Role of Micelle Size in Cell Transcytosis-Based Tumor Extravasation, Infiltration, and Treatment Efficacy.

Transcytosis-based active transport of cancer nanomedicine has shown great promise for enhancing its tumor extravasation and infiltration and antitumor activity, but how the key nanoproperties of nanomedicine, particularly particle size, influence the transcytosis remains unknown. Herein, we used a transcytosis-inducing polymer, poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), and fabricated stable OPDEA-based micelles with different sizes (30, 70, and 140 nm in diameter) from its amphiphilic block copolymer, OPDEA-block-polystyrene (OPDEA-PS). The study of the micelle size effects on cell transcytosis, tumor extravasation, and infiltration showed that the smallest micelles (30 nm) had the fastest transcytosis and, thus, the most efficient tumor extravasation and infiltration. So, the 7-ethyl-10-hydroxyl camptothecin (SN38)-conjugated OPDEA micelles of 30 nm had much enhanced antitumor activity compared with the 140 nm micelles. These results are instructive for the design of active cancer nanomedicine.

Alternating [1.1.1]Propellane-(Meth)Acrylate Copolymers: A New Class of Dielectrics with High Energy Density for Film Capacitors.

Polymer dielectrics with high energy density are of urgent demand in electric and electronic devices, but the tradeoff between dielectric constant and breakdown strength is still unsolved. Herein, the synthesis and molar mass control of three alternating [1.1.1]propellane-(meth)acrylate copolymers, denoted as P-MA, P-MMA, and P-EA, respectively, are reported. These copolymers exhibit high thermal stability and are semi-crystalline with varied glass transition temperatures and melting temperatures. The rigid bicyclo[1.1.1]pentane units in the polymer backbone promote the orientational polarization of the polar ester groups, thus enhancing the dielectric constants of these polymers, which are 4.50 for P-EA, 4.55 for P-MA, and 5.11 for P-MMA at 10 Hz and room temperature, respectively. Moreover, the high breakdown strength is ensured by the non-conjugated nature of bicyclo[1.1.1]pentane unit. As a result, these copolymers show extraordinary energy storage performance; P-MA exhibits a discharge energy density of 9.73 J cm-3 at 750 MV m-1 and ambient temperature. This work provides a new type of promising candidates as polymer dielectrics for film capacitors, and offers an efficient strategy to improve the dielectric and energy storage properties by introducing rigid non-conjugated bicyclo[1.1.1]pentane unit into the polymer backbone.

Synthesis and Post-Functionalization of Poly(conjugated ester)s Based on 3-Methylene-1,5-dioxepan-2-one.

Poly(α-methylene ester)s are an attractive type of functional aliphatic polyesters that represent a platform for the fabrication of various biodegradable and biomedical polymers. Herein, we report the controlled ring-opening polymerization (ROP) of a seven-membered α-methylene lactone (3-methylene-1,5-dioxepan-2-one, MDXO) that was synthesized based on the Baylis-Hillman reaction. The chemoselective ROP of MDXO was catalyzed by diphenyl phosphate (DPP) at 60 °C or stannous octoate (Sn(Oct)2) at 130 °C, generating α-methylene-containing polyester (PMDXO) with a linear structure and easily tunable molar mass. The ring-opening copolymerization of MDXO with ε-caprolactone or 1,5-dioxepan-2-one was also performed under the catalysis of DPP or Sn(Oct)2 to afford copolymers with different compositions and sequence structures that are influenced by the kinds of monomers and catalysts. PMDXO is a slowly crystallizable polymer with a glass transition temperature of ca. -33 °C, and its melting temperature and enthalpy are significantly influenced by the thermal history. The thermal properties of the copolymers are dependent on their composition and sequence structure. Finally, the post-modification of PMDXO based on the thiol-Michael addition reaction was briefly explored using triethylamine as a catalyst. Given the optimized condition, PMDXO could be dually modified to afford biodegradable polyesters with different functionalities.

Fluoride-Triggered Self-Degradation of Poly(2,4-disubstitued 4-hydroxybutyric acid) Derivatives.

