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A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1 H -pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33 , exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8 + T-cells, and helper CD4 + T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 ( BPR5K230 ) with excellent oral bioavailability ( F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.

Poly(ethylene oxide) (PEO)-based solid electrolyte suffers from limited anodic stability and an intrinsic flammable issue, hindering the achievement of high energy density and safe all-solid-state lithium batteries. Herein, we surprisingly found out that a bromine-rich additive, decabromodiphenyl ethane (DBDPE), could be preferably oxidized at an elevated voltage and decompose to lithium bromide at an elevated potential followed by inducing an organic-rich cathode/electrolyte interphase (CEI) on NCM811 surface, enabling both high-voltage resistance (up to 4.5 V) and flame-retardancy for the PEO-based electrolyte. On the basis of this novel solid electrolyte, all-solid-state Li/NCM811 batteries deliver an average reversible capacity of 151.4 mAh g -1 over the first 150 cycles with high capacity retention (83.0%) and high average Coulombic efficiency (99.7%) even at a 4.5 V cutoff voltage with a unprecedented flame-retardant properties. In view of these exploration, our studies revealed the critical role of LiBr in inducing an organic-rich thin and uniform CEI passivating layer with enhanced lithium ion surface diffusion and high-voltage resistant properties, which provides a new protocol for the further design of a high-voltage PEO-based all-solid-state electrolyte.

Gamma radiolysis behaviors and mechanisms of silica-filled o -cresol formaldehyde epoxy are studied at 2.20 × 10 -5 to 1.95 × 10 -1 Gy/s. The radiolysis-induced changes in chemical structures do not severely affect its thermostability. The slightly deteriorated mechanical strength at temperature exceeding 100 °C is accompanied by the declining glass transition temperature (from 185.9 to 172.2 °C) and enhanced damping ability. The gas yields of hydrogen, methane, and carbon dioxide manifest a remarkable dose rate effect. Based on the Schwarzschild law, their yields at an extremely low dose rate are accurately predicted by the established master curves. Besides, the latent radiolysis of gas products and postradiation effect are found with caution. The radiation-caused residual spin species are proved to be composed of silica defects and a phenoxy-type free radical with a tert -butyl group, according to the experimental results, theoretical calculations, and spectra simulations. The lower vertical ionization potential (7.6 eV) and adiabatic ionization potential (7.1 eV) are primarily due to the ionization of the benzene ring moiety with the tert -butyl group, which is likely to suffer from radiolysis. The calculated bond dissociation energy (260.8-563.5 kJ/mol) of the typical chemical bonds of epoxy is consistent with its radiolytic vulnerability and degradation mechanisms.

Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 ( 9 ), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 ( 12 ) exhibited potent CSF1R activity (IC 50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo , oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.

The γ radiolysis behavior of polydimethylsiloxane (PDMS) in the radiation-thermal environments (dose rate, 0.2 Gy/s) is studied to pinpoint the basic knowledge of the temperature (20-70 °C) effects. The non-monotonous temperature effects on the formation of gas products, paramagnetic species in silica, and cross-linking density are proposed to correlate with the complex chemical reaction mechanisms. Besides, molecular dynamics simulation and theoretical calculation are first performed simultaneously based on the radical chemistry and intricate material composition, making it easier to comprehend and further harness the radiolysis mechanisms and structure deterioration of PDMS. The γ radiation-induced primary gas products and dominant cross-linking phenomena are reproduced by the molecular dynamics simulations with a reactive force field, and the reaction mechanisms and physicochemical interactions among PDMS chains, gas products, reactive radicals, and silica fillers are thoroughly studied at the atomic scale. The thermochemistry of the barrierless radical coupling reactions and reactions with explicit high-barrier transition states is calculated at the M06-2X theoretical level with the 6-311g(d, p) basis set. The barrierless reactions are all exothermal with the heat release of 321-618 kJ/mol, while the potential barriers for reactions with explicit transition states vary between 37 and 229 kJ/mol. The results show that γ radiation-induced radicals are crucial for the ensuing gas formation and cross-linking reactions, especially for the radical coupling reactions. The radical chemistry involved in the radiolytic PDMS is the key to understand and simulate its radiolysis behavior, according to the experimental and simulated results.

The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC 50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25 , which demonstrated an 8-fold higher oral AUC ( F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC -amplified cancers including SCLC.

