Facile Access to Multisensitive and Self-Healing Hydrogels with Reversible and Dynamic Boronic Ester and Disulfide Linkages.

Multifunctional and multiresponsive hydrogels have presented a promising platform to design and fabricate smart devices for application in a wide variety of fields. However, their preparations often involve multistep preparation of multiresponsive polymer precursors, tedious reactions to introduce functional groups or sophisticated molecular designs. In this work, a multifunctional boronic acid-based cross-linker bis(phenylboronic acid carbamoyl) cystamine (BPBAC) was readily prepared from inexpensive commercially available 3-carboxylphenylboronic acid (CPBA) and cystamine dihydrochloride, which has the ability to cross-link the cis-diols and catechol-containing hydrophilic polymers to form hydrogels. Due to the presence of the reversible and dynamic boronate ester and disulfide bonds, the obtained hydrogels were demonstrated to not only possess pH, glucose, and redox triresponsive features, but also have autonomic self-healing properties under ambient conditions. Moreover, we can modulate the rheological and mechanical properties by simply adjusting the BPBAC amount. The features, such as commercially available starting materials, easy-to-implement approach, and versatility in controlling cross-linking network and mechanical properties, make the strategy described here a promising platform for fabricating multifunctional and smart hydrogels.

Improving the refolding efficiency for proinsulin aspart inclusion body with optimized buffer compositions.

Successfully recovering proinsulin's native conformation from inclusion body is the crucial step to guarantee high efficiency for insulin's manufacture. Here, two by-products of disulfide-linked oligomers and disulfide-isomerized monomers were clearly identified during proinsulin aspart's refolding through multiple analytic methods. Arginine and urea are both used to assist in proinsulin refolding, however the efficacy and possible mechanism was found to be different. The oligomers formed with urea were of larger size than with arginine. With the urea concentrations increasing from 2 M to 4 M, the content of oligomers decreased greatly, but simultaneously the refolding yield at the protein concentration of 0.5 mg/mL decreased from 40% to 30% due to the increase of disulfide-isomerized monomers. In contrast, with arginine concentrations increasing up to 1 M, the refolding yield gradually increased to 50% although the content for oligomers also decreased. Moreover, it was demonstrated that not redox pairs but only oxidant was necessary to facilitate the native disulfide bonds formation for the reduced denatured proinsulin. An oxidative agent of selenocystamine could increase the yield up to 80% in the presence of 0.5 M arginine. Further study demonstrated that refolding with 2 M urea instead of 0.5 M arginine could achieve similar yield as protein concentration is slightly reduced to 0.3 mg/mL. In this case, refolded proinsulin was directly purified through one-step of anionic exchange chromatography, with a recovery of 32% and purity up to 95%. All the results could be easily adopted in insulin's industrial manufacture for improving the production efficiency.

Controlling the reactivity of the Se-Se bond by the supramolecular chemistry of cucurbituril.

We describe a new strategy to control the reactivity of SeSe bond by using supramolecular chemistry of cucurbituril. We have demonstrated that selenocystamine (SeCy) and cucurbit[6]uril (CB[6]) can form a stable supramolecular complex (Ka =5.5×10(6) M(-1) ). Before complexation, the free SeSe bond in SeCy is rather sensitive to redox stimuli and gets disrupted quickly with addition of reductant or oxidant. However, after binding with CB[6], the SeSe bond becomes quite inert and hardly reacts with reductant or oxidant. One advantage of this supramolecular protection is that it can be applied in a wide pH range from weakly acidic to basic. Additionally, the supramolecular complex formed by SeCy and CB[6] can be reversibly dissociated simply with addition of Ba(2+) .

Rational design of a selective covalent modifier of G protein ßγ subunits.

