Linear Polymer Precursors Research Articles

Polymer Synthesis Based on Self‐Accelerating 1,3‐Dipolar Cycloaddition Click Reactions†

AbstractThis review reports our recent work on developing polymer synthesis methods based on a self‐accelerating double‐strain‐promoted 1,3‐dipole‐alkyne cycloaddition (DSPDAC) click reaction. In DSPDAC, the cycloaddition of 1,3‐dipole with the first alkyne of sym‐dibenzo‐1,5‐cyclooctadiene‐3,7‐diyne (DIBOD) activates the second unreacted alkyne, which reacts with 1,3‐dipole much faster than the original alkyne of DIBOD. When using DIBOD and bis‐dipole compounds as monomer pairs, the self‐accelerating property of DSPDAC allows us to develop a stoichiometric imbalance‐promoted step‐growth polymerization method. It could produce polymers with ultrahigh molecular weight in the presence of excess DIBOD monomers. When using DIBOD to ring‐close linear polymers with 1,3‐dipole end groups, the self‐accelerating property of DSPDAC facilitates us to develop a unique bimolecular ring‐closure method. It could efficiently prepare pure cyclic polymers in the presence of excess DIBOD small linkers to linear polymer precursors.

Highly effective anti-tumor nanomedicines based on HPMA copolymer conjugates with pirarubicin prepared by controlled RAFT polymerization

Here, we describe innovative synthesis of well-defined biocompatible N-(2-hydroxypropyl) methacrylamide (HPMA)-based polymer carriers and their drug conjugates with pirarubicin intended for controlled drug delivery and pH-triggered drug activation in tumor tissue. Polymer carrier synthesis was optimized to obtain well-defined linear HPMA-based polymer precursor with dispersity close to 1 and molar mass close to renal threshold with minimal synthesis steps. The developed synthesis enables preparation of tailored polymer nanomedicines with highly enhanced biological behavior in vivo, especially the biodistribution, urine elimination, tumor accumulation and anticancer activity. Statement of SignificanceThe manuscript reports on novel synthesis and detailed physicochemical characterization and in vivo evaluation of well-defined biocompatible hydrophilic copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) and their drug conjugates with pirarubicin enabling controlled drug delivery and pH-triggered drug activation in tumor tissue. Polymer carrier synthesis was optimized to obtain well-defined linear HPMA-based polymer precursor with minimal synthesis steps using controlled polymerization. Compared to previously published HPMA-based polymer drug conjugates whose polymer carriers were prepared by classical route via free radical polymerization, the newly prepared polymer drug conjugates exhibited enhanced biological behavior in vivo, especially the prolonged blood circulation, urine elimination, tumor accumulation and excellent anticancer activity. We believe that the newly prepared well-defined polymer conjugates could significantly enhance tumor therapy in humans.

High-Affinity N-(2-Hydroxypropyl)methacrylamide Copolymers with Tailored N-Acetyllactosamine Presentation Discriminate between Galectins.

N-Acetyllactosamine (LacNAc; Galβ4GlcNAc) is a typical disaccharide ligand of galectins. The most abundant members of these human lectins, galectin-1 (Gal-1) and galectin-3 (Gal-3), participate in a number of pathologies including cancerogenesis and metastatic formation. In this study, we synthesized a series of fifteen N-(2-hydroxypropyl)methacrylamide (HPMA)-based glycopolymers with varying LacNAc amounts and presentations and evaluated the impact of their architecture on the binding affinity to Gal-1 and Gal-3. The controlled radical reversible addition-fragmentation chain transfer copolymerization technique afforded linear polymer precursors with comparable molecular weight (Mn ≈ 22,000 g mol-1) and narrow dispersity (D̵ ≈ 1.1). The precursors were conjugated with the functionalized LacNAc disaccharide (4-22 mol % content in glycopolymer) prepared by enzymatic synthesis under catalysis by β-galactosidase from Bacillus circulans. The structure-affinity relationship study based on the enzyme-linked immunosorbent assay revealed that the type of LacNAc presentation, individual or clustered on bi- or trivalent linkers, brings a clear discrimination (almost 300-fold) between Gal-1 and Gal-3, reaching avidity to Gal-1 in the nanomolar range. Whereas Gal-1 strongly preferred a dense presentation of individually distributed LacNAc epitopes, Gal-3 preferred a clustered LacNAc presentation. Such a strong galectin preference based just on the structure of a multivalent glycopolymer type is exceptional. The prepared nontoxic, nonimmunogenic, and biocompatible glycopolymers are prospective for therapeutic applications requiring selectivity for one particular galectin.

