Multicomponent reactions (MCRs) can form unique structures with interesting functions, therefore, multifunctional polymers might be simply prepared using MCRs as coupling tools to simultaneously link and generate different functional groups. To verify this concept, a new fluorescent polymer containing phenylboronic acid has been facilely prepared via a one pot method by combining the Hantzsch reaction with reversible addition–fragmentation chain transfer (RAFT) polymerization. The Hantzsch-RAFT system has been found robust to smoothly achieve predesigned multifunctional polymer, which can be used for cell conjugation through the interaction between phenylboronic acid and glycoprotein on cell membrane. The conjugated cells could be directly observed due to the fluorescent Hantzsch moiety in the polymer chain, demonstrating a new application of the old Hantzsch reaction (>130 years) outside organic chemistry. Meanwhile, the conjugated cells remained excellent dispersity in the presence of coagulation protein (lectin), implying that multifunctional polymer a possible anticoagulant for cell separation. We believe that the current research paves a new way to exploit new applications of MCRs in interdisciplinary fields and might prompt the development of other multifunctional polymers based on different MCRs.

Recently, amphiphilic fluorescent polymers based on aggregation-induced emission (AIE) have been attracting much attention for their application in the bioimaging field. In this study, by employing PEGMA and TPB as hydrophilic and hydrophobic segments, respectively, novel amphiphilic polymers with AIE features were successfully prepared via the combination of RAFT polymerization and the Hantzsch reaction for the first time. For the same 25% feed ratio of TPB, the molar fraction of TPB in two-step PEG-DHP1 polymers and one-pot PEG-DHP2 polymers was respectively about 20.2% and 23.5%, and their weight average molecular weights (Mn) were about 21 000 and 25 000 with a narrow PDI. From the 1H NMR analysis, the polymer structure by the one-pot method was similar to that by the two-step method. When the feed ratio was increased to 30%, the molar fraction of TPB in one-pot PEG-DHP3 polymers and the corresponding Mn respectively changed to 27.6% and 20 000. In aqueous solution, the obtained amphiphilic PEG-DHP2 polymers tended to self-assemble into fluorescent organic nanoparticles (FONs) with 100–200 nm size, whose fluorescence spectrum presented the maximal emission peak at 460 nm with the obvious AIE phenomenon. More importantly, as a result of the high water dispersibility, good fluorescence, nano morphology and excellent biocompatibility, the as-prepared polymers are attractive for application in cell imaging.

By using an easily available PEG derivative and biopolymer chitosan, a self-healing hydrogel has been facilely prepared through the dynamic Schiff base. This biocompatible self-healing hydrogel can be used for drug-delivery, 3D cell culture and as a basic platform to develop some organic-inorganic biohybrids. This mini-review summarized recent research about that chitosan based self-healing hydrogel and related materials, and discussed some future bio-applications of that hydrogelDownload high-res image (179KB)Download full-size imageA chitosan-based biocompatible self-healing hydrogel has been facilely prepared and used for bioapplications.

Post-polymerization modification (PPM) has been widely applied to achieve new functional polymers by introducing functional groups to polymer precursors via efficient organic reactions. Most modification reactions were only studied as the coupling tools, and the unique functions stemming from the modification reactions were usually neglected. Here, a commercial monomer containing a β-keto-ester was used to prepare a water soluble copolymer precursor, and the tri-component Biginelli reaction has been utilized as the side chain modification approach to prepare a series of new polymers. Besides giving outstanding modification performance (rapid reaction rate, ∼100% modification yield), the Biginelli linking group also possesses the new function of adhesion. As a result, when other adhesive functional groups were introduced through the Biginelli reaction, water soluble polymer adhesives comparable to commercial glues could be realized (∼7.55 MPa on a brass substrate). Moreover, the copolymer containing a phenylboronic acid group is not only an effective adhesive on different types of substrates (metal, plastic, bone), but also safe in the in vivo test, indicating the potential application of this polymer in bio-related fields. All these results suggested that the introduction of functional groups through a newly generated functional linkage can be simply realized by some multicomponent reactions, opening a new way to prepare functional polymers through the PPM strategy.

Chemotherapy has contributed greatly in clinical anti-tumor treatment. However, the traditional method of drug delivery by intravenous injection has several drawbacks, such as low delivery efficiency, high toxicity and frequent pain caused by injection. To overcome these defects, intra-tumor injection has been proposed in recent years, and the development of suitable carriers to locate the drug at the desired position for optimum dispersal is crucial to realize the superiority of intra-tumor injection. Herein, we report the application of a chitosan-based self-healing hydrogel, constructed through Schiff's bases, as an injectable drug carrier for in vivo intra-tumor therapy. This smart carrier could deliver highly concentrated anti-tumor drug (Taxol) to the desired position (human hepatocarcinoma tumor) for steady in situ release at a safe level. The self-healing drug carrier could adapt to the intra-tumor structure and regenerate as a whole, thus avoiding the fast leak of loaded drug, leading to admirable therapeutic effects compared with controls (direct injection of drug solution or use of non-self-healable thermal-sensitive hydrogel as the drug carrier). Due to its excellent biocompatibility and high operability, this injectable self-healing hydrogel might be a promising drug carrier for tumor chemotherapy and other medical applications.