G protein-coupled receptors transduce signals through heterotrimeric G protein Gα and Gßγ subunits, both of which interact with downstream effectors to regulate cell function. Gßγ signaling has been implicated in the pathophysiology of several diseases, suggesting that Gßγ could be an important pharmaceutical target. Previously, we used a combination of virtual and manual screening to find small molecules that bind to a protein-protein interaction "hot spot" on Gßγ and block regulation of physiological effectors. One of the most potent and effective compounds from this screen was selenocystamine. In this study, we investigated the mechanism of action of selenocystamine and found that selenocysteamine forms a covalent complex with Gßγ by a reversible redox mechanism. Mass spectrometry and site-directed mutagenesis suggest that selenocysteamine preferentially modifies GßCys204, but also a second undefined site. The high potency of selenocystamine in Gßγ inhibition seems to arise from both high reactivity of the diselenide group and binding to a specific site on Gß. Using structural information about the "hot spot," we developed a strategy to selectively target redox reversible compounds to a specific site on Gßγ using peptide carriers such as SIGCAFKILGY(-cysteamine) [SIGC(-cysteamine)]. Mass spectrometry and site-directed mutagenesis indicate that SIGC(-cysteamine) specifically and efficiently leads to cysteamine (half-cystamine) modification of a single site on Gß, likely GßCys204, and inhibits Gßγ more than a hundred times more potently than cystamine. These data support the concept that covalent modifiers can be specifically targeted to the Gßγ "hot spot" through rational incorporation into molecules that noncovalently bind to Gßγ.

PEGylated derivatives of cystamine as enhanced treatments for nephropathic cystinosis.

The genetic disease, nephropathic cystinosis is characterized by lysosomal accumulation of the amino acid cystine. Crystallization of cystine in affected organs, if untreated, results in mortality of the affected individuals by their middle to late teens. The only approved treatment for cystinosis is administration of cysteamine. However, cysteamine is associated with an offending odor and taste and this, coupled to a rapid first pass metabolism and a 6h dosing regimen, suggest a clear need to improve the therapy. A number of PEGylated derivatives of cystamine, the disulfide counterpart of cysteamine, have been synthesised and evaluated in cultured cystinotic fibroblasts for toxicity and efficacy. All of the tested compounds were non-cytotoxic and displayed a remarkable depletion of intralysosomal cystine.

Synthesis and in vitro evaluation of novel pro-drugs for the treatment of nephropathic cystinosis.

As part of our continuing work to obtain new pro-drugs for the treatment of nephropathic cystinosis, a number of glutaric and succinic acid derivatives of cystamine have been designed, synthesised and biologically evaluated in vitro. These compounds have been designed as odourless and tasteless pro-drugs which will release multiple molecules of cysteamine upon administration. All of the synthesised compounds evaluated in this study were non-cytotoxic and displayed a greater ability than cysteamine to deplete the levels of cystine in cultured fibroblasts.

Use of pH-Active Catechol-Bearing Polymeric Nanogels with Glutathione-Responsive Dissociation to Codeliver Bortezomib and Doxorubicin for the Synergistic Therapy of Cancer.

Synergistic therapy holds promising potential in cancer treatment. Here, the inclusion of catechol moieties, a disulfide cross-linked structure, and pendent carboxyl into the network of polymeric nanogels with glutathione (GSH)-responsive dissociation and pH-sensitive release is first disclosed for the codelivery of doxorubicin (DOX) and bortezomib (BTZ) in synergistic cancer therapy. The pendent carboxyl groups and catechol moieties are exploited to absorb DOX through electrostatic interaction and conjugate BTZ through boronate ester, respectively. Both electrostatic interactions and boronate ester are stable at neutral or alkaline pH, while they are instable in an acidic environment to further recover the activities of BTZ and DOX. The polymeric nanogels possess a superior stability to prevent the premature leakage of drugs in a physiological environment, while their structure is destroyed in response to a typical endogenous stimulus (GSH) to unload drugs. The dissociation of the drug-loaded nanogels accelerates the intracellular release of DOX and BTZ and further enhances the therapeutic efficacy. In vitro and in vivo investigations revealed that the dual-drug loaded polymeric nanogels exhibited a strong ability to suppress tumor growth. This study thus proposes a new perspective on the production of multifunctional polymeric nanogels through the introduction of different functional monomers.