An Efficient Ring-Closure Method for Preparing Well-Defined Cyclic Polynorbornenes.

An efficient bimolecular ring-closure method is developed to prepare the well-defined cyclic polynorbornenes by combining the living ring-opening metathesis polymerization (ROMP) with the self-accelerating double strain-promoted azide-alkyne cycloaddition (DSPAAC) reaction. In this method, ROMP is used to synthesize the well-defined linear polynorbornenes with both azide terminals by virtue of a N-hydroxysuccinimide-ester-functionalized Grubbs initiator following the modification of polymer end groups. DSPAAC click reaction is then used to ring-close the linear polymer precursors and prepare the corresponding well-defined cyclic polynorbornenes using the sym-dibenzo-1,5-cyclooctadiene-3,7-diyne (DIBOD) as small linkers. The self-accelerating DSPAAC ring-closing reaction facilitates this method to efficiently prepare pure cyclic polynorbornenes in the presence of a molar excess of DIBOD small linkers to the linear polynorbornene precursors. This is the first report to prepare well-defined polynorbornenes with cyclic topology based on the ring-closure strategy for cyclic polymers.

A versatile method for cyclic polymers from conjugated and unconjugated vinyl monomers

ABSTRACTA versatile method was introduced to prepare cyclic polymers from both conjugated and unconjugated vinyl monomers. It was developed on the combination of the RAFT polymerization and the self‐accelerating double strain‐promoted azide‐alkyne click (DSPAAC) reaction. In this approach, a switchable chain transfer agent 1 was designed to have hydroxyl terminals and a functional pyridinyl group. The protonation and deprotonation of pyridinyl group endowed the chain transfer agent 1 with a switchable control capability to RAFT polymerization of both conjugated and unconjugated vinyl monomers. Based on this, RAFT polymerization and the following hydroxyl end group modification were used to prepare various azide‐terminated linear polymers including polystyrene, poly(N‐vinylcarbazole), and polystyrene‐block‐poly(N‐vinylcarbazole). Using sym‐dibenzo‐1,5‐cyclooctadiene‐3,7‐diyne (DBA) as small linkers, the corresponding cyclic polymers were then prepared via the DSPAAC reaction between DBA and azide terminals of the linear precursors. Due to the self‐accelerating property of DSPAAC reaction, this bimolecular ring‐closing reaction could efficiently produce the pure cyclic polymers using excess molar amounts of DBA to linear polymer precursors. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1811–1820

Efficient Heterodifunctional Unimolecular Ring‐Closure Method for Cyclic Polymers by Combining RAFT and SuFEx Click Reactions

A novel ring-closure strategy for cyclic polymers by combining reversible addition-fragmentation chain transfer polymerization (RAFT) and the sulfur(VI)-fluoride exchange (SuFEx) click reaction is presented. Herein, a new heterodifunctional trithiocarbonate RAFT agent, 2-((tert-butyldimethylsilyl)oxy)ethyl (4-(fluorosulfonyl)benzyl) carbonotrithioate (TBDMS-FSBCT), containing both tert-butyldimethylsilyl ether and sulfonyl fluoride moieties, is developed. The polymerization behavior of TBDMS-FSBCT is first demonstrated by a standard RAFT polymerization procedure for two types of vinyl monomers, N-isopropylacrylamide (NIPAAm) (conjugated vinyl monomer) and N-vinylpyrrolidone (NVP) (unconjugated vinyl monomer). The tert-butyldimethylsilyl ether and sulfonyl fluoride groups at the α and ω positions of the obtained linear polymer precursors (L-PNIPAAm and L-PVP) are verified by 1 H, 13 C, and 19 F NMR spectra. Subsequent intramolecular SuFEx click cyclization of the α,ω-heterofunctionalized linear precursors in air at room temperature conveniently yields the corresponding cyclic polymers (C-PNIPAAm and C-PVP). Overall, this is the first report on the preparation of cyclic polymers based on the SuFEx reaction under ambient conditions. It is envisioned that the approach may open an avenue for the formation of cyclic polymers.