A new method for the construction of functionalized furo[3,2- c ]coumarins via MBH-type/acyl-transfer/Wittig reaction is reported. The current approach would open a new route for the simultaneous formation of two rings in a one-pot reaction which is accompanied by incorporation of a keto functionality on the furan ring by activating the terminal alkynoates with phosphine. Furthermore, this protocol could also be applicable to the internal alkynoates/propiolamides to generate the 2,3-disubstituted furo[3,2- c ]coumarins/furo[3,2- c ]quinolinones by excluding the acyl-transfer reaction.

In this study, we synthesized a series of small-molecule benzotrithiophenes (BTTs) and used them as hole transporting materials (HTMs) in perovskite solar cells (PSCs). The asymmetric benzo[2,1- b :-3,4- b ':5,6- b ″]trithiophene unit was used as the central core to which were appended various donor groups, namely, carbazole (BTT-CB), thieno thiophene (BTT-FT), triphenylamine (BTT-TPA), and bithiophene (BTT-TT). The extended aromatic core in the asymmetric BTT provided full planarity, thereby favoring intermolecular π-stacking and charge transport. The physical, optical, and electrical properties of these small-molecule HTMs are reported herein. BTT-TT displayed good crystallinity and superior hole mobility, when compared with those of the other three HTMs, and formed smooth and uniform surfaces when covering the perovskite active layer. Accordingly, among the devices prepared in this study, a PSC incorporating BTT-TT as the HTM achieved the highest power conversion efficiency (18.58%). Moreover, this BTT-TT-containing device exhibited good stability after storage for more than 700 h. Thus, asymmetric BTTs are promising candidate materials for use as small-molecule HTMs in PSCs.

Electrodynamic systems for bioanalytical applications constantly suffer from biofouling due to electrical field-induced nonspecific bioadsorption on electrode surfaces. To minimize this issue, surface modification using anti-biofouling and conductive materials is necessary to not only protect the electrode surface from nonspecific bioadsorption but also maintain desired electrodynamic properties for electrode operation. In this study, we designed and prepared a conductive, zwitterionic, and self-doped sulfonated polyaniline (SPANI) coating on Au electrode surfaces for anti-biofouling applications. The zwitterionic coating was fabricated by electrochemical polymerization of aniline on the Au electrode surface functionalized with cysteamine (HS-CH 2 CH 2 -NH 2 ) and then a post-polymerization treatment with fuming sulfuric acid. We found that the SPANI-coated electrodes exhibited an excellent anti-biofouling ability in dielectrophoresis (DEP) capturing-and-releasing processes, with a very low average residual mass rate of 1.44% for the SPANI-5s electrode, whereas electrodes modified with poly(ethylene glycol) (PEG) gave an average residual mass rate of 14.30%. Even under continuous operation for more than 1 h, the SPANI-5s electrode still showed stable anti-biofouling ability for an 11-cycle E. coli capturing-and-releasing DEP process, with the residual mass rate for all 11 cycles being kept at or below 2.18% to give an average residual mass rate of 1.62% with a standard deviation of 0.40%. This study demonstrates that electrodynamic systems with zwitterionic SPANI coated on open electrode surfaces can excellently function with decent conductance and anti-biofouling performance.

Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a , with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.

Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.

Flurbiprofen, a hydrophobic COX inhibitor, was coordinated axially with oxoplatin to form a new conjugate, cis, cis, trans-[Pt(IV)(NH 3 ) 2 Cl 2 (flurbiprofen) 2 ]. The successful synthesis of this new conjugate was confirmed by 1 H, 13 C, and 195 Pt NMR. The potential of this conjugate being reduced to cisplatin and subsequently exerting its DNA cross-linking ability was verified using cyclic voltammetry (CV), HPLC, and mass spectrometry (MS). This conjugate showed markedly higher cytotoxicity on many cancer cell lines than cisplatin, flurbiprofen, and their physical mixture (mole ratio, cisplatin:flurbiprofen = 1:2). This is consistent with the result of an apoptosis-inducing assay. This conjugate spontaneously assembles carrier-free nanoparticles in aqueous solution, which is confirmed by DLS, TEM, SEM, and AFM, and thus facilitates cellular uptake and markedly improves its cytotoxicity and apoptosis-inducing ability in vitro.