Melanoma-targeted chemo-thermo-immuno (CTI)-therapy using N-propionyl-4-S-cysteaminylphenol-magnetite nanoparticles elicits CTL response via heat shock protein-peptide complex release.

Melanogenesis substrate, N-propionyl-4-S-cysteaminylphenol (NPrCAP) is specifically taken up by melanoma cells and inhibits their growth by producing cytotxic free radicals. By taking advantage of this unique chemical agent, we have established melanoma-targeting intracellular hyperthermia by conjugating NPrCAP with magnetite nanoparticles (NPrCAP/M) upon exposure to an alternating magnetic field (AMF). This treatment causes cytotoxic reaction as well as heat shock responses, leading to elicitation of antitumor immune response, which was proved by tumor rechallenge test and CTL induction. We found the level of heat shock protein 72 (Hsp72) to be increased in the cell lysate and culture supernatant after intracellular hyperthermia. Melanoma-specific CD8(+) T-cell response to dendritic cells loaded with hyperthermia-treated tumor lysate was enhanced when compared with non-treated tumor lysate. When heat shock protein, particularly Hsp72, was immuno-depleted from hyperthermia-treated tumor cell lysate, specific CD8(+) T-cell response was abolished. Thus, it is suggested that antitumor immune response induced by hyperthermia using NPrCAP/M is derived from the release of HSP-peptide complex from degraded tumor cells. Therefore, this chemo-thermo-immuno (CTI)-therapy might be effective not only for primary melanoma but also for distant metastasis because of induction of systemic antimelanoma immune responses.

Relationship between three polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T, A1298C, and G1793A) gene and risk of prostate cancer: a case-control study.

BACKGROUND: We hypothesized that genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene are associated with prostate cancer risk. METHODS: We genotyped three MTHFR polymorphisms (C677T, A1298C, and G1793A) and measured serum total homocysteine (tHcy), folate, and vitamin B12 levels in a case-control study of 174 cases and 348 normal healthy controls. The cancer-free controls were frequency matched to the cases by age (±2 years), educational level, occupational status, ethnicity, and smoking status. RESULTS: We found that the MTHFR 677TT and 1298CC genotypes were associated with an about 40% reduction in risk of prostate cancer (adjusted OR = 0.59, 95% CI = 0.41-0.94, and adjusted OR = 0.58, 95% CI = 0.32-0.91, respectively) compared to the 677CC, and 1298AA genotypes. The combined variant genotypes of 1298AC + 677CC were associated with a 30% reduction in risk of prostate cancer (OR = 0.70; 95% CI = 0.53-0.79). In contrast, the variant genotypes of 1793GA + 677CT were associated with slightly increased risk for prostate cancer (OR = 1.64; 95% CI = 0.86-2.15). Regarding prostate cancer aggressiveness, the 677TT genotype was associated with more than 50% decreased risk of high-grade prostate cancer (Gleason score >7) compared with the 677CC and 677CT genotypes (OR = 0.35, 95% CI = 0.24-0.64; P = 0.001). There was no significant difference in plasma levels of tHcy, folate, and vitamin B12 between the two groups with any genotypes. CONCLUSION: These data suggest that all three MTHFR polymorphisms may play a pivotal role in the developing prostate cancer. Larger studies in different ethnic populations and incorporating dietary folate intake are needed to replicate our findings.

Noninvasive evaluation of antiangiogenic effect in a mouse tumor model by DCE-MRI with Gd-DTPA cystamine copolymers.