Self-immolative polymers are a special kind of degradable polymers that depolymerize into small molecules through a cascade of reactions upon stimuli-triggered cleavage of the polymer chain ends. This work reports the design and synthesis of a fluoride-triggered self-immolative polyester. A 2,4-disubstitued 4-hydroxy butyrate is first confirmed to quickly cyclize in solution to form a γ-butyrolactone derivative. Then, the Passerini three component reaction (P-3CR) of an AB dimer (A: aldehyde, B: carboxylic acid) with tert-butyl isocyanide or oligo(ethylene glycol) isocyanide affords two poly(2,4-disubstitued 4-hydroxybutyrate) derivatives (P2 and P3). Two silyl ether end-capped polymers (P4 and P5) are abtained from P2 and P3, and their degradation in solution is examined by NMR spectrum and size exclusion chromatography. Polymers P4 and P5 are stable in the absence of tetrabutylammonium fluoride (TBAF), while in the presence of TBAF, the molar masses of P4 and P5 gradually decrease with time together with the increase of the amount of formed 2,4-disubstitued γ-butyrolactone. The depolymerization mechanism is proposed. The first step is the fast removal of the silyl ether by fluoride. Then, the released hydroxyl group initiates the quick head-to-tail depolymerization of the polyester via intramolecular cyclization.

Redox-Responsive Fluorescent Polycarbonates Based on Selenide for Chemotherapy of Triple-Negative Breast Cancer.

Transient increase of reactive oxygen species (ROS) is vital for some physiological processes, whereas the chronic and sustained high ROS level is usually implicated in the inflammatory diseases and cancers. Herein, we report the innovative redox-responsive theranostic micellar nanoparticles that are able to load anticancer drugs through coordination and hydrophobic interaction and to fluorescently monitor the intracellular redox status. The nanoparticles were formed by the amphiphilic block copolymers composed of a PEG segment and a selenide-containing hydrophobic polycarbonate block with a small fraction of coumarin-based chromophore. Under the alternative redox stimulation that might be encountered in the physiological process of some healthy cells, these nanoparticles underwent the reversible changes in size, morphology, and fluorescence intensity. With the assistance of small model compounds, we clarified the chemistry behind these changes, that is, the redox triggered reversible transformation between selenide and selenoxide. Upon the monotonic oxidation similar to the sustained high ROS level of cancer cells, the nanoparticles could be disrupted completely, which was accompanied by the drastic decrease in fluorescence. Cisplatin and paclitaxel were simultaneously coloaded in the nanoparticles with a moderate efficacy, and the coordination between selenide and platinum improved the stability of the drug-loaded nanoparticles against dilution. The naked nanoparticles are cytocompatible, whereas the dual drug-loaded nanoparticles exhibited a concentration dependent and synergistic cytotoxicity to triple-negative breast cancer (TNBC) cells. Of importance, the drug-loaded nanoparticles are much more toxic to TNBC cells than to normal cells due in part to ROS overproduction in the former cell lines.

ROS-Responsive Chalcogen-Containing Polycarbonates for Photodynamic Therapy.

Reactive oxygen species (ROS)-responsive polymers have attracted attention for their potential in photodynamic therapy. Herein, we report the ROS-responsive aliphatic polycarbonates prepared by the ring-opening polymerization (ROP) of three six-membered cyclic carbonate monomers with ethyl selenide, phenyl selenide or ethyl telluride groups. Under catalysis of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), all three monomers underwent the controlled anionic ROP, showing a feature of equilibrium polymerization due to the bulky effect of 5,5-disubstituents. With PEG macroinitiator, three series amphiphilic block copolymers were prepared. They could form spherical nanoparticles of ∼100 nm, which were stable in neutral phosphate buffer but dissociated rapidly under triggering of H2O2. We studied the H2O2-induced oxidation profiles of selenide- or telluride-containing small molecules by 1H NMR and revealed the factors that affect the oxidation kinetics and products. On this basis, the oxidative degradation mechanism of the copolymer nanoparticles has been clarified. Under the same oxidative condition, the telluride-containing nanoparticle degraded with the fastest rate while the phenyl selenide-based one degraded most slowly. These ROS-responsive nanoparticles could load photosensitizer chlorin e6 (Ce6) and anticancer drug doxorubicin (DOX). Under red light irradiation, Ce6-sensitized production of 1O2 that triggered the degradation of nanoparticles, resulting in an accelerated payload release. In vitro cytotoxicity assays demonstrate that the nanoparticles coloaded with DOX and Ce6 exhibited a synergistic cell-killing effect to MCF-7 cells, representing a novel responsive nanoplatform for PDT and/or chemotherapy.