In this paper we describe a modified (AEG/CH) coated separator for Li-S batteries in which the shuttling phenomenon of the lithium polysulfides is restrained through two types of interactions: activated expanded graphite (AEG) flakes interacted physically with the lithium polysulfides, while chitosan (CH), used to bind the AEG flakes on the separator, interacted chemically through its abundance of amino and hydroxyl functional groups. Moreover, the AEG flakes facilitated ionic and electronic transfer during the redox reaction. Live H-cell discharging experiments revealed that the modified separator was effective at curbing polysulfide shuttling; moreover, X-ray photoelectron spectroscopy analysis of the cycled separator confirmed the presence of lithium polysulfides in the AEG/CH matrix. Using this dual functional interaction approach, the lifetime of the pure sulfur-based cathode was extended to 3000 cycles at 1C-rate (1C = 1670 mA/g), decreasing the decay rate to 0.021% per cycle, a value that is among the best reported to date. A flexible battery based on this modified separator exhibited stable performance and could turn on multiple light-emitting diodes. Such modified membranes with good mechanical strength, high electronic conductivity, and anti-self-discharging shield appear to be a scalable solution for future high-energy battery systems.

Vitamin E derivatives possess many essential features for drug-delivery applications, such as biocompatibility, stability, improvement of water solubility of hydrophobic compounds, anticancer activity, and the ability to overcome multidrug resistance (MDR). Herein, vitamin E derivatives are used to overcome MDR through a combined P-glycoprotein (P-gp) inhibition and mitochondrial impairment strategy. A novel nanomicellar drug-delivery system as a carrier for doxorubicin (DOX) was developed, in which d-α-tocopheryl polyethylene glycol 1000 succinate was used as a P-gp inhibitor, α-tocopheryl succinate was introduced as a mitochondrial disrupting agent, and d-α-tocopheryl polyethylene glycol 2000 succinate was used as the main building block of micelles. The optimal ratio between the components of the nanocarrier was determined. The resultant DOX-loaded mixed micelles exhibited a suitable size of 52.08 nm, high drug-loading encapsulation efficiency (>98%), high stability, and pH-dependent drug release. In vitro experiments demonstrated a significantly increased cytotoxic activity of DOX-loaded mixed micelles against resistant MCF-7/Adr cells (45-fold higher than DOX after 48 h of treatment). In vivo studies revealed superior antitumor efficiency with less cardio- and hepatotoxicities of DOX-loaded micelles compared with that of free DOX. These results highlight that the developed DOX-loaded mixed micelles have a promising potential to overcome MDR in chemotherapy for clinical usage.

Viruses have evolved to be outstandingly efficient at gene delivery, but their use as vectors is limited by safety risks. Inspired by the structure of viruses, we constructed a virus-mimicking vector (denoted as TR4@siRNA@Tf NCs) with virus-like architecture and infection properties. Composed of a hydrophilic peptide, an aggregation-induced emission (AIE) luminogen, and a lipophilic tail, TR4 imitates the viral capsid and endows the vector with AIE properties as well as efficient siRNA compaction. The outer glycoprotein transferrin (Tf) mimics the viral envelope protein and endows the vector with reduced cytotoxicity as well as enhanced targeting capability. Because of the strong interaction between Tf and transferrin receptors on the cell surface, the Tf coating can accelerate the intracellular release of siRNA into the cytosol. Tf and TR4 are eventually cycled back to the cell membrane. Our results confirmed that the constructed siRNA@TR4@Tf NCs show a high siRNA silencing efficiency of 85% with significantly reduced cytotoxicity. These NCs have comparable transfection ability to natural viruses while avoiding the toxicity issues associated with typical nonviral vectors. Therefore, this proposed virus-like siRNA vector, which integrates the advantages of both viral and nonviral vectors, should find many potential applications in gene therapy.

High-efficiency gene transfer and suitably low cytotoxicity are the main goals of gene transfection systems based on nonviral vectors. In addition, it is desirable to track the gene transfer process in order to observe and explain the mechanism. Herein, inspired by viral structures that are optimized for gene delivery, we designed a small-molecule gene vector (TR4) with aggregation-induced emission properties by capping a peptide containing four arginine residues with tetraphenylethene (TPE) and a lipophilic tail. This novel vector can self-assemble with plasmid DNA to form nanofibers in solution with low cytotoxicity, high stability, and high transfection efficiency. pDNA@TR4 complexes were able to transfect a variety of different cell lines, including stem cells. The self-assembly process induces bright fluorescence from TPE, which makes the nanofibers visible by confocal laser scanning microscopy (CLSM). This allows us for the tracking of the gene delivery process.