The efficacy of polydisulfide-based biodegradable macromolecular Gd(III) complexes, Gd-DTPA cystamine copolymers (GDCC), for assessing tumor microvascular characteristics and monitoring antiangiogenesis therapy was investigated in a mouse model using dynamic contrast-enhanced MRI (DCE-MRI). The mice bearing human colon tumor xenografts were intraperitoneally injected with an antiangiogenesis agent Avastin three times in a week at a dose of 200 mug/mouse. DCE-MRI with GDCC of 40 kDa (GDCC-40) was performed before and at 36 h after the first treatment with Avastin and at the end of treatment (7 days). Gd(DTPA-BMA) was used as a low molecular weight control. The tumor vascular parameters, endothelial transfer coefficient K(trans) and factional plasma volume f(PV), were calculated from the DCE-MRI data with a two-compartment model. The K(trans) and f(PV) in tumor periphery estimated by DCE-MRI with GDCC-40 before and after the antiangiogenesis treatment correlated well to tumor growth before and after the treatment in the tumor model. In contrast, the parameters estimated by Gd(DTPA-BMA) did not show significant correlation to the therapeutic efficacy. This study demonstrates that DCE-MRI with the biodegradable macromolecular MRI contrast agent can provide effective assessment of the antiangiogenic efficacy of Avastin in the animal tumor model based on measured vascular parameters in tumor periphery.

Selenium and sulfur in exchange reactions: a comparative study.

Cysteamine reduces selenocystamine to form hemiselenocystamine and then cystamine. The rate constants are k(1) = 1.3 × 10(5) M(-1) s(-1); k(-1) = 2.6 × 10(7) M(-1) s(-1); k(2) = 11 M(-1) s(-1); and k(-2) = 1.4 × 10(3) M(-1) s(-1), respectively. Rate constants for reactions of cysteine/selenocystine are similar. Reaction rates of selenium as a nucleophile and as an electrophile are 2-3 and 4 orders of magnitude higher, respectively, than those of sulfur. Sulfides and selenides are comparable as leaving groups.

Selenium functionalized intraocular lenses inhibit posterior capsule opacification in an ex vivo canine lens capsular bag assay.

The purpose of this study was to determine the inhibitory effect of selenocystamine coated intraocular lenses (IOLs) on the formation of posterior capsule opacification (PCO) in an ex vivo canine lens capsular bag assay. Selenocystamine was covalently bound to the surface of poly(2-hydroxyethyl methacrylate) (poly(HEMA)) discs. Three groups of canine lens capsules (6 coated IOLs (SeIOLs), 7 non-coated control IOLs and 8 empty capsules) were cultured for 10 days. During the culture period PCO was scored based on visual inspection of the capsules using phase contrast microscopy. On day 10 all the capsules were prepared for light microscopic examination and lens epithelial cells (LECs) were quantified. Proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (alpha-SMA) and cleaved caspase-3 were examined by immunohistochemistry. Additionally, cell viability assays were performed on LECs cultured in tissue culture medium pre-incubated with either a SeIOL or control IOL. The viability assays demonstrated that no detectable cytotoxic leachables were associated with the functionalized IOLs. The central posterior capsule was free of cells underneath all SeIOLs, although large numbers of LECs populated the capsular periphery. Apoptotic cells were observed underneath the periphery of some SeIOLs. Both the PCO scores and LEC counts of SeIOL containing capsules were significantly lower than those of control group capsules (p < 0.01 and p = 0.0004, respectively). The use of selenium functionalized IOLs resulted in a significant reduction of PCO in this ex vivo model. Binding of selenocystamine to a foldable IOL may provide an effective method to prevent population of the central posterior capsule with LECs.

Growth inhibition of re-challenge B16 melanoma transplant by conjugates of melanogenesis substrate and magnetite nanoparticles as the basis for developing melanoma-targeted chemo-thermo-immunotherapy.