Inspired by nature's two-stage strategy to efficiently synthesize numerous proteins using limited amino acids, a two-stage polymer preparation method has been successfully developed via the combination of ultra-fast RAFT polymerization (stage 1) and post polymerization modification (PPM) through the tricomponent Biginelli reaction (stage 2). Only using 3 monomers, 6 polymer precursors with different main-chain sequences have been quickly prepared in stage 1. In stage 2, by combinatorial synthesis, these 6 polymer precursors underwent the Biginelli reaction in a high-throughput (HTP) manner to rapidly generate 60 derivatives with precisely-controlled structures and various molecular diversities, suggesting the straightforward promotion of polymer synthesis efficiency by learning nature's strategy. Furthermore, HTP-analyses have been attempted to quickly screen some distinctively functional polymers, such as the possible polymeric radical scavengers, metal chelating agents, CT imaging agents, etc., realizing the benefit of HTP in polymer chemistry to efficiently synthesize and analyze a large number of samples. We believe that current research opens a new way to effectively prepare and characterize new libraries of polymers with abundant diversity and functions, and might promote a broader study of multicomponent reactions, combinatorial synthesis and HTP technologies in polymer science.

The Hantzsch reaction, one of the oldest and most famous multicomponent reactions (MCRs), has been introduced into polymer chemistry recently as an efficient coupling tool to prepare multifunctional polymers. In this mini-review, we summarized recent results of polymer preparation through the Hantzsch reaction, including polycondensation, post-polymerization modification (PPM), one-pot strategy, etc. Since the Hantzsch products provide unique fluorescence properties to thereof obtained polymers, the primary applications of these multifunctional polymers in bio-related fields have also been discussed.

•Modulus regulated 3D-Cell proliferation is studied in a self-healing hydrogel.•This self-healing hydrogel is growth-factor-free, modulus tunable and injectable.•3D cell proliferation before and after injection is presented.•The proliferating rates of the encapsulated cells are quantified.•This hydrogel offer potentially higher therapeutic efficiency for cell-therapy.Cell therapy has attracted wide attention among researchers in biomaterial and medical areas. As a carrier, hydrogels that could keep high viability of the embedded cells have been developed. However, few researches were conducted on 3D cell proliferation, a key factor for cell therapy, especially after injection. In this study, we demonstrated for the first time the proliferation regulation of the 3D-embedded L929 cells in a modulus-tunable and injectable self-healing hydrogel before and after injection without adding specific growth factor. The cells showed a stiffness-dependent proliferation to grow faster in higher stiffness hydrogels. The proliferating rates of the encapsulated cells before and after injection were quantified, and the shearing force as a possible negative influence factor was discussed, suggesting the both internal property of the hydrogel and injection process are critical for further practical applications. Due to the high operability and good biocompatibility, this injectable self-healing hydrogel can be a promising carrier for cell therapy.Proliferation of the 3D-embedded cells was studied using a modulus-tunable self-healing hydrogel carrier, especially after injection.

Polyethylene glycol (PEG) derivatives have been widely used in bio-related research. However, PEG oligomers (with different molecular weights) or PEG based monomers (with different chain end groups) actually have different chemical and physical properties, which might lead to potential toxicity. In this work, the cytotoxicity of a series of PEG derivatives (oligomers and monomers) has been measured using human cervical cancer cells (HeLa) and a cell line of fibroblasts derived from mice (L929) as model cells. Most of the PEG oligomers are safe to both types of cells except triethylene glycol (TEG), which is toxic at high concentrations to L929 cells. On the other hand, PEG-based monomers including poly(ethylene glycol) methyl ether acrylate (mPEGA) and poly(ethylene glycol) methyl ether methacrylate (mPEGMA) showed obvious cytotoxicity. Subsequently, those toxic PEG derivatives have been studied to reveal the different mechanisms of their toxicity. This current research evaluated the cytotoxicity of PEG derivatives and pointed out the potential hazard of ‘safe’ biomaterials, which might offer a useful reference for people to use the PEG derivatives in future biomedical research.

An injectable and self-healable hydrogel was synthesized using dynamic imine bonds as cross-links. The hydrogel was formed between glycol chitosan and a dibenzaldehyde terminated copolymer, poly(N-isopropylacrylamide)-co-poly(acrylic acid) (DF poly(NIPAM-co-AA)). The polymer gelator DF poly(NIPAM-co-AA) was synthesized by the polymerization of comonomers of NIPAM and AA using a dibenzaldehyde-terminated chain transfer agent (DF CTA). Besides its injectable and self-healable property, the hydrogel was also dual pH and temperature responsive following the properties of the polymer gelator, DF poly(NIPAM-co-AA). Drug-loaded hydrogels showed distinct release behaviours responsive to the surroundings of varied pH values and temperatures. Being non-cytotoxic, the hydrogel was also successfully applied for 3D cell cultivation of L929 cells, revealing the hydrogel's potential applications as carriers in drug delivery and cell therapy systems.

Aggregation-induced emission (AIE) dyes have received wide-spread concern since their inception. Several types of AIE-based fluorescent nanoparticle (FNP) have been developed, and the potential applications of these FNPs have also been explored. Recent studies of AIE-based FNPs in biological areas have suggested that they show promise as bio-materials for cell imaging and other biomedical applications. This article reviews recent progress in the synthesis of AIE-based FNPs via non-covalent, covalent and novel one-pot strategies, and the subsequent cell-imaging of those AIE-based FNPs. Many successes have been achieved, and there is still plenty of space for the development of AIE-based FNPs as new bio-materials.