Many theranostic nanomedicines (NMs) have been fabricated by packaging imaging and therapeutic moieties together. However, concerns about their potential architecture instability and pharmacokinetic complexity remain major obstacles to their clinical translation. Herein, we demonstrated the use of CuInS/ZnS quantum dots (ZCIS QDs) as "all-in-one" theranostic nanomedicines that possess intrinsic imaging and therapeutic capabilities within a well-defined nanostructure. ZCIS QDs were exploited for multispectral optical tomography (MSOT) imaging and synergistic PTT/PDT therapy. Due to the intrinsic fluorescence/MSOT imaging ability of the ZCIS QDs, their size-dependent distribution profiles were successfully visualized at tumor sites in vivo. Our results showed that the smaller nanomedicines (ZCIS NMs-25) have longer tumor retention times, higher tumor uptake, and deeper tumor penetration than the larger nanomedicines (ZCIS NMs-80). The ability of ZCIS QDs to mediate photoinduced tumor ablation was also explored. Our results verified that under a single 660 nm laser irradiation, the ZCIS NMs had simultaneous inherent photothermal and photodynamic effects, resulting in high therapy efficacy against tumors. In summary, the ZCIS QDs as "all-in-one" versatile nanomedicines allow high therapeutic efficacy as well as noninvasively monitoring tumor site localization profiles by imaging techniques and thus hold great potential as precision theranostic nanomedicines.

Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.

Photodynamic therapy (PDT) offers an alternative for cancer treatment by using ultraviolet or visible light in the presence of a photosensitizer and molecular oxygen, which can produce highly reactive oxygen species that ultimately leading to the ablation of tumor cells by multifactorial mechanisms. However, this technique is limited by the penetration depth of incident light, the hypoxic environment of solid tumors, and the vulnerability of photobleaching reduces the efficiency of many imaging agents. In this work, we reported a cellular level dual-functional imaging and PDT nanosystem BMEPC-loaded DNA origami for photodynamic therapy with high efficiency and stable photoreactive property. The carbazole derivative BMEPC is a one- and two-photon imaging agent and photosensitizer with large two-photon absorption cross section, which can be fully excited by near-infrared light, and is also capable of destroying targets under anaerobic condition by generating reactive intermediates of Type I photodynamic reactions. However, the application of BMEPC was restricted by its poor solubility in aqueous environment and its aggregation caused quenching. We observed BMEPC-loaded DNA origami effectively reduced the photobleaching of BMEPC within cells. Upon binding to DNA origami, the intramolecular rotation of BMEPC became proper restricted, which intensify fluorescence emission and radicals production when being excited. After the BMEPC-loaded DNA origami are taken up by tumor cells, upon irradiation, BMEPC could generate free radicals and be released due to DNA photocleavage as well as the following partially degradation. Apoptosis was then induced by the generation of free radicals. This functional nanosystem provides an insight into the design of photosensitizer-loaded DNA origami for effective intracellular imaging and photodynamic therapy.

Carrier-free pure nanodrugs (PNDs) that are composed entirely of pharmaceutically active molecules are regarded as promising candidates to be the next generation of drug formulations and are mainly formulated from supramolecular self-assembly of drug molecules. It benefits from the efficient use of drug compounds with poor aqueous solubility and takes advantage of nanoscale drug delivery systems. Here, a type of all-in-one nanoparticle consisting of multiple drugs with enhanced synergistic antiproliferation efficiency against drug-resistant cancer cells has been created. To nanoparticulate the anticancer drugs, 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) were chosen as a typical model. The resulting HD nanoparticles (HD NPs) were formulated by a "green" and convenient self-assembling method, and the water-solubility of 10-hydroxycamptothecin (HCPT) was improved 50-fold after nanosizing by coassembly with DOX. The formation process was studied by observing the morphological changes at various reaction times and molar ratios of DOX to HCPT. Molecular dynamics (MD) simulations showed that DOX molecules tend to assemble around HCPT molecules through intermolecular forces. With the advantage of nanosizing, HD NPs could improve the intracellular drug retention of DOX to as much as 2-fold in drug-resistant cancer cells (MCF-7R). As a dual-drug-loaded nanoformulation, HD NPs effectively enhanced drug cytotoxicity to drug-resistant cancer cells. The combination of HCPT and DOX exhibited a synergistic effect as the nanosized HD NPs improved drug retention in drug-resistant cancer cells against P-gp efflux in MCF-7R cells. Furthermore, colony forming assays were applied to evaluate long-term inhibition of cancer cell proliferation, and these assays confirmed the greatly improved cytotoxicity of HD NPs in drug-resistant cells compared to free drugs.

