A Transformable and Bulky Methacrylate Monomer That Enables the Synthesis of an MMA-nBA Alternating Copolymer: Sequence-Dependent Self-Healing Properties.

In this study, we designed a methacrylate molecule with an alkyl-substituted trichloro salicylic acid pendant as a transformable bulky monomer to enable the synthesis of an alternating copolymer of methyl methacrylate (MMA) and n-butyl acrylate (nBA). The adamantyl-substituted methacrylate monomer (1-Ad) showed very low homopolymerization propensity in radical polymerizations, but afforded the alternating copolymer with nBA via copolymerization. The 1-Ad units in the resultant copolymer were quantitatively and selectively transformed into MMA via transesterification with methanol to yield the alternating copolymer of MMA and nBA. Its alternating sequence was clearly demonstrated by a structural analysis via 13 C NMR spectroscopy as well as the low reactivity ratios for the 1-Ad and nBA pair. Finally, we verified the superior self-healing ability of the alternating copolymer compared to that of the corresponding 1 : 1 statistical copolymer.

Photoinduced free radical-releasing systems and their anticancer properties.

Cancer has been a serious threat and impact on the health and life of human. Phototherapy is considered as a promising therapeutic method to replace the traditional treatment in clinic owing to its noninvasive nature and high efficiency. Photoinitiators have long been used in the field of photopolymerization; however, few studies have been carried out on their potential as anticancer agents under light irradiation. In this study, the effect of a photoinitiator, diphenyl (2, 4, 6-trimethylbenzoyl) phosphine oxide (TPO), on breast cancer is investigated and the related mechanism is elucidated. It is found that TPO has low dark toxicity and significant phototoxicity. TPO can inhibit cell growth and development and promote cell apoptosis through a mitochondrial pathway under light irradiation. Further studies show that cell apoptosis is induced by free radicals produced from the photolysis of TPO to activate JNK phosphorylation. Overall, we identify the antitumor effects of TPO in vitro for the first time, and provides a proof of concept for its application as a novel photolatent therapeutic drug.

Degradable Hydrogel Adhesives with Enhanced Tissue Adhesion, Superior Self-Healing, Cytocompatibility, and Antibacterial Property.

Degradable hydrogel adhesives with multifunctional advantages are promising to be candidates as hemostatic agents, surgical sutures, and wound dressings. In this study, hydrogel adhesives are constructed by catechol-conjugated gelatin from natural resource, iron ions (Fe3+ ), and a synthetic polymer. Specifically, the latter is prepared by the radical ring-opening copolymerization of a cyclic ketene acetal monomer 5,6-benzo-2-methylene-1,3-dioxepane and N-(2-ethyl p-toluenesulfonate) maleimide. By the incorporation of ester bonds in the backbone and the combination with quaternary ammonium salt pendants in the polymer, it exhibits excellent degradability and antibacterial property. Remarkably, doping the synthetic polymer into the 3,4-dihydroxyphenylacetic acid-modified gelatin network forms a semi-interpenetrating polymer network which can effectively improve the rigidity, tissue adhesion, and antibacterial property of fabricated hydrogel adhesives. Moreover, non-covalent bonds from coordination interaction between catechol and Fe3+ contribute to the fast self-healing of the developed hydrogel adhesives. These hydrogel adhesives with the multiple merits including the degradability, enhanced tissue adhesion, superior self-healing, good cytocompatibility, and antibacterial property show the great potential to be used as tissue adhesives in biomedical fields.

Cytotoxic and cytocompatible comparison among seven photoinitiators-triggered polymers in different tissue cells.