A multicomponent combinatorial polymerization method has been exploited as a new intersection between combinatorial chemistry, polymer chemistry, and organic chemistry. The tricomponent Biginelli reaction has been employed as a model multicomponent reaction (MCR) to efficiently prepare a library of polycondensates with continuously changed chain structure but different physical properties. The naturally increased reaction modules (monomers) directly doubled the number of polymers in the library, effectively improving the efficiency of polymer preparation. The glass transition temperatures (Tg) of those homologous polymers have been mapped for the first time to predict the Tg values of absent polymer homologues with good to excellent accuracy. Meanwhile, the Tg maps have also been used to reveal the regular change in Tg according to the polymer structure (linking group, monomer chain length, etc.), initially suggesting the academic significance of the multicomponent combinatorial polymerization system. We believe that the current research paves a straightforward way to synthesize new libraries of polymers via MCRs and might prompt the broader study of MCRs in interdisciplinary fields.

Fluorescent PEGylation agents have been facilely synthesized through the Hantzsch reaction. Different from other methods, a protein reactive group has been linked at the PEG chain ends through a Hantzsch ester, which is inherently fluorescent, to in situ generate fluorescent protein-reactive PEGs. Therefore, after conjugation with a protein, the multifunctional polymers can not only act as a protective umbrella to the protein like normal PEGylation agents, but also introduce new functions to the protein conjugates to achieve multifunctional protein conjugates. The multifunctional protein conjugates are directly visible under UV and retain nearly intact bioactivity, preliminarily suggesting the new application of the ‘old’ Hantzsch reaction in other areas (polymer chemistry, chemical biology) outside organic chemistry.

Facile preparation of well-defined and multifunctional polymers is of great importance for the development of polymer-based drug carriers. By performing enzymatic transacylation during RAFT polymerization, diverse monomers with different functions were generated in situ and simultaneously copolymerized via the RAFT process to form a well-defined multifunctional copolymer precursor which contains fluorine, polyethylene glycol (PEG), benzaldehyde and azido groups. The glucose moiety (which represents a possible targeting group for tumor treatment) was conjugated to this precursor via a copper-catalyzed azide alkyne cycloaddition (CuAAc) reaction to generate the polymer drug carrier. A 19F MRI phantom was performed for the polymer drug carrier, indicating its potential as a possible 19F MRI tracer. The polymer drug carrier has been shown to specifically bind to lectin due to the contained glucose moiety, demonstrating its potential targeting effect. Then, doxorubicin (dox, an anticancer drug) was conjugated with the polymer drug carrier through imine chemistry to generate a target polymer–dox complex. This polymer–dox complex possesses amphiphilic character and self-assembles in aqueous solution into spherical micelles with a size of ∼30 nm, which exhibit much faster release of dox at pH 5.5 than at pH 7.4. Subsequent cell experiments showed that the polymer–dox complex is less toxic than native dox to normal cells while retaining similar cytotoxicity against cancer cells, suggesting that the polymer drug carrier is potentially a safe and effective drug delivery system. We believe that as several reactive moieties can be implanted into the polymer structure in a one-pot manner to achieve a multifunctional polymer precursor for efficient post-modification, this concurrent tandem polymerization (CTP) system might be useful for the development of novel anticancer theranostic nanomedicines.

By the one-pot combination of the four-component Ugi reaction and RAFT polymerization, multifunctional chain transfer agents (CTAs) containing both protein-reactive groups and trithiolcarbonate could be generated in situ while taking part in the RAFT process. As a result, well-defined polymers containing both fluorescent and protein reactive groups at the chain end were facilely synthesized. Those polymers were successfully used in protein conjugation to create multifunctional protein conjugates by introducing both a synthetic polymer and fluorescent group on the protein surface. Biotin can also be directly used in this system to get a fluorescent biotin polymer for conjugation with avidin, suggesting that this one-pot system may become a general way to prepare different multifunctional polymers for protein modification.

Recently, the Biginelli reaction, one of the most famous multicomponent reactions, has been introduced into the polymer chemistry to highly efficiently synthesize some interesting functional polymers. In this mini-review, several applications of the Biginelli reaction in polymer chemistry have been summarized, including polycondensation, post-polymerization modification, one-pot synthesis of well-defined polymer, etc. Meanwhile, the utilization of the Biginelli reaction in material science and chemical biology, and the future development of the Biginelli reaction in polymer chemistry have also been discussed.

The tricomponent Biginelli reaction and the tetracomponent Hantzsch reaction which share the same reaction modules (aldehyde and β-ketone ester) have been found compatible. Therefore, a series of copolycondensates containing both 1,4-dihydropyridine (1,4-DHP) and 3,4-dihydropyrimidin-2(1H)-one (3,4-DHPM) in the main chains via the simultaneous Hantzsch and Biginelli reactions have been facilely synthesized. The ratio of 1,4-DHP and 3,4-DHPM in the polymer congeners could be easily tuned by changing the feeding ratio of reactants, and the thermal properties of the obtained polymers are thereby adjusted. As the first attempt to prepare copolycondensate through the combination of two multicomponent reactions (MCRs), the current method revealed and utilized the interesting compatibility between MCRs, providing a new strategy to prepare multicomponent functional polymers.

A highly reactive thiourea-contained polycondensate, poly(dihydropyrimidin-2(1H)-thione) (poly(DHPMT)) has been facilely synthesized via the Biginelli polycondensation using thiourea and a difunctional compound containing benzaldehyde and β-keto ester groups as monomers. The thiourea moiety in the polymer structure has similar reactivity as the thiourea, thus the poly(DHPMT) is an excellent polymer precusor for preparing new functional polymers through the postpolymerization modification (PPM) strategy. After simple reaction with functional haloalkanes, the parent poly(DHPMT) could be almost completely converted (>99%) to daughter polymers containing alkene or alkyne side groups. Then, the daughter polymers have been further transferred to granddaughter polymers through another PPM via thiol–ene or Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reactions. Besides, when 3-phenylpropargyl chloride was used as the reactant, a bright yellow fluorescent polymer could be simply achieved due to the in situ formed conjugated heterocycle in the polymer structure, further demonstrating the diversity of the functional polymers through PPM. Considering the easily available monomers, simple polycondensation, and the excellent reactivity of the thiourea moiety in the polymer structure, this thiourea-contained Biginilli polycondensate might be a versatile platform for new functional polymer preparation.