Melanogenesis substrate, N-propionyl-cysteaminylphenol (NPrCAP), is selectively incorporated into melanoma cells and inhibits their growth by producing cytotoxic free radicals. Magnetite nanoparticles also disintegrate cancer cells and generate heat shock protein (HSP) upon exposure to an alternating magnetic field (AMF). This study tested if a chemo-thermo-immunotherapy (CTI therapy) strategy can be developed for better management of melanoma by conjugating NPrCAP on the surface of magnetite nanoparticles (NPrCAP/M). We examined the feasibility of this approach in B16 mouse melanoma and evaluated the impact of exposure temperature, frequency, and interval on the inhibition of re-challenged melanoma growth. The therapeutic protocol against the primary transplanted tumor with or without AMF exposure once a day every other day for a total of three treatments not only inhibited the growth of the primary transplant but also prevented the growth of the secondary, re-challenge transplant. The heat-generated therapeutic effect was more significant at a temperature of 43 degrees C than either 41 degrees C or 46 degrees C. NPrCAP/M with AMF exposure, instead of control magnetite alone or without AMF exposure, resulted in the most significant growth inhibition of the re-challenge tumor and increased the life span of the mice. HSP70 production was greatest at 43 degrees C compared to that with 41 degrees C or 46 degrees C. CD8(+)T cells were infiltrated at the site of the re-challenge melanoma transplant.

Plasma homocysteine is adversely associated with glomerular filtration rate in asymptomatic black and white young adults: the Bogalusa heart study.

That plasma homocysteine is elevated markedly in renal dysfunction is well recognized. But whether the increased homocysteine is an independent correlate of glomerular filtration rate, a marker of renal function, in asymptomatic younger individuals is not clear. The aim of this study was to determine the association between plasma homocysteine and renal function in a biracial (black-white) community-based cohort of asymptomatic young adults. Plasma homocysteine along with cardiovascular disease risk factor variables were measured in 805 white and 330 black subjects, ages 24-44 years, enrolled in the Bogalusa Heart Study. Modification of Diet in Renal Disease Study equation was used to calculate the estimated glomerular filtration rate (eGFR) from serum creatinine level. Males versus females showed higher homocysteine levels (8.83 +/- 3.16 vs. 7.35 +/- 2.84 micromol/L, p < 0.0001) and lower eGFR (99.1 +/- 17.6 vs. 102.5 +/- 21.0 mL/min/1.73 m(2), p = 0.024). Whites versus blacks had lower eGFR (97.3 +/- 18.0 vs. 110.0 +/- 20.6 mL/min/1.73 m(2), p < 0.0001). In a multivariate regression analysis that included age, race, sex, body mass index, blood pressure, lipoprotein variables, insulin resistance index and homocysteine, white race, age and homocysteine, in that order, were independently and negatively associated with eGFR. The odds ratio (95% confidence interval) of individuals in the homocysteine quintiles II, III, IV and V vs. I for having the risk of impaired eGFR defined as <10th percentile was 2.28 (0.95-5.50, p = 0.065), 2.97 (1.24-7.12, p = 0.015), 3.32 (1.45-7.60, p = 0.005) and 6.99 (3.06-15.94, p < 0.0001), respectively. Homocysteine is an independent correlate of renal function in asymptomatic black and white young adults.

Benextramine and derivatives as novel human monoamine oxidases inhibitors: an integrated approach.

The two human monoamine oxidase isoforms (namely MAO A and MAO B) are enzymes involved in the catabolism of monoamines, including neurotransmitters, and for this reason are well-known and attractive pharmacological targets in neuropsychiatric and neurodegenerative diseases, for which novel pharmacological approaches are necessary. Benextramine is a tetraamine disulfide mainly known as irreversible α-adrenergic antagonist, but able to hit additional targets involved in neurodegeneration. As the molecular structures of monoamine oxidases contain nine cysteine residues, the aim of this study was to evaluate benextramine and eleven structurally related polyamine disulfides as potential MAO inhibitors. Most of the compounds were found to induce irreversible inactivation of MAOs with inactivation potency depending on both the polyamine structure and the enzyme isoform. The more effective compounds generally showed preference for MAO B. Structure-activity relationships studies revealed the key role played by the disulfide core of these molecules in the inactivation mechanism. Docking experiments pointed to Cys323, in MAO A, and Cys172, in MAO B, as target of this type of inhibitors thus suggesting that their covalent binding inside the MAO active site sterically impedes the entrance of substrate towards the FAD cofactor. The effectiveness of benextramine in inactivating MAOs was demonstrated in SH-SY5Y neuroblastoma cell line. These results demonstrated for the first time that benextramine and its derivatives can inactivate human MAOs exploiting a mechanism different from that of the classical MAO inhibitors and could be a starting point for the development of pharmacological tools in neurodegenerative diseases.