Photoinitiators (PIs) are widely used for photopolymerization in industrial area and recently paid close attention to in biomedical field. However, there are few reports on their toxicity to human health. Here we explored cytotoxicity and cytocompatibilty of seven commercial and industrial-used PIs for developing their potential clinical application. Phenylbis(acyl) phosphine oxides (BAPO), 2-Benzyl-2-(dimethylamino)-4'-morpholinobutyrophenone (369), 4,4'-Bis(diethylamino) benzophenone (EMK), Diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide (TPO), and 2-Isopropylthioxanthone (ITX) caused different extent cytotoxicities to four tissue types of cells at the concentrations of 1 to 50 µM under a non-irradiation condition, of which the BAPO cytotoxicity was the highest, whereas Ethyl (2,4,6-trimethylbenzoyl) phenylphosphinate (TPOL) and Methyl benzoylformate (MBF) displayed the lowest cellular toxicity. The cell lines and primary cells appeared highly sensitive to BAPO toxicity, the primary lymphocytes relatively to photoinitiator 369 (369) and EMK toxicities, LO2 cells to EMK and TPO toxicities, the primary lymphocytes and HUVEC-12 cells to MBF toxicity, but only HEK293T cells not to 369 toxicity. Furthermore, these PIs led to increasing cytotoxicity to different extents after exposure to 455 nm blue light, which is consistent with non-irradiation tendency. All the cells presented low sensitivity to TPOL and MBF, of which TPOL-triggered polymer is dramatically superior in its cytocompatibility to MBF, and in its transparency to clinically exclusively-used camphorquinone (CQ). The novel findings indicate that BAPO is the most toxic among the seven PIs, but TPOL and MBF are the least toxic, directing their development and application. Combined their triggered polymer cytocompatibility and color with reported deep curing efficiency, TPOL is more promising to be applied especially to clinical practice.

Backbone-Degradable Polymers via Radical Copolymerizations of Pentafluorophenyl Methacrylate with Cyclic Ketene Acetal: Pendant Modification and Efficient Degradation by Alternating-Rich Sequence.

This work deals with syntheses of backbone-degradable polymers via the radical copolymerization of pentafluorophenyl methacrylate (PFMA) with 5,6-benzo-2-methylene-1,3-dioxepane (BMDO), which undergoes ring-opening propagation to afford an ester-bonded backbone. The combination of the electron-deficient methacrylate with the electron-rich cyclic monomer allowed high crossover copolymerization, and the electronic effect was clarified by the comparison with the copolymerization of methyl methacrylate (MMA) and BMDO. The PFMA units of the resultant copolymer underwent quantitative alcoholysis or aminolysis transformation into methacrylate or methacrylamide units along with the pendant functionalization. The alternating-rich sequence was achieved by feeding an excess ratio of BMDO, which was supported by MALDI-TOF-MS of the copolymer obtained by the RAFT copolymerization. The methanolysis-transformed copolymer carrying MMA units was decomposed under basic condition, and the degradation efficiency was superior to that of the copolymer obtained via radical copolymerization of MMA with BMDO because of the alternating-rich sequence.

Peripheral RAFT Polymerization on a Covalent Organic Polymer with Enhanced Aqueous Compatibility for Controlled Generation of Singlet Oxygen.

A covalent organic polymer (COP) is prepared by crosslinking the photosensitizer 4,4',4'',4'''-(porphyrin-5,10,15,20-tetrayl)tetraaniline (TAPP) with 4,4'-(anthracene-9,10-diyl)dibenzoic acid (ADDA) via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/4-dimethylaminopyridine coupling. The COP is further modified with a hydrophilic polymer, poly(poly(ethylene glycol) methyl ether methacrylate) by grafting-from reversible-addition-fragmentation chain transfer (RAFT) polymerization to enhance its solubility in various solvents. The modified COP can bind singlet oxygen through the formation of endoperoxide by ADDA upon the exposure to red light irradiation. Singlet oxygen can be then released via the photodynamic mechanism or the cycloreversion by endoperoxide when heated at 110 °C. These results open new possibilities for simultaneous generation of singlet oxygen by the photodynamic route and singlet oxygen carriers, demonstrating promise for treating hypoxic tumors.

Recent advances in light-regulated non-radical polymerisations.