A novel multicomponent system has been constructed through the combination of Hantzsch reaction and reversible addition–fragmentation chain transfer (RAFT) polymerization in a one-pot manner. Compared to traditional stepwise methods, this one-pot system exhibits much more advantages to facilely and efficiently prepare well-defined poly(1,4-dihydropyridine)s (poly(1,4-DHP)s). A series of poly(1,4-DHP) derivatives have also been successfully prepared through this Hantzsch–RAFT system using different aldehydes as reactants, suggesting this system is a general and versatile approach to prepare well-defined functional polymers with 1,4-DHPs as side groups. Since 1,4-DHP derivatives are an important class of bioactive molecules in the pharmaceutical field, this simple method to prepare poly(1,4-DHP)s might have potential to prepare related functional polymers for biological and pharmaceutical applications.

The development of fluorescent organic nanoparticles (FONs) based on aggregation induced emission (AIE) dyes has attracted significant research interest in recent years. In this work, a novel one-pot strategy for the fabrication of AIE-based FONs was developed via a combination of RAFT polymerization and enzymatic transesterification for the first time. During this procedure, a hydrophobic tetraphenylethene-functionalized AIE dye (denoted as TPEOH) with a hydroxyl end functional group and a hydrophilic polyethylene glycol monomethyl ether (mPEG-OH, Mn = 350) were simultaneously attached onto the methacrylate monomer via enzymatic transesterification. The amphiphilic copolymer formed after RAFT polymerization of the functionalized methacrylate monomers tended to self-assemble into FONs with the hydrophobic AIE core covered by a hydrophilic PEG shell. The molar fractions of TPE and PEG in the polymer were about 30.5% and 69.5%, respectively, while Mn was 4700 g mol−1 with a narrow polydispersity index (PDI) (∼1.30). The obtained amphiphilic polymer nanoparticles (denoted as TPE-PEG) demonstrated good fluorescence performance and excellent dispersibility in aqueous solution. More importantly, these FONs possessed a spherical morphology with a uniform size (about 200 nm) and excellent biocompatibility, making them promising for bioimaging applications.

The Ugi reaction, one of the most famous multicomponent reactions, has recently been introduced into polymer chemistry as a novel, efficient and useful tool to prepare multifunctional polymers. In this review, the recent progress on the utilization of the Ugi reaction in polymer chemistry, including monomer synthesis, polycondensation, post-polymerization modification (PPM) etc. has been summarized. Meanwhile, the applications of the multifunctional polymers synthesized via the Ugi reaction and the future development of the Ugi reaction in polymer chemistry have also been discussed.

The reactions for polymer synthesis should be simple and efficient using easily available raw materials. A new difunctional monomer containing benzaldehyde and beta-keto ester groups (monomer AB) has been successfully prepared on a medium scale, and the corresponding poly(dihydropyrimidin-2(1H)-one)s (DP ∼84) can be synthesized via the Biginelli polycondensation in a short time (∼1 h). The in situ generated polycondensates could glue two metal sheets, demonstrating an interesting metal bonding property which cannot be observed in small molecules. The optimized multifunctional monomers (AB2, A2B2 monomers) were subsequently used for the in situ polycondensation between metal sheets, and metal bonding strength could be improved to the similar level of commercial cyanoacrylate glue. Since the monomers could be easily prepared on a large scale and the polymerization could be simply performed, the Biginelli polycondensation might have potential as a new strategy to synthesize new functional polymers.

In recent years, fluorescent organic nanoparticles (FONs) based on aggregation induced emission (AIE) dyes have received increasing attention for their potential in biology and biochemistry. In this contribution, a novel one-pot method for the fabrication of AIE-based FONs was developed via a combination of reversible addition–fragmentation chain-transfer (RAFT) polymerization and Schiff base reaction for the first time. During this procedure, an aldehyde functionalized hydrophobic tetraphenylethene AIE dye (named TPEA) reacted with the amine group of an amino-ended methacrylamide monomer by the Schiff base reaction, and the vinyl group in the monomer synchronously participated in RAFT polymerization together with a PEGMA monomer to form a new fluorescent copolymer. The as-prepared copolymer tended to self-assemble into FONs with the hydrophobic AIE core covered by a hydrophilic PEG shell, and the molar fractions of TPEA and PEG in the copolymer were about 20% and 80%, respectively, with 29200 g mol−1 (Mn) and a narrow polydispersity index (PDI) (∼1.30). The prepared amphiphilic copolymer nanoparticles (named TPEA-PEG) exhibited good fluorescence features and excellent dispersibility in aqueous solution. More importantly, these FONs presented a spherical morphology, uniform size (∼100 nm), and excellent biocompatibility, making them promising candidates for bioimaging applications.

A hexa-component system has been successfully developed for simple polymer conjugation on carbon nanotubes. The well-known Ugi reaction has been recognized as a multicomponent click (MCC) reaction to efficiently collaborate with π–π stacking and RAFT polymerization to construct this delicate one-pot system. The CNT–(co)polymer composites inherit the properties of the conjugated polymers and can be well dispersed in both organic and aqueous solvents. As a simple and efficient method, this one-pot system might have the potential to be a general approach to prepare carbon-based composites.