In situ nanoarchitecturing and active-site engineering toward highly efficient carbonaceous electrocatalysts

Oxygen reduction reaction (ORR) lies at the heart of many renewable energy technologies. Development of facile approaches toward highly active carbon materials for ORR is urgently desirable. We accidentally discovered a method for preparing heteroatom-doped carbon catalyst through an in situ self-templating and self-sacrificing strategy during the carbonization of a single polymer precursor. The prepared N,S co-doped and hierarchical porous carbon possesses a large specific surface area up to 2446 m2 g−1, which is the state-of-the-art among the porous carbons prepared by direct pyrolysis of linear polymer precursors. The use of in situ nanoarchitecturing and active-site engineering ensures that the N,S co-doped porous carbon catalyst has sufficient active sites for charge/mass transport and catalysis. As expected, as-prepared carbonaceous electrocatalyst exhibited superior ORR activity in both alkaline and acidic electrolytes and outperformed the state-of-the-art benchmark Pt/C and the best carbonaceous electrocatalysts for ORR in aqueous media so far. Moreover, the N,S co-doped carbon catalyst was demonstrated to be a highly efficient air cathode for Zn–air batteries. Thus, this study provides a new and economical method of fabricating feasible carbon electrocatalysts with exceptional catalytic activities for energy conversion and storage.

Thermodynamics of single polyethylene and polybutylene glycols with hydrogen-bonding ends: A transition from looped to open conformations.

A variety of linear polymer precursors with hydrogen bonding motifs at both ends enable us to design supramolecular polymer systems with tailored macroscopic properties including self-healing. In this study, we investigate thermodynamic properties of single polyethylene and polybutylene glycols with hydrogen bonding motifs. In this context, we first build a coarse-grained model of building blocks of the supramolecular polymer system based on all-atom molecular structures. The density of states of the single precursor is obtained using the stochastic approximation Monte Carlo method. Constructing canonical partition functions from the density of states, we find the transition from looped to open conformations at transition temperatures which are non-monotonously changing with an increasing degree of polymerization due to the competition between chain stiffness and loop-forming entropy penalty. In the complete range of chain length under investigation, a coexistence of the looped and open morphologies at the transition temperature is shown regardless of whether the transition is first-order-like or continuous. Polyethylene and polybutylene glycols show similar behavior in all the thermodynamic properties but the transition temperature of the more flexible polybutylene glycol is shown to change more gradually.

Self-accelerating click reaction for preparing cyclic polymers from unconjugated vinyl monomers

An efficient metal-free bimolecular homodifunctional ring-closure method was developed specifically for preparing well-defined cyclic polymers from unconjugated vinyl monomers. In this approach, well-defined homodifunctional linear polymers with azide terminals were prepared by using the reversible addition chain transfer polymerization/macromolecular design by interchange of xanthates (RAFT/MADIX) to polymerize unconjugated vinyl monomers in the presence of a diazide xanthate chain transfer agent. The self-accelerating double strain-promoted azide-alkyne cycloaddition (DSPAAC) reaction was then applied to ring-close the linear polymer precursors with sym-dibenzo-1,5-cyclooctadiene-3,7-diyne (DBA) as small linkers, leading to the formation of corresponding cyclic polymers. By virtue of the self-accelerating property of DSPAAC ring-closing reaction, this novel method smartly eliminated the requirement of equimolar amounts of the telechelic polymers and small linkers in the traditional bimolecular ring-closure methods for pure cyclic polymers. More importantly, the usage of excess DBA small linkers could significantly enhance the preparation efficiency of cyclic polymers. Moreover, the cyclic polymers resulted from this novel method could be conveniently cleaved back to linear polymers by a mild aminolysis of the S-C(S) bond within the cyclic polymer backbone.