Tumor metastasis is the major obstacle for cancer treatment. Previous studies have shown that butein exhibits antiangiogenesis property and anticancer effects in different kinds of human cancer cells. However, the effects of butein on metastasis and energy metabolism of cancer cells are mostly unknown. This study showed that butein significantly inhibited invasion of cancer cells without acting in a cytotoxic fashion. It was further demonstrated that butien dramatically suppressed cancer metastasis by an in vivo CAM-intravasation model. Additionally, butein concentration-dependently repressed the expression and activity of matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (uPA). The study indicated that butein may repress MMP-9 and uPA proteolytic activities and subsequently inhibit cancer metastasis via Akt/mTOR/p70S6K translational machinery. Moreover, butein may partly suppress cancer metastasis by down-regulating ATP synthesis via both oxidative and glycolytic metabolism. The results suggest that butein is a potential antimetastatic agent worthy of further development for cancer treatment.

The aim of this study was to determine the size-dependent penetration ability of gold nanoparticles and the potential application of ultrasmall gold nanoparticles for intranucleus delivery and therapy. We synthesized gold nanoparticles with diameters of 2, 6, 10, and 16 nm and compared their intracellular distribution in MCF-7 breast cancer cells. Nanoparticles smaller than 10 nm (2 and 6 nm) could enter the nucleus, whereas larger ones (10 and 16 nm) were found only in the cytoplasm. We then investigated the possibility of using ultrasmall 2 nm nanoparticles as carriers for nuclear delivery of a triplex-forming oligonucleotide (TFO) that binds to the c-myc promoter. Compared to free TFO, the nanoparticle-conjugated TFO was more effective at reducing c-myc RNA and c-myc protein, which resulted in reduced cell viability. Our result demonstrated that the entry of gold nanoparticles into the cell nucleus is critically dependent on the size of the nanoparticles. We developed a strategy for regulating gene expression, by directly delivering TFOs into the nucleus using ultrasmall gold nanoparticles. More importantly, guidelines were provided to choose appropriate nanocarriers for different biomedical purposes.

We proposed a facile film treatment with formic acid to enhance the conductivity of poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) by 4 orders of magnitude. The effect of formic acid concentration on conductivity was investigated; conductivity increased fast with increasing concentration up to 10 M and then increased slightly, the highest conductivity being 2050 S cm(-1) using 26 M concentration. Formic acid treated PEDOT:PSS films also exhibited very high transmittances. The mechanism of conductivity enhancement was explored through SEM, AFM, and XPS. Formic acid with its high dielectric constant screens the charge between PEDOT and PSS bringing about phase separation between them. Increased carrier concentration, removal of PSS from the film, morphology, and conformation change with elongated and better connected PEDOT chains are the main mechanisms of conductivity enhancement. ITO-free polymer solar cells were also fabricated using PEDOT:PSS electrodes treated with different concentrations of formic acid and showed equal performance to that of ITO electrodes. The concentrated acid treatment did not impair the desirable film properties as well as stability and performance of the solar cells.

The development of cellular resistance to platinum-based chemotherapies is often associated with reduced intracellular platinum concentrations. In some models, this reduction is due to abnormal membrane protein trafficking, resulting in reduced uptake by transporters at the cell surface. Given the central role of platinum drugs in the clinic, it is critical to overcome cisplatin resistance by bypassing the plasma membrane barrier to significantly increase the intracellular cisplatin concentration enough to inhibit the proliferation of cisplatin-resistant cells. Therefore, rational design of appropriate nanoscale drug delivery platforms (nDDPs) loaded with cisplatin or other platinum analogues as payloads is a possible strategy to solve this problem. This review will focus on the known mechanism of membrane trafficking in cisplatin-resistant cells and the development and employment of nDDPs to improve cell uptake of cisplatin.

Volvalerenol A (1), an unprecedented type of triterpenoid with a 7/12/7 tricyclic ring system, was obtained from the ethanol extracts of the roots of Valeriana hardwickii. The structure and relative configurations were established by comprehensive analysis of MS and NMR spectroscopic data. The possible biogenetic pathway of 1 was also deduced.