With the increasing interest in the use of luminescent probes in biomedical applications, the development of fluorescent organic nanoparticles (FONs) on the basis of aggregation induced emission (AIE) dyes has attracted great research attention. In this study, a polymerizable tetraphenylethene-functionalized AIE dye (named as TPEV) with a vinyl end functional group was synthesized by a “one-step” Suzuki coupling reaction of 4-vinylphenylboronic acid and bromotriphenylethylene, and the as-prepared hydrophobic AIE dye TPEV subsequently participated in the reversible addition–fragmentation chain transfer (RAFT) polymerization together with the hydrophilic monomer of poly(ethylene glycol) monomethacrylate (PEGMA) to obtain a new amphiphilic copolymer (denoted as TPEV–PEG) with transformed side fluorescent groups. The Mn value of the obtained copolymer was about 29800 g mol−1 with a narrow polydispersity index (PDI) of about 1.30. The molar ratio of TPE to PEG segment in the copolymer was respectively about 19.2% to 80.8%, and it was easy for the TPEV–PEG copolymer to self-assemble into FONs with the hydrophobic AIE core encapsulated by a hydrophilic PEG shell. The research results further showed that the TPEV–PEG FONs presented good fluorescent features with the maximal emission peak at 480 nm, high dispersibility in water solution with homogeneous spherical morphology (∼200 nm) and excellent biocompatibility, giving them good potential for bioimaging applications.

Due to the good biocompatibility, ε-polylysine (Ply) has been extensively investigated for various biomedical applications. In this study, a fluorescent monomer (named Flu-MA) was firstly synthesized through acylation reaction of fluorescein by methacryloyl chloride, and the initiator of ε-polylysine bromide (named Ply-Br) was prepared by the introduction of a bromine atom into Ply by the acylation reaction of Ply with α-bromoisobutyryl bromide. Subsequently, a novel amphiphilic fluorescent polymer (Flu-Ply) was successfully fabricated by ATRP via incorporation of Flu-MA monomer into Ply chains for the first time. The structure and properties of the obtained Flu-Ply fluorescent polymer were investigated in detail by 1H NMR, TEM, UV-vis, FL and FTIR, and the results confirmed the successful incorporation of Flu-MA into Ply by ATRP. As a result of Flu-MA and Ply respectively endowing the as-prepared Flu-Ply polymer with fluorescence and water dispersibility, it tended to self-assemble into fluorescent organic nanoparticles (FONs) with excellent biocompatibility. More importantly, the good fluorescence, uniform spherical morphology, excellent biocompatibility and water dispersibility of Flu-Ply FONs exhibited an attractive prospect for bioimaging applications.

By ‘grafting to’ strategy, polymers (poly(ethylene glycol), poly(methyl methacrylate)) have been facilely linked on carbon nanotube (CNT) surface through simultaneous π–π stacking and mercaptoacetic acid locking imine (MALI) reaction to achieve the CNT–polymer complex. The targeted polymers could be effectively anchored on CNT surface under mild condition (room temperature, catalyst free), and the therefore obtained CNT–polymer complex can be well dispersed in regular used organic or aqueous solvents, suggesting this simple method an efficient approach to prepare CNT–polymer nanocomposite.

•An one-pot strategy has been developed to facilely prepare polymer modified multi-walled carbon nanotube (MWCNT).•The polymer-MWCNT can be well dispersed in organic and aqueous solutions while has the unique property of the anchored polymers.•Supramolecular hydrogel could be simply obtained using the PEG-MWCNT and α-cyclodextrin.The Biginelli reaction has been utilized as an effective click reaction to collaborate with π–π stacking to prepare carbon nanotube-polymer conjugates. The synthesized polymers are successfully anchored on carbon nanotube surface via ‘grafting to’ strategy, and the obtained carbon nanotube-polymer composites possessing characteristic properties of anchored polymer can be well dispersed in general solution to expand carbon nanotubes application realm.

A multicomponent reaction (MCR) has been carried out on the platform of controlled radical polymerization (CRP) to construct a ‘one pot’ MCR-CRP system for the facile preparation of well-defined functional polymers. In the current work, a novel ‘one pot’ system has been built through a combination of the Kabachnik–Fields (KF) reaction and reversible addition fragmentation chain transfer (RAFT) polymerization. Compared to a traditional stepwise method and polymer post-polymerization modification, this novel ‘one pot’ system exhibited distinct advantages to much more facilely and efficiently prepared well-defined poly(aminophosphonate)s (polyAPPs). A series of unique polyAPPs have also been successfully prepared through this KF–RAFT system, suggesting this novel method is a general and versatile approach to prepare well-defined organophosphorous polymers.

A novel and facile method, involving enzymatic monomer synthesis and a photocontrolled polymerization technique, has been successfully employed for the preparation of high-order multiblock copolymers. New acrylate monomers were synthesized via enzymatic transacylation between an activated monomer, i.e., 2,2,2-trifluoroethyl acrylate (TFEA), and various functional alcohols. These synthesized monomers were successfully polymerized without further purification via photoinduced electron transfer–reversible addition–fragmentation chain transfer (PET-RAFT) polymerization under low energy blue LED light (4.8 W) in the presence of an iridium-based photoredox catalyst (fac-[Ir(ppy)3]). In this condition, PET-RAFT allows us to achieve high monomer conversion (∼100%) with excellent integrity of the end group (>80%). Different multiblock (co)polymers, including poly(hexyl acrylate) pentablock homopolymer, poly(methyl acylate-b-ethyl acrylate-b-n-propyl acrylate-b-n-butyl acrylate-b-n-pentyl acrylate) pentablock copolymer, and poly(3-oxobutyl acrylate-b-methyl acrylate-b-3-(trimethylsilyl)prop-2-yn-1-yl acrylate) triblock copolymer containing functional groups were rapidly prepared via sequential addition of monomers without purification steps.