Oxidation-Responsive Aliphatic Polycarbonates from N-Substituted Eight-Membered Cyclic Carbonate: Synthesis and Degradation Study.

Oxidation-responsive aliphatic polycarbonates represent a promising branch of functional biodegradable polymers. This paper reports the synthesis and ring-opening polymerization (ROP) of an eight-membered cyclic carbonate possessing phenylboronic pinacol ester (C3) and the H2 O2 -triggered degradation of its polymer (PC3). C3 is prepared from the inexpensive and readily available diethanolamine with a moderate yield and undergoes the well-controlled anionic ROP with a living character under catalysis of 1,8-diazabicyclo[5.4.0]undec-7-ene. It can also be copolymerized with l-lactide, trimethylene carbonate, and 5-ter-butyloxycarbonylamino trimethylene carbonate, affording the copolymers with a varied distribution of the repeating units. To clearly demonstrate the oxidative degradation mechanism of PC3, this paper first investigates the H2 O2 -induced decomposition of small-molecule model compounds by proton nuclear magnetic resonance (1 H NMR). It is found that the adduct products formed by the in-situ-generated secondary amines and p-quinone methide (QM) are thermodynamically unstable and can decompose slowly back to QM and the amines. On this basis, this paper further studies the H2 O2 -accelerated degradation of PC3 nanoparticles that are prepared by the o/w emulsion method. A sequential process of oxidation of the phenylboronic ester, 1,6-elimination of the in-situ-generated phenol, releasing CO2 and intramolecular cyclization or isomerization is proposed as the degradation mechanism of PC3.

Oxidation-Responsive Polymer-Drug Conjugates with a Phenylboronic Ester Linker.

Polymer-drug conjugates have attracted great interest as one category of various promising nanomedicines due to the advantages of high drug-loading capacity, negligible burst release, and improved pharmacokinetics as compared with the small molecular weight drugs or the polymeric delivery systems with physically encapsulated drugs. Herein, a new type of oxidation-responsive polymer-drug conjugates composed of a poly(ethylene glycol) (PEG) block and a hydrophobic polyacrylate block to which Naproxen is attached through a phenylboronic ester linker is reported. The amphiphilic block copolymers are synthesized through the reversible addition-fragmentation chain transfer polymerization of the Naproxen-containing acrylic monomer using a PEG chain transfer agent. In neutral aqueous buffer, the conjugates formed nanoparticles with diameters of ≈150-300 nm depending on the length of the hydrophobic segment. The dynamic covalent bond of the phenylboronic ester is stabilized due to the hydrophobic microenvironment inside the nanoparticles. Upon exposure to H2 O2 , the phenylboronic ester is oxidized rapidly into the phenol derivative which underwent a 1,6-elimination reaction, releasing the intact Naproxen. The rate of drug release is influenced by the concentration of H2 O2 and the hydrophobic block length. This type of oxidation-responsive polymer-drug conjugate is feasible for other drugs containing hydroxyl group or amino group.

Shell-sheddable, pH-sensitive supramolecular nanoparticles based on ortho ester-modified cyclodextrin and adamantyl PEG.