Effect of chain stiffness on the structure of single-chain polymer nanoparticles

Polymeric single-chain nanoparticles (SCNPs) are soft nano-objects synthesized by purely intramolecular cross-linking of single polymer chains. By means of computer simulations, we investigate the conformational properties of SCNPs as a function of the bending stiffness of their linear polymer precursors. We investigate a broad range of characteristic ratios from the fully flexible case to those typical of bulky synthetic polymers. Increasing stiffness hinders bonding of groups separated by short contour distances and increases looping over longer distances, leading to more compact nanoparticles with a structure of highly interconnected loops. This feature is reflected in a crossover in the scaling behaviour of several structural observables. The scaling exponents change from those characteristic for Gaussian chains or rings in θ-solvents in the fully flexible limit, to values resembling fractal or ‘crumpled’ globular behaviour for very stiff SCNPs. We characterize domains in the SCNPs. These are weakly deformable regions that can be seen as disordered analogues of domains in disordered proteins. Increasing stiffness leads to bigger and less deformable domains. Surprisingly, the scaling behaviour of the domains is in all cases similar to that of Gaussian chains or rings, irrespective of the stiffness and degree of cross-linking. It is the spatial arrangement of the domains which determines the global structure of the SCNP (sparse Gaussian-like object or crumpled globule). Since intramolecular stiffness can be varied through the specific chemistry of the precursor or by introducing bulky side groups in its backbone, our results propose a new strategy to tune the global structure of SCNPs.

Efficient Homodifunctional Bimolecular Ring-Closure Method for Cyclic Polymers by Combining RAFT and Self-Accelerating Click Reaction.

An efficient metal-free homodifunctional bimolecular ring-closure method is developed for the formation of cyclic polymers by combining reversible addition-fragmentation chain transfer (RAFT) polymerization and self-accelerating click reaction. In this approach, α,ω-homodifunctional linear polymers with azide terminals are prepared by RAFT polymerization and postmodification of polymer chain end groups. By virtue of sym-dibenzo-1,5-cyclooctadiene-3,7-diyne (DBA) as small linkers, well-defined cyclic polymers are then prepared using the self-accelerating double strain-promoted azide-alkyne click (DSPAAC) reaction to ring-close the azide end-functionalized homodifunctional linear polymer precursors. Due to the self-accelerating property of DSPAAC ring-closing reaction, this novel method eliminates the requirement of equimolar amounts of telechelic polymers and small linkers in traditional bimolecular ring-closure methods. It facilitates this method to efficiently and conveniently produce varied pure cyclic polymers by employing an excess molar amount of DBA small linkers.

Factors Influencing the Formation of Single-Chain Polymeric Nanoparticles Prepared via Ring-Opening Polymerization

The development of single-chain polymeric nanoparticles (SCNP) has been of great scientific interest in recent years. Recently, we have developed a robust system to form SCNP at high polymer concentration (ca. 100 mg mL–1) via organocatalyzed ring-opening polymerization (ROP). In this approach, linear polymer precursors functionalized with pendent polymerizable caprolactone moieties undergo self-cross-linking in the presence of organocatalyst and alcohol initiator. Following on from our previous communication, we report in here a more in-depth fundamental investigation to better understand our system. For this, we have synthesized various linear random copolymer precursors (i.e., poly(oligo(ethylene glycol) acrylate) (P1), polystyrene (P2), and poly(methyl acrylate) (P3)) by reversible addition–fragmentation chain transfer (RAFT) polymerization, and their abilities to form SCNP at high polymer concentration were evaluated. It was found that only P1, which contains oligo(ethylene glycol) side chains, was able to successfully form SCNP while the other linear precursors resulted in multichain aggregates, indicating the importance of side-chain brushes in aiding SCNP formation at high polymer concentration. Furthermore, we tested several multifunctional alcohol initiators (mono-, di-, and tetrahydroxy) and found that the initiator structure has no effect on the SCNP formation process. In addition, we investigated the effect of initiator concentration and observed that the particle size can be reduced (from 7.6 to 6.6 nm) when the initiator and linear precursor are in equimolar concentration. It is anticipated that the information derived from this study may lead to the development of new SCNP for targeted (bio)applications.