Theranostic combinations usually contain an imaging, a therapeutic and a cloaking component to simultaneously fulfil diagnostic and therapeutic functions. Using upgraded PEGylation technology, a straightforward one-pot strategy based on thiolactone ring-opening has been developed to facilely synthesize a multifunctional PEGylation agent, fluorescent protein-reactive poly(ethylene glycol) (PEG), which can subsequently react with a model therapeutic protein to form a fluorescent PEGylated protein as a model of sophisticated theranostic combinations.

Multicomponent reactions (MCRs) and click reactions have a number of significant features in common, such as modularity, high efficiency and atom economy. Some MCRs can thus be considered as a new type of click reaction: a multicomponent click reaction. The well-known Ugi reaction has been utilized as a green click reaction to efficiently stitch two different polymer chains together under very benign conditions (25 °C, catalyst free). Mid-functional block copolymers and miktoarm star copolymers which are normally difficult to synthesize have thus been easily prepared, indicating the promising potential of the Ugi reaction in polymer chemistry to prepare sophisticated structural copolymers.

Some multicomponent reactions (MCRs) are similar to click reactions to give highly selective products with reliable high yield and effective atom utilization, implying that they can also be recognized as click reactions. The addition of mercaptoacetic acid to an imine bond can be considered as a clickable MCR since this catalyst free reaction can occur smoothly under benign conditions in a short time with water as the only byproduct. This reaction has thus been introduced into polymer chemistry and different functional polymers have been successfully synthesized through modification of polymer chain-ends, linkage of two polymer chains and polycondensation.

Based on the production of baking bread, rolls, cake, beer or Chinese steamed bread, a novel microorganism inspired macro/super-porous hydrogel composed of specific polymers and single-celled fungi, yeast, was prepared by the production of carbon dioxide (CO2) via a fermentation method. The appearance, porous structure, swelling behavior and adsorption properties of the resulting hydrogels were investigated by optical microscopy, scanning electron microscopy (SEM), UV/Vis spectroscopy and gravimetric methods. The resultant hydrogel presents a yellowish brown color similar to that of ale yeast, and the integration of polymeric materials and fungi has significantly improved the pore shape/size, swelling and adsorption properties of the hydrogels. Both super- and macro-pores with diameters ranging from 1 mm to 5 μm exist in the hierarchical matrix of the hydrogels. The super/macro-porous hydrogels can absorb water very rapidly and swell to an equilibrium state in less than 60 min. With increasing consumption of yeast or sugar, the adsorption capacity (Qt) of hydrogels can be increased by 1.39–1.87 times. After adsorbing cationic dye crystal violet (CV), pores of the hydrogel matrix were blocked and a dense layer was formed. By using same fermentation method porous fibers, elastomers, ceramics and metals could be obtained, which might have potential applications in the fields of cell culture, catalytic substrates, chemical separation and battery electrodes.

The Ugi reaction has been utilized as a multicomponent click reaction to efficiently synthesize a series of multifunctional PEGylation agents, and those PEG derivatives were successfully conjugated on a protein surface to generate corresponding multifunctional protein–polymer conjugates, indicating the promising potential of the Ugi reaction in the field of PEGylation.

A novel, highly efficient methodology to synthesize gradient glycopolymers has been successfully developed involving concurrent enzymatic monomer transformation and reversible addition–fragmentation chain transfer (RAFT) polymerization. By synchronizing enzymatic monomer transformation with polymerization, a continuous supply of the second monomer (glycomonomer) is achieved during the polymerization, resulting in a gradient sugar distribution in the final polymer. Detailed studies of the process using GPC and NMR indicate that the gradient glycopolymers synthesized by RAFT were well controlled. Subsequently, 1,2:3,4-di-O-isopropylidene-6-O-methacryloyl-α-d-galactopyranose (DIMAG) moieties were deprotected to regenerate the sugar and achieve amphiphilic bioactive glycopolymers. We demonstrate the synthesis of a set of glycopolymers with different sequential structures, such as statistical, gradient and block glycopolymers. The glycopolymers with block structure show higher affinities toward the RCA120 lectin receptor compared with other structural counterparts. Furthermore, simulation of the self-assembly of three types of copolymers and their binding to lectins provides fundamental insight into this result, revealing the mechanisms underlying the dependence of self-assembling structures and protein adsorption kinetics on the molecular architectures of copolymers.

Water soluble and biocompatible fluorescent organic nanoparticles based on aggregation-induced emission (AIE) material were facilely prepared by mixing AIE material and surfactant. The utilization of such fluorescent organic nanoparticles for cell imaging applications was further explored.