Light is one of the non-invasive stimuli which can be used in the spatiotemporal control of chemical reactions. Over the past decade, light has found wide applications in polymer science such as polymer synthesis, release of small molecules from polymers and polymeric photosensors etc. Reviews on light-regulated polymerisations have predominately focused on the free radical process. However, the marriage of light to non-radical polymerisations, e.g. ionic, ring-opening, metathesis, step-growth and supramolecular photopolymerisations, has also spurred tremendous research interest to develop materials. These kinds of non-radical photopolymerisations, compared to the free radical approach, are advantageous in overcoming oxygen inhibition, accessing novel polymer structures and fabricating degradable and dynamic polymers. The relevant light-regulation techniques involved in these polymerisations are usually based on photolinking reactions and photoactivation of latent species. These species produce initiators, catalysts or monomers upon light irradiation to manipulate polymer formation. These techniques have been successfully implemented to adapt conditional polymerisations under light, discover novel polymerisation methods and precisely control polymer structures. This review aims to highlight the recent progress in light-regulated non-radical polymerisations in the development of polymerisation techniques as well as the applications in materials science, emphasising the remaining challenges and promising perspective in the relevant fields.

A new 3D organotypic model of ovarian cancer to help evaluate the antimetastatic activity of RAPTA-C conjugated micelles.

INTRODUCTION: Ovarian cancer is often diagnosed at a late stage, when disease has spread to extra-pelvic regions such as the omentum. There are limited treatment options available for women with extensive disease and tumours often relapse after current chemotherapy regimens. Therefore, novel drugs should be investigated for the treatment of ovarian cancer. A 3D organotypic model of ovarian cancer can provide a specific platform for the evaluation of nano-drugs. Using patient derived primary cells, the 3D model mimics the ovarian metastatic microenvironment allowing efficient and reproducible testing of many nanoparticles. Dichlororuthenium(ii) (p-cymene) (1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) conjugated fructose-micelles have been used as the promising nano-drug for the treatment of metastatic cancer. Therefore we aimed to investigate the anti-metastatic properties of RAPTA-C conjugated micelles in ovarian cancer metastasis. METHODS: Ovarian cancer cell adhesion and invasion into a model of omentum were analyzed with and without RAPTA-C conjugated micelles in a range of conditions. RESULTS: We observed that RAPTA-C showed low general toxicity to both primary healthy and cancer cell lines. RAPTA-C loaded micelles significantly enhance the internalization of ruthenium inside the cells compared to free drugs. RAPTA-C did not affect adhesion of OVCAR4 ovarian cancer cells; however, it significantly inhibited invasion of these cells within the omentum model, either in its free form or as cargos inside the micelles. However, when OVCAR4 were treated prior to implantation, invasion was not inhibited. CONCLUSION: A 3D organotypic model provides a clinically relevant and simple method to evaluate the efficiency of nano-drug treatment of ovarian cancer. The ability to inhibit metastasis of RAPTA-C delivered in fructose coated nanoparticles was investigated for the first time via this model. These results provide a good basis to continue the development of this nano-drug in vivo.

Delivery of Amonafide from Fructose-Coated Nanodiamonds by Oxime Ligation for the Treatment of Human Breast Cancer.

The introduction of a strategy toward polymer/nanodiamond hybrids with high polymer grafting density and accessible polymer structural characterization is of critical importance for nanodiamonds' surface modification and bioagent attachment for their biomedical application. Here, we report a glycopolymer/nanodiamond hybrid drug delivery system, which was prepared by grafting amonafide-conjugated glycopolymers onto the surface of nanodiamonds via oxime ligation. Poly(1-O-methacryloyl-2,3:4,5-di-O-isopropylidene-ß-d-fructopyranose)-b-poly(3-vinylbenzaldehyde-co-methyl methacrylate), featuring pendant aldehyde groups, is prepared via RAFT polymerization. The anticancer drug amonafide is conjugated to the polymer chains via imine chemistry, resulting in acid-degradable imine linkages. The obtained amonafide-conjugated glycopolymers are subsequently grafted onto the surface of aminooxy-functionalized nanodiamonds via oxime ligation. The molecular weight of the conjugated polymers is characterized by size-exclusion chromatography (SEC), while the successful conjugation and corresponding grafting density is assessed by nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric aanalysis (TGA). Our results indicate that the mass percentage of amonafide in the polymer chains is around 17% and the surface density of polymer chains is 0.24 molecules/nm2. The prepared drug delivery system has a hydrodynamic size around 380 nm with low PDI (0.3) and can effectively deliver amonafide into breast cancer cell and significantly inhibit the cancer cell viability. In 2D cell culture models, the IC50 values of ND-Polymer-AMF delivery system (7.19 µM for MCF-7; 4.92 µM for MDA-MB-231) are lower than those of free amonafide (11.23 µM for MCF-7; 13.98 µM for MDA-MB-231). An inhibited cell viability of nanodiamonds/polymer delivery system is also observed in 3D spheroids' models, suggesting that polymer-diamonds hybrid materials can be promising platforms for breast cancer therapy.