Single-walled carbon nanotubes (SWCNTs) are broadly used for various biomedical applications such as drug delivery, in vivo imaging, and cancer photothermal therapy due to their unique physiochemical properties. However, once they enter the cells, the effects of SWCNTs on the intracellular organelles and macromolecules are not comprehensively understood. Cytochrome c (Cyt c), as a key component of the electron transport chain in mitochondria, plays an essential role in cellular energy consumption, growth, and differentiation. In this study, we found the mitochondrial membrane potential and mitochondrial oxygen uptake were greatly decreased in human epithelial KB cells treated with SWCNTs, which accompanies the reduction of Cyt c. SWCNTs deoxidized Cyt c in a pH-dependent manner, as evidenced by the appearance of a 550 nm characteristic absorption peak, the intensity of which increased as the pH increased. Circular dichroism measurement confirmed the pH-dependent conformational change, which facilitated closer association of SWCNTs with the heme pocket of Cyt c and thus expedited the reduction of Cyt c. The electron transfer of Cyt c is also disturbed by SWCNTs, as measured with electron spin resonance spectroscopy. In conclusion, the redox activity of Cyt c was affected by SWCNTs treatment due to attenuated electron transfer and conformational change of Cyt c, which consequently changed mitochondrial respiration of SWCNTs-treated cells. This work is significant to SWCNTs research because it provides a novel understanding of SWCNTs' disruption of mitochondria function and has important implications for biomedical applications of SWCNTs.

This work demonstrated that ultrasmall gold nanoparticles (AuNPs) smaller than 10 nm display unique advantages over nanoparticles larger than 10 nm in terms of localization to, and penetration of, breast cancer cells, multicellular tumor spheroids, and tumors in mice. Au@tiopronin nanoparticles that have tunable sizes from 2 to 15 nm with identical surface coatings of tiopronin and charge were successfully prepared. For monolayer cells, the smaller the Au@tiopronin NPs, the more AuNPs found in each cell. In addition, the accumulation of Au NPs in the ex vivo tumor model was size-dependent: smaller AuNPs were able to penetrate deeply into tumor spheroids, whereas 15 nm nanoparticles were not. Owing to their ultrasmall nanostructure, 2 and 6 nm nanoparticles showed high levels of accumulation in tumor tissue in mice after a single intravenous injection. Surprisingly, both 2 and 6 nm Au@tiopronin nanoparticles were distributed throughout the cytoplasm and nucleus of cancer cells in vitro and in vivo, whereas 15 nm Au@tiopronin nanoparticles were found only in the cytoplasm, where they formed aggregates. The ex vivo multicellular spheroid proved to be a good model to simulate in vivo tumor tissue and evaluate nanoparticle penetration behavior. This work gives important insights into the design and functionalization of nanoparticles to achieve high levels of accumulation in tumors.

Tumor resistance to chemotherapy is the major obstacle to employ cisplatin, one of the broadly used chemotherapeutic drugs, for effective treatment of various tumors in the clinic. Most acknowledged mechanisms of cancer resistance to cisplatin focus on increased nuclear DNA repair or detoxicity of cisplatin. We previously demonstrated that there was a unique metabolic profile in cisplatin-resistant (CP-r) human epidermoid adenocarcinoma KB-CP 20 and hepatoma BEL 7404-CP 20 cancer cells. In this study, we further defined hyperpolarized mitochondrial membrane potentials (Δψ(m)) in CP-r KB-CP 20 and BEL 7404-CP 20 cells compared to the cisplatin-sensitive (CP-s) KB-3-1 and BEL 7404 cells. Based on the mitochondrial dysfunction, mitaplatin was designed with two mitochondrial-targeting moieties [dichloroacetate (DCA) units] to the axial positions of a six-coordinate Pt(IV) center to sensitize cisplatin resistance. It was found that mitaplatin induced more apoptosis in CP-r KB-CP 20 and BEL 7404-CP 20 cells than that of cisplatin, DCA and cisplatin/DCA compared on an equal molar basis. There was more platinum accumulation in mitaplatin-treated CP-r cells due to enhanced transmembrane permeability of lipophilicity, and mitaplatin also showed special targeting to mitochondria. Moreover, in the case of treatment with mitaplatin, the dramatic collapse of Δψ(m) was shown in a dose-dependent manner, which was confirmed by FACS and confocal microscopic measurements. Reduced glucose utilization of CP-r cells was detected with specifically inhibited phosphorylation of pyruvate dehydrogenase (PDH) at Ser-232, Ser-293, and Ser-300 of the E1α subunit when treated with mitaplatin, which was indicated to modulate the abnormal glycolysis of resistant cells. The present study suggested novel mitochondrial mechanism of mitaplatin circumventing cisplatin resistance toward CP-r cells as a carrier across membrane to produce CP-like cytotoxicity and DCA-like mitochondria-dependent apoptosis. Therefore, mitochondria targeting compounds would be more vulnerable and selective to overcome cisplatin resistance due to the unique metabolic properties of CP-r cancer cells.

