the properties of PTMC, many approaches have been developed that involve introducing functional groups, and some relevant reviews have been published.8, 9

Combinations with ethylene glycol (EG) are also important in biomedical applications. Poly(EG) (PEG) is one of the most commonly used biomedical polymers due to its specific properties. Oligo(EG) (OEG), which has a shorter polymer main chain, is used for the same reason. The hydrophilic nature of EG and OEG and their ability to suppress the adsorption of non-specific proteins are attractive properties for biomedical applications. Monomer and polymer designs are essential to produce various biomaterials, although there are some size limitations in actual use (Figure 1). Copolymers with hydrophobic polymers form nano-sized structures, such as micelles, nanoparticles and nanofibers, by self-assembly, leading to the production of various biomaterials.

Figure 1
figure 1

Illustration of scale difference from molecular design to biomedical application. (a) Monomer design with functional moieties and biocompatible structure. (b) Polymer structure control, including factors involving tacticity, block and random copolymers, graft polymers and star copolymers. (c) Nano structure control through polymer assembly, such as micelle and segregated films. (d) Cell experiments, such as particles for drug delivery and gene delivery. (e) Biomaterials for medical application to tissues and organs.

In this focused review, we analyzed PTMC derivatives possessing EG units. The use of EG as an initiator for TMC and TMC’s derivative polymerization were beyond the scope of the current review. We focused on reference papers describing biomedical applications of PTMC and EG units. Sections were created based on the polymer structure as follows: (i) diblock polymers, (ii) triblock polymers, (iii) star-shaped polymers, (iv) copolymers with more than three monomer units and (v) TMC derivatives with EG units (Figure 2). Some studies were relevant to more than one section.

Figure 2
figure 2

Structures of PTMC derivatives with EG units, together with other monomer units. (a) Diblock polymers. (b) Triblock polymers. (c) Star-shaped polymers. (d) Copolymers including more than three monomer units. (e) TMC derivatives as a monomer. EG, ethylene glycol; PTMC, poly(trimethylene carbonate); TMC, trimethylene carbonate.

Diblock copolymers of PTMC with EG units

There are some approaches to preparing diblock copolymers of PTMC and EG units, such as the post-polymerization of TMC after epoxide polymerization10 and cationic polymerization using a PEG initiator.11 Usually, diblock copolymers of PTMC and PEG are synthesized by polymerization of TMC with one chain end protected PEG as an initiator; monomethylether-PEG (mPEG) is most commonly utilized as the initiator (Figure 3a). Diblock copolymers of PTMC and PEG possess both hydrophilic and hydrophobic moieties, and they are frequently used as nanostructured building block units and film preparations. For example, mPEG–PTMC has been used as a reflexive interface and compared with cholesterol–PTMC with selective adsorption.12 It has also been used to regulate protein immobilization and adsorption on a film surface.13

Figure 3
figure 3

Diblock and triblock copolymers with TMC and EG units. EG, ethylene glycol; TMC, trimethylene carbonate.

mPEG–PTMC forms micelles and nanoparticles that are incorporated into hydrophobic compounds, such as pyrene,14 dexamethasone15 and paclitaxel.mPEG-(PCL/PTMC)

The random copolymers using CL and TMC as a hydrophobic moiety with mPEG as a hydrophilic moiety are known (Figure 5a). Préat and coworkers67 reported that 14C-labeled mPEG-(PCL/PTMC) was employed for the controlled drug release of risperidone after forming micelles. Similarly, mPEG-(PCL/PTMC) using PEG (Mn=550–2000) formed micelles that increased the solubility of lipophilic drugs and were designed to be applied in the oral delivery of poorly water-soluble drugs.68 The transport mechanism of mPEG-(PCL/PTMC) micelles across the intestinal barrier has been investigated.69 Using paclitaxel as an anti-cancer drug, the micelle of mPEG-(PCL/PTMC) has been evaluated by examining the viability of HeLa cells.70 As other examples, ketoprofen, furosemide71 and curcumin72 have been employed to increase the solubility of micelles in mPEG-(PCL/PTMC). The detailed structure of micelles prepared by mPEG-(PCL/PTMC) has been investigated by electron paramagnetic resonance and fluorescence.73 In addition, passive diffusion through the lipid bilayer of mPEG-(PCL/PTMC) has been examined using artificial membranes and liposomes.74 Furthermore, the safety of the micelles of mPEG-(PCL/PTMC) has been thoroughly investigated both in vitro and in vivo.75

Figure 5
figure 5

Examples of copolymers bearing TMC, EG and additional monomer units. EG, ethylene glycol; TMC, trimethylene carbonate.

After the copolymerization of CL and TMC derivatives with dibromomethyl groups at the TMC side chain using mPEG as an initiator, azido groups have been introduced into the block copolymer, which enables the click reaction along the entire block copolymer.76, 77, 78 Interestingly, propagyl 3,3′-ditiopropionate has been used as a cross-linker to create dual degradable nanoparticles.76

PEG–(PCL/PTMC)

When PEG is used as an initiator of the random copolymerization of CL and TMC, (PCL/PTMC)–PEG–(PCL/PTMC) is obtained (Figure 5b). For example, PEG has been used as an initiator for ring-opening polymerization of TMC and CL, followed by introduction of acryloyl groups79 or phenylazide groups80 at the chain ends. In a study using acryloyl groups,79 stereolithographic microarchitectures were prepared by a computer-aided surface photo irradiation technique. The resulting copolymers were used for in vivo drug delivery systems. Bone morphogenetic protein 6 and transforming growth factor beta-3 were also released in a controlled manner from the hydrogel matrix.81

By controlling the ratio of TMC to CL, thermogelled (PCL/PTMC)–PEG–(PCL/PTMC) has been obtained.82 TMC at 25–40% of CL has been found to create a polymer that gels in a physiologically important temperature range of 10–50 °C.