Fructose-Coated Nanodiamonds: Promising Platforms for Treatment of Human Breast Cancer.

Well-defined carboxyl end-functionalized glycopolymer Poly(1-O-methacryloyl-2,3:4,5-di-O-isopropylidene-ß-d-fructopyranose) (Poly(1-O-MAipFru)62) has been prepared via reversible addition-fragmentation chain transfer polymerization and grafted onto the surface of amine-functionalized nanodiamonds via a simple conjugation reaction. The properties of the nanodiamond-polymer hybrid materials ND-Poly(1-O-MAFru)62 are investigated using infrared spectroscopy, thermogravimetric analysis, dynamic light scattering, and transmission electron microscopy. The dispersibility of the nanodiamonds in aqueous solutions is significantly improved after the grafting of the glycopolymer. More interestingly, the cytotoxicity of amine-functionalized nanodiamonds is significantly decreased after decoration with the glycopolymer even at a high concentration (125 µg/mL). The nanodiamonds were loaded with doxorubicin to create a bioactive drug delivery carrier. The release of doxorubicin was faster in media of pH 5 than media of pH 7.4. The nanodiamond drug delivery systems with doxorubicin are used to treat breast cancer cells in 2D and 3D models. Although the 2D cell culture results indicate that all nanodiamonds-doxorubicin complexes are significantly less toxic than free doxorubicin, the glycopolymer-coated nanodiamonds-doxorubicin show higher cytotoxicity than free doxorubicin in the 3D spheroids after treatment for 8 days. The enhanced cytotoxicity of Poly(1-O-MAFru)62-ND-Dox in 3D spheroids may result from the sustained drug release and deep penetration of these nanocarriers, which play a role as a "Trojan Horse". The massive cell death after 8-day incubation with Poly(1-O-MAFru)62-ND-Dox demonstrates that glycopolymer-coated nanodiamonds can be promising platforms for breast cancer therapy.

A new strategy to synthesize bottlebrushes with a helical polyglutamate backbone via N-carboxyanhydride polymerization and RAFT.

Polyglutamate bottlebrushes with poly(oligo(ethylene glycol)acrylate) as side chains were successfully prepared for the first time by combination of N-carboxyanhydride polymerization and reversible addition-fragmentation chain transfer (RAFT) polymerization. This work has provided a metal-free polymerization strategy and can be applicable to synthesize well-defined polypeptide bottlebrushes for bio-application purposes.

Thiaflavan scavenges radicals and inhibits DNA oxidation: a story from the ferrocene modification.

4-Thiaflavan is a sulfur-substituted flavonoid with a benzoxathiin scaffold. The aim of this work is to compare abilities of sulfur and oxygen atom, hydroxyl groups, and ferrocene moiety at different positions of 4-thiaflavan to trap radicals and to inhibit DNA oxidation. It is found that abilities of thiaflavans to trap radicals and to inhibit DNA oxidation are increased in the presence of ferrocene moiety and are further improved by the electron-donating group attaching to thiaflavan skeleton. It can be concluded that the ferrocene moiety plays the major role for thiaflavans to be antioxidants even in the absence of phenolic hydroxyl groups. On the other hand, the antioxidant effectiveness of phenolic hydroxyl groups in thiaflavans can be improved by the electron-donating group. The influences of sulfur and oxygen atoms in thiaflavans on the antioxidant property of para-hydroxyl group exhibit different manners when the thiaflavans are used to trap radicals and to inhibit DNA oxidation.