Photodegradable and size-tunable single-chain nanoparticles prepared from a single main-chain coumarin-containing polymer precursor

A polyester bearing coumarin moieties in the main chain was used to prepare photodegradable single-chain nanoparticles (SCNPs) of variable sizes. While the intra-chain photodimerization of the chromophore determines the size of SCNPs, the photocleavage occurring under UV irradiation at a different wavelength breaks down the ultra-small nanoparticles.

Injectable and tunable poly(ethylene glycol) analogue hydrogels based on poly(oligoethylene glycol methacrylate)

Injectable PEG-analogue hydrogels based on poly(oligoethylene glycol methacrylate) have been developed based on complementary hydrazide and aldehyde reactive linear polymer precursors. These hydrogels display the desired biological properties of PEG, form covalent networks in situ following injection, and are easily modulated for improved control over their functionality and physiochemical properties.

Surfactant-Free Synthesis of Biodegradable, Biocompatible, and Stimuli-Responsive Cationic Nanogel Particles

Nanogels have attracted much attention lately because of their many potential applications, including as nanocarriers for drug and gene delivery. Most nanogels reported previously, however, are not biodegradable, and their synthesis often requires the use of surfactants. Herein we report a surfactant-free method for the preparation of biodegradable, biocompatible, and stimuli-responsive cationic nanogels. The nanogels were synthesized by simply coaservating linear polymer precursors in mixed solvents followed by in situ cross-linking with homobifunctional cross-linkers. The versatility of this approach has been demonstrated by employing two different polymers and various cross-linkers to prepare nanogel particles with diameters ranging from 170 to 220 nm. Specifically, disulfide-containing tetralysine (TetK)- and oligoethylenimine (OEI)-based prepolymers were prepared and the subsequent nanogels were formed by covalently cross-linking the polymer coacervate phase. Nanogel particles are responsive to pH changes, increasing in size and zeta-potential with concomitant lowering of solution pH. Furthermore, as revealed by AFM imaging, nanogel particles were degradable in the presence of glutathione at concentrations similar to those in intracellular environment (10 mM). Both the nanogel and the polymer precursors were determined to exhibit minimal cytotoxicity against fibroblast 3T3 cells by flow cytometric analyses and fluorescent imaging. This study demonstrates a new surfactant-free method for preparing biodegradable, biocompatible, and stimuli-responsive nanogels as potential nanocarriers for the delivery of drugs and genes.

Size‐Tunable Polymeric Nanoreactors for One‐Pot Synthesis and Encapsulation of Quantum Dots

Hydrophilic polymeric nanoparticles are synthesized through a Bergman cyclization- mediated intramolecular chain collapse of structurally well-defined linear polymers, and then used as size-tunable nanoreactors to fabricate and encapsulate quantum dots in a one-pot reaction. Crystalline quantum dots are formed in all of these nanoreactors and visualized by transmission electron microscopy. Smaller nanoreactors produce one quantum dot each while larger nanoreactors form a number, resulting in fluorescence quenching. By controlling the molecular weight of the linear polymer precursor, a variable number of nanocrystals are fabricated and assembled in a single nanoreactor.

Organoboron star polymers via arm-first RAFT polymerization: synthesis, luminescent behavior, and aqueous self-assembly

The first examples of organoboron star polymers were prepared by arm-first RAFT polymerization using a novel luminescent organoboron crosslinker in combination with PS, PNIPAM, P4VP, and PNIPAM-b-PS as linear polymer precursors. Well-defined star architectures with a luminescent core were successfully obtained as confirmed by GPC-MALLS, NMR, DLS, and TEM analysis. The PNIPAM-b-PS stars are amphiphilic and undergo self-assembly in water with formation of super-aggregates that exhibit strong green fluorescence. The P4VP stars lend themselves to further functionalization at the periphery.