We report a new type of pH-sensitive supramolecular aggregates which possess a programmable character of sequential dePEGylation and degradation. As a platform of designing and building multifunctional supramolecular nanoparticles, a family of 6-OH ortho ester-modified ß-cyclodextrin (ß-CD) derivatives have been synthesized via the facile reaction between ß-CD and cyclic ketene acetals with different alkyl lengths. These asymmetric acid-labile ß-CD derivatives formed amphiphilic supramolecules with adamantane-modified PEG through host-guest interaction in polar solvents such as ethanol. The supramolecules can self-assemble in water to form acid-labile supramolecular aggregates. The results of TEM and light scattering measurements demonstrate that the size and morphology of the aggregates are influenced by the alkyl or PEG length and the host-guest feed ratio. By carefully balancing the alkyl and PEG lengths and adjusting the host-guest ratio, well-dispersed vesicles (50-100 nm) or sphere-like nanoparticles (200-500 nm) were obtained. Zeta potential measurements reveal that these supramolecular aggregates are capable of being surface-functionalized via dynamic host-guest interaction. The supramolecular aggregates were stable at pH 8.4 for at least 12 h as proven by the (1)H NMR and LLS measurements. However, rapid dePEGylation occurred at pH 7.4 due to the hydrolysis of the ortho ester linkages locating at the interface, which resulted in aggregation of the dePEGylated hydrophobic inner cores. Upon further decreasing the pH to 6.4, the hydrophobic cores were further degraded due to the acid-accelerated hydrolysis of the ortho esters. The incubation stability of the acid-labile supramolecular aggregates in neutral buffer could be improved by incorporating hydrophobic poly(ε-caprolactone) into the core of the aggregates.

Glucose-responsive hydrogels based on dynamic covalent chemistry and inclusion complexation.

A novel glucose-responsive hydrogel system based on dynamic covalent chemistry and inclusion complexation was described. Hydrogels are formed by simply mixing the solutions of three components: poly(ethylene oxide)-b-poly vinyl alcohol (PEO-b-PVA) diblock polymer, α-cyclodextrin (α-CD) and phenylboronic acid (PBA)-terminated PEO crosslinker. Dynamic covalent bonds between PVA and PBA provide sugar-responsive crosslinking, and the inclusion complexation between PEO and α-CD can promote hydrogel formation and enhance hydrogel stability. The ratios of the three components have a remarkable effect on the gelation time and the mechanical properties of the final gels. In rheological measurements, the hydrogels are demonstrated to possess solid-like behaviour and good structural recovery ability after yielding. The sugar-responsiveness of the hydrogels was examined by protein loading and release experiments, and the results indicate that this property is also dependent on the compositions of the gels; at a proper component ratio, a new glucose-responsive hydrogel system operating at physiological pH can be obtained. The combination of good biocompatibility of the three components and the easy preparation of hydrogels with tunable glucose-responsiveness may enable an alternative design of hydrogel systems that finds potential applications in biomedical and pharmaceutical fields, such as treatment of diabetes.

Combination of ATRA and ATRC for the synthesis of periodic vinyl copolymers.

A new approach to periodic vinyl copolymers via combination of atom transfer radical addition (ATRA) and atom transfer radical coupling (ATRC) is reported. The two examples are methyl methacrylate (MMA) and styrene (St) periodic copolymer (P(SMMS)) and acrylonitrile (AN) and St periodic copolymer (P(SAAS)). First, two monomer sequence units (MSU) with built-in sequence, SMMS and SAAS, are synthesized through the controlled ATRA of two ATRP initiators with St. Then, the ATRC of SMMS and SAAS are conducted at high radical conditions to generate two types of high-molecular-weight copolymers, P(SMMS) and P(SAAS). Though side reactions can not be totally avoided, characterizations of the polymer structure with a variety of means confirm that the main chain structures of P(SMMS) and (PSAAS) are predominantly with the periodic sequences from the MSUs. Attempts to suppress the side reactions are successful via the MNP-mediated ATRC of SMMS and SAAS.

Synthesis and antibacterial properties of fluorinated biodegradable cationic polyesters.