Biomimetic engineering endothelium-like coating on cardiovascular stent through heparin and nitric oxide-generating compound synergistic modification strategy.

Co-immobilization of two or more molecules with different and complementary functions to prevent thrombosis, suppress smooth muscle cell (SMC) proliferation, and support endothelial cell (EC) growth is generally considered to be promising for the re-endothelialization on cardiovascular stents. However, integration of molecules with distinct therapeutic effects does not necessarily result in synergistic physiological functions due to the lack of interactions among them, limiting their practical efficacy. Herein, we apply heparin and nitric oxide (NO), two key molecules of the physiological functions of endothelium, to develop an endothelium-mimetic coating. Such coating is achieved by sequential conjugation of heparin and the NO-generating compound selenocystamine (SeCA) on an amine-bearing film of plasma polymerized allylamine. The resulting surface combines the anti-coagulant (anti-FXa) function provided by the heparin and the anti-platelet activity of the catalytically produced NO. It also endows the stents with the ability to simultaneously up-regulate α-smooth muscle actin (α-SMA) expression and to increase cyclic guanylate monophosphate (cGMP) synthesis of SMC, thereby significantly promoting their contractile phenotype and suppressing their proliferation. Importantly, this endothelium-biomimetic coating creates a favorable microenvironment for EC over SMC. These features impressively improve the antithrombogenicity, re-endothelialization and anti-restenosis of vascular stents in vivo.

No association between global leukocyte DNA methylation and homocysteine levels in schizophrenia patients.

Meta-analysis recently suggested that a 5 muM increase in homocysteine is associated with a 70% higher risk for schizophrenia. Elevated homocysteine is reported to alter macromolecule methylation. We studied whether elevated plasma homocysteine levels in schizophrenia are associated with altered leukocyte global DNA methylation. DNA was extracted from peripheral blood leukocytes of 28 schizophrenia patients vs. 26 matched healthy controls. Percent of global genome DNA methylation was measured using the cytosine-extension method. Homocysteine levels were higher in schizophrenia patients than in controls. No difference in global DNA methylation between schizophrenia patients and control subjects was found (74.0%+/-14.8 vs. 69.4+/-22.0, p=0.31). A significant interaction between diagnosis and smoking on DNA methylation was obtained (F=6.8, df=1,47, p=0.032). Although leukocytes may be a useful cell model to evaluate epigenetic changes such as global DNA methylation in brain, future studies should compare global DNA methylation in peripheral tissue vs. brain in laboratory animals.

Pulse radiolysis studies on reactions of hydroxyl radicals with selenocystine derivatives.

Reactions of hydroxyl radicals (*OH) with selenocystine (SeCys) and two of its analogues, diselenodipropionic acid (SeP) and selenocystamine (SeA), have been studied in aqueous solutions at pHs of 1, 7, and 10 using the pulse radiolysis technique coupled with absorption detection. All of these diselenides react with *OH radicals with rate constants of approximately 10(10) M(-1) s(-1), producing diselenide radical cations ( approximately 1-5 micros after the pulse), with an absorption maximum at 560 nm, by elimination of H(2)O or OH(-) from hydroxyl radical adducts. Assignment of the 560 nm band to the diselenide radical cation was made by comparing the transient spectra with those produced upon reaction of diselenides with specific one-electron oxidants, Cl(2)(*-) (pH 1) and Br(2)(*-) radicals (pHs of 7 and 10). SeP having a carboxylic acid functionality showed quantitative conversion of hydroxyl radical adducts to radical cations. The compounds SeCys and SeA, having an amino functional group, in addition to the radical cations, produced a new transient with lambda(max) at 460 nm, at later time scales ( approximately 20-40 micros after the pulse). The rate and yield of formation of the 460 nm band increased with increasing concentrations of either SeCys or SeA. In analogy with similar studies reported for analogous disulfides, the 460 nm transient absorption band has been assigned to a triselenide radical adduct. The one-electron reduction potentials of the compounds were estimated to be 0.96, 1.3, and 1.6 V versus NHE, respectively, for SeP, SeCys, and SeA at pH 7. From these studies, it has been concluded that the electron-donating carboxylic acid group decreases the reduction potential and facilitates quantitative conversion of hydroxyl radical adducts to radical cations, while the electron-withdrawing NH(3)(+) group not only increases the reduction potential but also leads to fragmentation of the hydroxyl radical adduct to selenyl radicals, which are converted to triselenide radical adducts.