Interaction of poly(N-isopropylacrylamide) (pNIPAM) based nanoparticles and their linear polymer precursor with phospholipid membrane models

Poly(N-isopropylacrylamide) (pNIPAM) is a thermoresponsive polymer which has promising applications in nanomedicine for drug delivery. The cross-linking of pNIPAM based copolymer using the chain collapse method leads to the synthesis of pNIPAM based polymer nanoparticles. This study looks at the interaction of pNIPAM polymers and pNIPAM nanoparticles with biomembrane models of, (i) a dioleoyl phosphatidylcholine (DOPC) monolayer on a mercury (Hg) electrode and (ii) DOPC and dimyristoyl phosphatidylcholine (DMPC) vesicles. The following techniques were used to follow the interactions: Dynamic light scattering (DLS), differential scanning calorimetry (DSC), rapid cyclic voltammetry (RCV) and electrochemical impedance spectroscopy (EIS). Results showed that the polymers interacted more extensively than the nanoparticles with the phospholipid. The interaction of the polymer was more rapid and led to a polymer-phospholipid conjugate whereas the nanoparticle adsorbed on the phospholipid monolayer surface and penetrated the monolayer at longer contact times. The association of the linear polymer with the phospholipid can be related to the larger molecular area available with the pendant −Cl groups and the inherent polymeric flexibility compared to the nanoparticle structure. The apparent dissociation constant for nanoparticles–DOPC complex was Kd,app=1.67∗10−5±1.2∗10−6moldm−3. The apparent kinetic constant of nanoparticle penetration through the DOPC monolayer was k2,app=1.054∗10−2±9.1∗10−4s−1. It can be concluded therefore that the pNIPAM nanoparticle because of its lower affinity for phospholipids is more appropriate for medical applications.

Synthesis, purification, and characterization of “perfect” star polymers via “Click” coupling

The copper (I)-catalyzed azide-alkyne cycloaddition “click” reaction was successfully applied to prepare well-defined 3, 6, and 12-arms polystyrene and polyethylene glycol stars. This study focused particularly on making “perfect” star polymers with an exact number of arms, as well as developing techniques for their purification. Various methods of characterization confirmed the star polymers high purity, and the structural uniformity of the generated star polymers. In particular, matrix-assisted laser desorption ionization-time-of-flight mass spectrometry revealed the quantitative transformation of the end groups on the linear polymer precursors and confirmed their quantitative coupling to the dendritic cores to yield star polymers with an exact number of arms. In addition to preparing well-defined polystyrene and poly(ethylene glycol)homopolymer stars, this technique was also successfully applied to amphiphilic, PCL-b-PEG star polymers. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Cyclic Azobenzene-Containing Side-Chain Liquid Crystalline Polymers: Synthesis and Topological Effect on Mesophase Transition, Order, and Photoinduced Birefringence

A cyclic side-chain liquid crystalline polymer (SCLCP) bearing azobenzene mesogens, namely, poly{6-[4-(4-methoxyphenylazo)phenoxy]hexyl methacrylate} (PAzoMA), was successfully synthesized by using “click” cyclization of the linear polymer precursor with alkyne and azide end groups. Samples of cyclic-PAzoMA of various molecular weights were prepared, characterized, and studied in comparison with their linear counterparts. The results show that the topological constraint arising from the tortuosity of the ring structure and the absence of chain ends in cyclic-SCLCPs affects profoundly the liquid crystalline (LC) phase transitions (temperature, enthalpy, and entropy) of mesogenic side groups and that this topological effect is more prominent for smaller SCLCP rings. Moreover, the photoinduced anisotropy in films as a result of the trans−cis photoisomerization of azobenzene mesogens was investigated, and cyclic-PAzoMA was found to behave differently from linear-PAzoMA. On the one hand, the cyclic polymer exh...