Antimicrobial peptide-mimicking antibacterial polymers represent a practical strategy to conquer the ever-growing threat of antimicrobial resistance. Herein, we report the syntheses and antibacterial performance of degradable amphiphilic cationic polyesters containing pendent quaternary ammonium motifs and hydrophobic alkyl or fluoroalkyl groups. These polyesters were conveniently prepared from poly(3-methylene-1,5-dioxepan-2-one) via highly efficient one-pot successive thiol-Michael addition reactions. The antibacterial activity of these polyesters against S. aureus and E. coli and their hemolytic activity toward red blood cells were evaluated; some of them showed moderate antibacterial activity and selectivity against Gram-positive S. aureus. The membrane disruption mechanism of these cationic polyesters was briefly explored by monitoring the bacteria killing kinetics and SEM observations. Moreover, the effects of cationic/hydrophobic ratio and the incorporation of fluoroalkyl groups on the antibacterial activity and selectivity of the polyesters were demonstrated.

Polymersomes from dual responsive block copolymers: drug encapsulation by heating and acid-triggered release.

A series of well-defined thermoresponsive diblock copolymers (PEO45-b-PtNEAn, n=22, 44, 63, 91, 172) were prepared by the atom transfer radical polymerization of trans-N-(2-ethoxy-1,3-dioxan-5-yl) acrylamide (tNEA) using a poly(ethylene oxide) (PEO45) macroinitiator. All copolymers are water-soluble at low temperature, but upon quickly heating to 37 °C, laser light scattering (LLS) and transmission electron microscopy (TEM) characterizations indicate that these copolymers self-assemble into aggregates with different morphologies depending on the chain length of PtNEA and the polymer concentration; the morphologies gradually evolved from spherical solid nanoparticles to a polymersome as the degree of polymerization ("n") of PtNEA block increased from 22 to 172, with the formation of clusters with rod-like structure at the intermediate PtNEA length. Both the spherical nanoparticle and the polymersome are stable at physiological pH but susceptible to the mildly acidic medium. Acid-triggered hydrolysis behaviors of the aggregates were investigated by LLS, Nile red fluorescence, TEM, and (1)H NMR spectroscopy. The results revealed that the spherical nanoparticles formed from PEO45-b-PtNEA44 dissociated faster than the polymersomes of PEO45-b-PtNEA172, and both aggregates showed an enhanced hydrolysis under acidic conditions. Both the spherical nanoparticle and polymersome are able to efficiently load the hydrophobic doxorubicin (DOX), and water-soluble fluorescein isothiocyanate-lysozyme (FITC-Lys) can be conveniently encapsulated into the polymersome without using any organic solvent. Moreover, FITC-Lys and DOX could be coloaded in the polymersome. The drugs loaded either in the polymersome or in the spherical nanoparticle could be released by acid triggering. Finally, the DOX-loaded assemblies display concentration-dependent cytotoxicity to HepG2 cells, while the copolymers themselves are nontoxic.

Facile synthesis of acid-labile polymers with pendent ortho esters.

This work presents a facile approach for preparation of acid-labile and biocompatible polymers with pendent cyclic ortho esters, which is based on the efficient and mild reactions between cyclic ketene acetal (CKA) and hydroxyl groups. Three CKAs, 2-ethylidene-1,3-dioxane (EDO), 2-ethylidene-1,3-dioxolane (EDL), and 2-ethylidene-4- methyl-1,3-dioxolane (EMD) were prepared from the corresponding cyclic vinyl acetals by catalytic isomerization of the double bond. The reaction of CKAs with different alcohols and diols was examined using trace of p-toluenesulfonic acid as a catalyst. For the monohydroxyl alcohols, cyclic ortho esters were formed by simple addition of the hydroxyl group toward CKAs with ethanol showing a much greater reactivity than iso-propanol. When 1,2- or 1,3-diols were used to react with the CKAs, we observed the isomerized cyclic ortho esters besides the simple addition products. Biocompatible polyols, that is, poly(2-hydroxyethyl acrylate) (PHEA) and poly(vinyl alcohol) (PVA) were then modified with CKAs, and the degree of substitution of the pendent ortho esters can be easily tuned by changing feed ratio. Both the small molecule ortho esters and the CKA-modified polymers demonstrate the pH-dependent hydrolysis profiles, which depend also on the chemical structure of the ortho esters as well as the polymer hydrophobicity.

Reduction-degradable linear cationic polymers as gene carriers prepared by Cu(I)-catalyzed azide-alkyne cycloaddition.