A degradable triple temperature-, pH-, and redox-responsive drug system for cancer chemotherapy.

In order to achieve a precise therapeutic effect of cancer treatment and improve the utilization of drugs, a temperature-, pH-, and redox-responsive drug delivery system were synthesized. Methacrylic acid (MAA), poly(N-isopropylacrylamide) (PNIPAM), 2-hydroxyethylmethacrylate (HEMA), and N,N'-bis(acryloyl)cystamine (BACy), a disulfide bond contained cross-linker, were polymerized by a distillation-precipitation polymerization. Doxorubicin (DOX), an anti-cancer drug, can be loaded into the loose nanoparticle (NP) effectively. The prepared drug delivery remains stable during blood circulation and, when the vectors accumulated at tumor tissues, the pH-response of MMA and temperature-response of PNIPAM makes volume shrinkage of vectors which benefit the diffusion of vectors into tumor tissues. After being endocytosed into tumor cell, the disulfide bond that contained in the drug delivery can be cleaved by glutathione (GSH), causing the decomposition of NPs, and then release all of the drug. Under the influence of three trigger factors, the triple stimuli-responsive drug delivery vectors can realize tumor accumulation, tumor penetration and controlled drug release. Thus, the prepared multi-responsive NP is ideal drug carriers for developing novel drug delivery systems. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3203-3210, 2018.

Plant-inspired gallolamine catalytic surface chemistry for engineering an efficient nitric oxide generating coating.

A novel concept of generating therapeutic gas, nitric oxide (NO) via catalytic phenolic-amine "gallolamine" surface chemistry is developed. The concept is realized using plant polyphenol, gallic acid, and a glutathione peroxidase-like organoselenium compound cystamine or selenocystamine through one-step phenol-amine molecular assembling process. The resulting NO-generating coating with phenolic-cystamine or -selenocystamine framework showed the ability for long-term, steady and controllable range of NO release rates being unparalleled with any existing NO-releasing or NO-generating surface engineering toolkits. STATEMENT OF SIGNIFICANCE: Developing a facile and versatile strategy for a NO-generating coating with long-term, stable and adjustable NO release is of great interest for the application of blood-contacting materials and devices. Covalent immobilization of glutathione peroxidase (GPx)-like compound to generate NO from a material surface by exposure of endogenously existed S-nitrothiol (RSNO) is a popular strategy. However, it is generally involved in multi-step and complicated processes. Moreover, the amount of immobilized GPx-like compounds is limited by the density of introduced reactive functional groups on a surface. Herein, we propose a novel concept of catalytic plant-inspired gallolamine surface chemistry for material-independent NO-generating coatings. The concept is realized using plant polyphenol, gallic acid, and a GPx-like organoselenium compound cystamine or selenocystamine through one-step phenol-amine molecular assembling process. Without tedious multi-step synthesis, complicated surface treatments, and leakage of toxic chemicals, our unprecedentedly simple, histocompatible and biocompatible phenolic-cystamine or -selenocystamine framework demonstrated long-term, on-demand and facile dose controls of NO generated from the engineering surfaces. These unique features of such a NO-generating coating imparted a material with ability to impressively improve anti-thrombogenicity in vivo. This work constitutes the first report of an interfacial catalytic coating based on material-independent surface chemistry by plant polyphenols. This concept not only expands the application of material-independent surface chemistry in an interfacial catalytic area, but also can be a new platform for antithrombotic materials.