Aggregation-induced emission (AIE) materials were facilely incorporated into mesoporous silica nanoparticles (MSNs) via one-pot surfactant templated method. Cell imaging and cancer therapy applications of such fluorescent MSNs were further explored. We demonstrated that AIE-MSN nanocomposites showed strong fluorescence and uniform morphology, making them promising for both cell imaging and cancer therapy.Keywords: aggregation-induced emission; biomedical applications; cancer therapy; cell imaging; drug delivery; mesoporous silica nanoparticles;

A novel methodology to facilely synthesize gradient copolymers has been successfully developed by concurrent enzymatic monomer transformation and reversible addition-fragmentation chain transfer (RAFT) polymerization. By synchronizing enzymatic monomer transformation with polymerization, continuous supply of a second monomer is achieved during the polymerization, resulting in gradient monomer distribution in the final polymer. Various alcohols were used for in situ monomer transformation with trifluoroethyl methacrylate (TFEMA), and corresponding gradient copolymers could be successfully prepared. This method is facile and versatile, providing an alternative candidate for preparing gradient polymers with specific monomer sequences.

Looking at ‘old’ reactions from new perspectives sometimes brings new breakthroughs in current hot research areas. We therefore reinvestigated the successful multicomponent reactions (MCRs) in organic chemistry, and are pleased to find the Biginelli reaction, one of the most famous MCRs, has almost all the ‘clickable’ features reported in ‘click chemistry’. The modules of the Biginelli reaction are easily obtained with even more functionalities and diversity, and the reaction can be carried out under mild conditions quickly, compatibly and nearly quantitatively with only water as the byproduct. In current research, the Biginelli reaction has been demonstrated as a new ‘click’ reaction via application in polymer chemistry and chemical biology. Through the modification of polymer chains (side or chain end groups), and the combination with living radical polymerization in a one pot strategy, functional homopolymer and copolymer have been quantitatively prepared, demonstrating the high efficiency and compatibility of the Biginelli reaction in polymer chemistry. Furthermore, we are surprised and excited to find Biginelli reaction can be used as a ‘catalyst free’ bioorthogonal-click reaction to anchor dyes on cell membrane, indicating its possible application in chemical biology. Thus, we address here the ‘clickable’ aspects of the Biginelli reaction, a MCR that is more than 120 years ‘old’. We hope the new insight into the MCRs might bring some new members to the click family as a new type of click reaction: multicomponent click reaction (MCR-Click) which might have potential applications in other areas, such as materials science, polymer chemistry and chemical biology in place of traditional organic chemistry.

PEGylation is a popular approach for the surface functionalization of nanoparticles to achieve improved properties and better performance. Herein, we developed a facile method for surface PEGylation of hydrophobic fluoridated hydroxyapatite (FAp):Ln3+ (Ln = Eu or Tb) nanorods via hydrophobic interactions between oleic acid and amphiphilic synthetic copolymers, which were synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerization using stearyl methacrylate (SMA) and poly(ethylene glycol) methacrylate (PEGMA) as monomers. Our results demonstrated that the morphology and fluorescent properties of the FAp nanorods are not significantly changed by the PEGylation procedure, and the resulting FAp nanorods were found to be stable in aqueous solution. More importantly, these PEGylated FAp nanorods are biocompatible with cells and could be utilized for cell imaging applications. Therefore, we believe that the method described in this work is a simple, efficient and general strategy for the surface PEGylation of hydrophobic nanoparticles.

A simultaneous multicomponent polymerization (MCP) system combining copper(I) catalyzed azide alkyne cycloaddition (CuAAC, ‘Click’ reaction), enzymatic transesterification and atom transfer radical polymerization (ATRP) has been successfully developed.

A straightforward methodology to facilely synthesize optically active polymers has been successfully developed through a one-pot combination of enzymatic resolution reaction and living radical polymerization.

Fluorescent nano-graphite oxides (NGO) with different size distribution were prepared via a one-pot hydrothermal route using ultrasmall graphite powder as starting material and subsequently separated using dialysis tubes with different molecular weight cutoff. The biomedical applications of these NGO for cell imaging were further investigated. Fourier transform infrared spectra demonstrated that many functional groups including the hydroxyl group, carboxyl group and epoxy group were present on NGO, which endowed them with good water solubility. These NGO showed size-dependent photoluminescence and excellent biocompatibility with A549 cells. As evidenced by laser scanning confocal microscopy images, NGO could be internalized by A549 cells and located in the cytoplasm. Given their good water solubility, size tunable photoluminescence and excellent biocompatibility, these NGO should be promising for bioimaging and various biomedical applications.

Water dispersible carbon-dots (CDs) with tunable photoluminescence were synthesized via one-pot hydrothermal oxidation of nanodiamond and subsequently utilized for cell imaging applications. The CDs were characterized by the following techniques including transmission electron microscopy, atomic force microscopy, Fourier transform infrared spectroscopy, UV–Visible spectroscopy, and fluorescent spectroscopy. Results showed that the size of CDs is mainly distributed at 3–7 nm. Many functional groups were introduced on the surface of CDs during hydrothermal oxidation procedure. Cell morphology observation and cell viability measurement demonstrated the good biocompatibility of CDs, suggesting their potential bioimaging applications.Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (205 K)Download as PowerPoint slideHighlights► Carbon-dots was derived from nanodimond. ► Carbon-dots with tunable photoluminescence. ► Carbon-dots show excellent biocompatibility. ► Carbon-dots were used to cell imaging.

Biocompatible fluorescent organic nanoparticles with tunable photoluminescence were prepared via the one-pot oxidation of polydopamine and subsequently utilized for cell imaging.

A straightforward method to prepare a novel magnetic self-healing hydrogel has been successfully developed.

A facile “one-pot” chemoenzymatic-ATRP has been successfully developed through the combination of copper-catalytic ATRP and enzyme-catalytic monomer transformation reactions.