Linear reduction-degradable cationic polymers with different secondary amine densities (S2 and S3) and their nonreducible counterparts (C2 and C3) were synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) step-growth polymerization of the dialkyne-oligoamine monomers and the diazide monomers. These polymers were studied with a goal of developing a set of new gene carriers. The buffering capacity and DNA binding ability of these polymers were evaluated by acid-base titration, gel retardation, and ethidium bromide (EB) exclusion assay. The polymers with lower amine density exhibit a weaker DNA-binding ability but a stronger buffering capacity in the range of pH 5.1 and 7.4. Particle size and zeta-potential measurements demonstrate that the polymers with higher amine density condense pDNA to form polyplexes with smaller sizes, while the disulfide bond in the backbone shows a negative effect on the condensing capability of the polymers, resulting in the formation of polyplexes with large size and nearly neutral surface. The reduction-sensitive polyplexes formed by polymer S2 or S3 can be disrupted by dithiothreitol (DTT) to release free DNA, which has been proven by the combination of gel retardation, EB exclusion assay, particles sizing, and zeta potential measurements. Cell viability measurements by MTT assay demonstrate that the reduction-degradable polymers (S2 and S3) have little cytotoxicity while the nonreducible polymers (C2 and C3) show obvious cytotoxicity, in particular, at high N/P ratios. In vitro transfection efficiencies of these polymers were evaluated using EGFP and luciferase plasmids as the reporter genes. Polymers S3 and S2 show much higher efficiencies than the nonreducible polymers C3 and C2 in the absence of 10% serum; unexpectedly, the lowest transfection efficiency has been observed for polymer S3 in the presence of serum.

ROS-Activated Ratiometric Fluorescent Polymeric Nanoparticles for Self-Reporting Drug Delivery.

Reactive oxygen species (ROS)-responsive theranostic nanomedicines have attracted wide interest in recent years because ROS stress is implicated in some pathological disorders such as inflammatory diseases and cancers. In this article, we report a kind of innovative ROS-responsive theranostic polymeric nanoparticles that are able to load hydrophobic drugs and to fluorescently self-report the in vitro or intracellular drug release under ROS triggering. The fluorescent nanoparticles were formed by amphiphilic block copolymers consisting of a poly(ethylene glycol) (PEG) segment and an oxidation-responsive hydrophobic block. The copolymers with different hydrophobic block lengths were synthesized by the atom transfer radical polymerization of a phenylboronic ester-containing acrylic monomer with a small fraction of a ROS-activatable 1,8-naphthalimide-based fluorescent monomer, using PEG-Br as the macroinitiator. The copolymer nanoparticles were stable in neutral phosphate buffer but degraded upon H2O2 triggering, with the degradation rate depending on the hydrophobic block length and the concentration of H2O2. The degradation of nanoparticles was accompanied by a colorimetric change of the fluorophore from blue to green, which affords the nanoparticles the ability to detecting H2O2 by a ratiometric fluorescent approach. Moreover, the nanoparticles could encapsulate doxorubicin (DOX) and the H2O2-triggered DOX release was well associated with the change in ratiometric fluorescence. Confocal laser scanning microscope results reveal that the fluorescent nanoparticles were internalized into A549 cells through the endocytosis pathway. The ROS-stimulated degradation of the nanoparticles and intracellular DOX release and the fate of the degraded polymers could be monitored by ratiometric fluorescent imaging. Finally, the naked nanoparticles and the degradation products are cytocompatible, whereas the DOX-loaded ones exhibit concentration-dependent cytotoxicity. Of importance, the stimulation with exogenous H2O2 or lipopolysaccharide enhanced obviously the cell-killing capability of the DOX-loaded nanoparticles because of the ROS-enhanced intracellular DOX release.

Self-assembly and supramolecular transition of poly(amidoamine) dendrons focally modified with aromatic chromophores.