Volvalerelactones A and B (1 and 2), two new sesquiterpenoid lactones with an unprecedented 3/7/6 tricyclic ring system, were isolated from the roots of Valeriana officinalis var. latifolia. Their structures and relative configurations were elucidated by spectroscopic data and single-crystal X-ray diffraction crystallography, and the absolute configuration was assigned by computational methods. The possible biosynthetic pathways of 1 and 2 were also proposed., (© 2011 American Chemical Society)

Charge-reversal functional gold nanoparticles first prepared by layer-by-layer technique were employed to deliver small interfering RNA (siRNA) and plasmid DNA into cancer cells. Polyacrylamide gel electrophoresis measurements of siRNA confirmed the occurrence of the charge-reversal property of functional gold nanoparticles. The expression efficiency of enhanced green fluorescent protein (EGFP) was improved by adjuvant transfection with charge-reversal functional gold nanoparticles, which also had much lower toxicity to cell proliferation. Lamin A/C, an important nuclear envelope protein, was effectively silenced by lamin A/C-siRNA delivered by charge-reversal functional gold nanoparticles, whose knockdown efficiency was better than that of commercial Lipofectamine 2000. Confocal laser scanning microscopic images indicated that there was more cy5-siRNA distributed throughout the cytoplasm for cyanine 5-siRNA/polyethyleneimine/cis-aconitic anhydride-functionalized poly(allylamine)/ polyethyleneimine/11-mercaptoundecanoic acid-gold nanoparticle (cy5-siRNA/PEI/PAH-Cit/PEI/MUA-AuNP) complexes. These results demonstrate the feasibility of using charge-reversal functional gold nanoparticles as a means of improving the nucleic acid delivery efficiency.

Protein microarrays are emerging as an important enabling technology for the simultaneous investigation of complicated interactions among thousands of proteins. The solution-based blocking protocols commonly used in protein microarray assays often cause cross-contamination among probes and diminution of protein binding efficiency because of the spreading of blocking solution and the obstruction formed by the blocking molecules. In this paper, an alternative blocking process for protein microarray assays is proposed to obtain better performance by employing a vapor-phase deposition method to form self-assembled surface coatings using a highly fluorinated organosilane as the blocking agent on the background surfaces. Compared to conventional solution-based blocking processes, our experimental results showed that this vapor-phase process could shorten the blocking time from hours to less than 10 min, enhance the binding efficiency by up to 6 times, reduce the background noise by up to 16 times, and improve the S/N ratio by up to 64 times. This facile blocking process is compatible with current microarray assays using silica-based substrates and can be performed on many types of silane-modified surfaces.

For this work, two different plastic microfluidic devices are designed and fabricated for applications in high-throughput residue analysis of food contaminants and drug screening of small-molecule libraries. Microfluidic networks on copolyester and poly(dimethylsiloxane) substrates are fabricated by silicon template imprinting and capillary molding techniques. The first device is developed to perform affinity capture, concentration, and direct identification of targeted compounds using electrospray ionization mass spectrometry. Poly(vinylidene fluoride) membranes sandwiched between the imprinted copolyester microchannels in an integrated platform provide continuous affinity dialysis and concentration of a reaction mixture containing aflatoxin B1 antibody and aflatoxins. The second microfluidic device is composed of microchannels on the poly(dimethylsiloxane) substrates. The device is designed to perform miniaturized ultrafiltration of affinity complexes of phenobarbital antibody and barbiturates, including the sequential loading, washing, and dissociation steps. These microfabricated devices not only significantly reduce dead volume and sample consumption but also increase the detection sensitivity by at least 1-2 orders of magnitude over those reported previously. Improvements in detection sensitivity are attributed to analyte preconcentration during the affinity purification step, limited analyte dilution in the microdialysis junction, minimal sample loss, and the amenability of ESI-MS to nanoscale sample flow rates.