Enzymatic transesterification was combined with RAFT polymerization to develop a new one-pot synthetic method for new polymer synthesis. This method contained in situ monomer transformation reaction between acyl donor monomer and primary alcohols such as hexanol and so on, followed by subsequent RAFT polymerization to get target polymers. The enzymatic reaction and RAFT polymerization tolerated each other and cooperated well to get new polymers with a completely transformed new monomer, high polymer yields, excellent control over the polymerization process, and good enzyme activity maintenance, providing a general and straightforward methodology for new polymer synthesis and modification.

Water dispersible and biocompatible polyPEGylated ND nanoparticles were prepared via surface-initiated atom transfer radical polymerization. Cell internalization study reveals that ND nanoparticles facilitate the transport of doxorubicin hydrochloride into A549 cells, indicating their potential applications in cancer therapy.

An inexpensive, biocompatible self-healing hydrogel as a new injectable cell therapy carrier has been facilely developed.

An efficient and general strategy for the dispersion of multi-walled carbon nanotubes in water and organic media was developed for the first time via the combination of mussel-inspired chemistry and the Michael addition reaction.

The biomedical applications of aniline oligomers and their derivatives have attracted increasing interest due to their electroactive and biodegradable properties. However, no reports have systematically examined the toxicity of these electroactive materials, which has severely hindered their biomedical applications. In this work, the cellular responses of aniline oligomers including aniline dimer, trimer and tetramer to mouse embryo fibroblast (NIH-3T3) cells and adenocarcinomic human alveolar basal epithelial (A549) cells were determined and compared for the first time. Our results demonstrated that the aniline trimer showed the highest cytotoxicity to both types of cells. Compared with the NIH-3T3 cells, aniline oligomers exhibited the least cytotoxicity to A549 cells. Taken together, we demonstrate that both the properties of aniline oligomers and cell types could influence the cellular responses of aniline oligomers. As the first report focused on the cytotoxicity of aniline oligomers, this work provides some fundamental and important information about the cytotoxicity of aniline oligomers, which should be valuable for their biomedical applications.

Polyethylene glycol (PEG) and poly(PEGMA) conjugated nanodiamond (ND) have been synthesized via “grafting to” and “grafting from” methods, respectively. In “grafting to” method, hydroxyl groups on ND surface were firstly oxidized to carboxyl groups, and then reacted with thionyl chloride to form acyl chloride groups. The acyl chloride functionalized ND (ND–COCl) was subsequently reacted with poly(ethylene glycol) monomethyl ether (mPEG) in the presence of triethylamine to generate mPEG conjugated ND (ND–mPEG). On the other hand, in “grafting from” method, ND–OH was modified with 2-bromoisobutyryl bromide (ND–Br), and then poly(PEG methyl ether methacrylate) (Poly(PEGMA)) chains were linked on the ND surface through surface-initiated atom transfer radical polymerization (ATRP) using ND–Br as the initiator and Cu(Br)/N,N,N′,N″,N″-pentmethyl diethylenetriamine (PMDETA) as the catalyst and ligand. The polymer conjugated ND particles were characterized using transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, thermal gravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS). TGA analyses demonstrated that the polymer weight ratios through “grafting to” and “grafting from” methods were 29.8% and 34.4%, respectively. The mPEG and poly(PEGMA) conjugated ND nanoparticles exhibited enhanced dispersibility in organic media. More importantly, due to the relative high graft ratios and molecular weight, poly(PEGMA) functionalized ND was also dispersed well in water. Given the excellent physicochemical and biological properties of PEG and ND, the methods described in current work might be useful for the preparation of functional ND nanoparticles for potential biomedical applications.Graphical abstract

An inexpensive, facile, and environmentally benign method has been developed for the preparation of multiresponsive, dynamic, and self-healing chitosan-based hydrogels. A dibenzaldehyde-terminated telechelic poly(ethylene glycol) (PEG) was synthesized and was allowed to form Schiff base linkages between the aldehyde groups and the amino groups in chitosan. Upon mixing the telechelic PEG with chitosan at 20 °C, hydrogels with solid content of 4–8% by mass were generated rapidly in <60 s. Because of the dynamic equilibrium between the Schiff base linkage and the aldehyde and amine reactants, the hydrogels were found to be self-healable and sensitive to many biochemical-stimuli, such as pH, amino acids, and vitamin B6 derivatives. In addition, chitosan could be digested by enzymes such as papain, leading to the decomposition of the hydrogels. Encapsulation and controlled release of small molecules such as rhodamine B and proteins such as lysozyme have been successfully carried out, demonstrating the potential biomedical applications of these chitosan-based dynamic hydrogels.

A straightforward method to prepare a novel magnetic self-healing hydrogel has been successfully developed.

A facile “one-pot” chemoenzymatic-ATRP has been successfully developed through the combination of copper-catalytic ATRP and enzyme-catalytic monomer transformation reactions.

Fluorescent nano-graphite oxides (NGO) with different size distribution were prepared via a one-pot hydrothermal route using ultrasmall graphite powder as starting material and subsequently separated using dialysis tubes with different molecular weight cutoff. The biomedical applications of these NGO for cell imaging were further investigated. Fourier transform infrared spectra demonstrated that many functional groups including the hydroxyl group, carboxyl group and epoxy group were present on NGO, which endowed them with good water solubility. These NGO showed size-dependent photoluminescence and excellent biocompatibility with A549 cells. As evidenced by laser scanning confocal microscopy images, NGO could be internalized by A549 cells and located in the cytoplasm. Given their good water solubility, size tunable photoluminescence and excellent biocompatibility, these NGO should be promising for bioimaging and various biomedical applications.