Three novel series of amphiphiles based on poly(amidoamine) dendrons (from G1 to G3) and having different aromatic chromophores (Cz I, Cz II, and Py) at the focal point were synthesized and studied for their self-assembly behavior in aqueous solution by using electronic microscopies (i.e., SEM and TEM), UV-vis, fluorescence, IR, and (1)H NMR spectroscopy. It was found that the generation of dendrons affected significantly the self-assembly of these amphiphiles in aqueous solution and the morphological structures of the resulting assemblies depended greatly on the architecture of the focal chromophores. As a result, the first generation of dendrons assembled readily into vesicles at low concentrations. These vesicular structures subsequently fused to form a stable tubular structure. Similar tubular structures could also be directly obtained through self-assembly of these amphiphilic dendrons at high concentrations. X-ray investigations showed that the resulting tubules possessed a lamellar structure. A head-to-head packing model of amphiphilic dendrons in the assemblies was proposed.

Supersensitive Oxidation-Responsive Biodegradable PEG Hydrogels for Glucose-Triggered Insulin Delivery.

Reactive oxygen species (ROS)-responsive polymers and hydrogels represent an emerging family of intelligent materials owing to the key functions of ROS in physiological processes or pathological diseases. Nonetheless, the weaknesses such as low sensitivity, slow response, instability, and low mechanical strength are associated with the limited ROS-responsive polymeric or supramolecular hydrogels. In this study, a novel type of oxidation-responsive degradable hydrogels was fabricated by the redox-initiated radical polymerization of a 4-arm-poly(ethylene glycol) (PEG) acrylic macromonomer that possesses a H2O2-cleavable phenylboronic acid linker in each of the arms. The macroscopic hydrogels have the features of good cytocompatibility, moderate mechanical strength, and fast response toward H2O2 of low concentration, owing to the covalently cross-linked hydrophilic PEG network and high sensitivity of the linker. They could encapsulate biomacromolecules, such as insulin and glucose oxidase (GOx), with high efficacy, affording a new glucose-responsive insulin-delivery platform on the basis of enzymatic transformation of a biochemical signal (glucose) into an oxidative stimulus (H2O2). Interestingly, in vitro results demonstrate that the same GOx-loaded hydrogel exhibited disparate degradation modes under different triggering molecules, that is, bulk degradation by H2O2 and surface erosion by glucose. Moreover, compared to the macroscopic hydrogel, the nanogel with a diameter of ∼160 nm prepared by inverse emulsion polymerization showed a much higher degradation rate even under triggering of 20 µM H2O2, a pathologically available concentration in vivo.

Facile synthesis of photo-cleavable polymers via Passerini reaction.

Passerini three-component reaction and multicomponent polymerization (MCP) were demonstrated to be facile methods for the preparation of photo-cleavable polymers, photo- and redox-dually cleavable polymers, as well as block copolymers.

Preparation and aggregation behavior of mannose-terminated poly(ethylene glycol)-b-poly(L-leucine) in water.

Amphiphilic diblock copolymers composed of poly(ethylene glycol) (PEG) and poly(l-leucine) (PLeu) with mannose at the chain end of PEG were synthesized by a combination of ring-opening polymerization (ROP) and click chemistry. First, an α-azido, ω-amino PEG (N(3)-PEG-NH(2)) was synthesized and converted to the corresponding amine hydrochloride (N(3)-PEG-NH(2)·HCl), which was used as a macroinitiator to initiate the ROP of L-leucine-N-carboxyanhydride (Leu-NCA), yielding three amphiphilic block copolymers with different chain lengths of PLeu (N(3)-PEG-b-PLeu). Then, click chemistry of the alkynyl mannose with N(3)-PEG-b-PLeu anchored a mannose moiety to the PEG chain end of the copolymer. The self-assembly behavior of these copolymers in water was investigated using transmission electron microscopy (TEM), laser light scattering (LLS) and circular dichroism (CD). Depending on the copolymer composition and the initial concentration of the copolymer in organic solvent, different morphologies (e.g. spherical micelle, wormlike micelle) were observed. The aggregation behavior was demonstrated to be controlled by secondary structure formation and the hydrophobic interactions of the PLeu segments. With mannose moieties on the surface of the aggregates, these aggregates could bind reversibly the lectin Concanavalin A (Con A).