Others

Random copolymerization of TMC and lactic acid (LA) with mPEG as an initiator has been shown to produce an amphiphilic block copolymer (Figure 5c),83, 84 which has been used with micelles to incorporate the anti-cancer drug 9-Nitro-20(S)-camptothecin. Similarly, the benzoyl group has been introduced into TMC to be copolymerized with LA using mPEG as an initiator.85 The benzoyl group can be deprotected to introduce a hydroxyl group into the polymer main chain, resulting in a reaction with biotin. Applying different protection approaches, benzyl groups with two hydroxyl groups have also been reported.86 Azido groups have been introduced into the TMC side moiety in a copolymer of LA with mPEG as the initiator87 and in side groups.88 Taking advantage of the click reaction, several micelles have been prepared and confirmed by TEM, such as g-palmitate.89 Copolymers of PEG and cyclic acetal have been used as initiators of TMC polymerization where PTMC–(PEG-cyclic acetal)–PTMC was obtained, which showed pH sensitivity (Figure 5d).90 Disulfide-coupled bis-(cyclic carbonate) as a functional TMC derivative has been copolymerized with TMC using mPEG as the initiator, producing micelles used in the controlled release of doxorubicin.91

More complicated block copolymers have been synthesized as a series of flexible poly(ether carbonate urethane)ureas.92 Urethane structure has also been introduced into copolymers with TMC, EG and LA units by diisocyanate dimerization and trimerization.93, 94, 95 Multi-block copolymers of TMC and EG units using PEG and propylene glycol have been applied as thermo gelling materials for effective drug delivery.96 This composition influenced the thermal and elastic properties. Using PEG-propylene oxide-PEG (Pluronic) as an initiator,97 TMC has been polymerized followed by construction of urethane moieties using 1,4-diisocyanatobutane. This polymer was employed to facilitate cell adhesion through Arg-Gly-Asp (RGD).

It is interesting to use natural compounds possessing the molecular recognition property. For example, a peptide has been introduced into a copolymer of TMC and EG and the peptide’s function to target cellular uptake was transferred to the molecule.98 Similarly, d-glucose has been introduced into a copolymer of TMC and EG together with paclitaxel to afford controlled release properties.99

TMC derivatives with EG units

The chemical and physical properties of polymers depend on their structure. For that reason, it is possible to gain an understanding of the characteristics of polymers from their homopolymer structure. To add functionality using this approach, specific monomer design is required. We categorized these monomers into two groups: those with a reactive connection and those that are directly introduced.

Reactive units on the side chain

A vinyl sulfone group has been introduced into TMC via thioether as a carbonate monomer (Figure 6a).100 That monomer provided a vinyl sulfone functionalized biodegradable polymer, which enabled selective Michel-type conjugation. For example, PEG-SH has been made connectable, and as a result biodegradable coatings were created under aqueous conditions. Dibromo groups have been introduced into TMC, and after polymerization they were converted into azido groups (Figure 6b).101 Alkyne-modified PEG was then connected to the PTMC backbone. Micelles with a stick-shaped morphology and a spherical morphology were prepared. An alkyne group has been introduced into TMC via an ester as a TMC monomer.102 It was possible to connect azo group-modified PEG to the polymer (Figure 6c).

Figure 6
figure 6

Examples of polymers with TMC derivatives bearing the EG unit as a monomer. EG, ethylene glycol; TMC, trimethylene carbonate.

A carboxylic acid group has been introduced into TMC as a carbonate monomer.103 Both PEG and mPEG have been connected by ester bonding, creating hydrogels (Figure 6d), and their porous structure was analyzed by SEM. Recently, the hemocompatibility of hydrated aliphatic polymers with subtle differences in their backbone structure was evaluated, and this study included TMC (Figure 6e).104 Carboxylic acid-modified TMC can be used in crosslinking structures with the diamine compound.105, 106

Direct introduction of EG units in the side chain

OEG units have been introduced into TMC directly (Figure 6f).107 In this study, the chain length of OEG varied by one unit (TMCM-MOE1OM), three units (TMCM-MOE3OM) and four units (TMCM-MOE4OM). An aqueous solution of the homopolymers showed a lower critical solution temperature (LCST). Interestingly, the LCST of poly(TMCM-MOE3OM) (Mn=7000–11000) was 33 °C, approximately body temperature, whereas the LCST of poly(TMCM-MOE4OM) was 72 °C. TMCM-MOE1OM has been used for block copolymerization, resulting in a specific segregation film in aqueous conditions.108, 109

Conclusion

Micelle formation using block copolymers with a hydrophobic moiety for TMC units and a hydrophilic moiety for EG units has been thoroughly investigated. Among the many comonomers, CL and LA were often used in various ratios to tune the resulting properties. Thermo-sensitive properties of OEG or PEG have also been of interest because they can enable the formation of gels.

To add to the combination of TMC and EG, additional chemical functionality has also been explored, including photoresponsive, crosslinking and prodrug properties. The introduction of specific functionalities affects the overall material properties. Much of the required functionality has been achieved through copolymerization using many different chemical species.

On the other hand, variation and irregular distribution of chemical structures are unavoidable due to the nature of the polymerization procedure. The functionalized TMC derivative as a monomer can confer well-defined and homogenous properties to materials, leading to easy tuning of material properties.