Search

Because of the complexity of cancer, combination therapy is becoming increasingly important to overcome multidrug resistance in cancer and to enhance apoptosis. Cancer treatment using nanocarriers to co-deliver small interfering RNA (siRNA) and small molecule anticancer drugs has gained more attention because of its ability to generate synergistic anticancer effects via different mechanisms of action. This article provides a brief review on the recent developments of nanotechnology-based anticancer drug and/or siRNA delivery systems for cancer therapy. Particularly, the synergistic effects of combinatorial anticancer drug and siRNA therapy in various cancer models employing multifunctional drug/siRNA co-delivery nanocarriers have been discussed. [ABSTRACT FROM AUTHOR]

Abstract: The risk of acquisition of resistance to chemotherapy remains a major hurdle in the management of various types of cancer patients. Several cellular and noncellular mechanisms are involved in developing both intrinsic and acquired resistance in cancer cells toward chemotherapy. This review covers the various multidrug resistance (MDR) mechanisms observed in cancer cells as well as the various strategies developed to overcome these MDR mechanisms. Extensive studies have been conducted during the last several decades to enhance the efficacy of chemotherapy by suppressing or evading these MDR mechanisms including the use of new anticancer drugs that could escape from the efflux reaction, MDR modulators or chemosensitizers, multifunctional nanocarriers, and RNA interference (RNAi) therapy. [Copyright &y& Elsevier]

Abstract: Gene therapy has emerged as one of the most promising therapeutic methods to treat various diseases. However, inadequate gene transfection efficacy during gene therapy demands further development of more efficient gene delivery strategies. Targeting genetic material to specific sites of action endows numerous advantages over non-targeted delivery. An ample variety of non-viral gene delivery vectors have been developed in recent years owing to the safety issues raised by viral vectors. Non-viral gene delivery vectors containing specific targeting ligands on their surfaces have been reported to enhance the gene transfection efficiency via receptor-mediated endocytosis for gene delivery. Among various targeting moieties investigated, carbohydrates and lectins (carbohydrate-binding proteins) played an essential role in gene delivery via either direct or reverse lectin targeting strategies. Lectins have a specific carbohydrate binding domain that can bind specifically to the carbohydrates. This review sheds light on various gene delivery nanovectors conjugated with either lectins or carbohydrates for enhanced gene transfection. [Copyright &y& Elsevier]

Abstract: An electrochemical breast cancer biosensor based on a chitosan-co-polyaniline (CHIT-co-PANI) copolymer coated onto indium–tin-oxide (ITO) was fabricated by immobilizing the complementary DNA (cDNA) probe (42 bases long) associated with the breast cancer susceptible gene BRCA1. Both the CHIT-co-PANI/ITO and the cDNA/CHIT-co-PANI/ITO electrodes were characterized with Fourier transform infrared (FTIR) spectroscopy, atomic force microscopy (AFM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). For the cDNA/CHIT-co-PANI/ITO electrode, the amperometric current decreased linearly with an increasing logarithm of molar concentration of the single-stranded target DNA (ssDNA) within the range of 0.05–25fmol. The bioelectrode exhibited a sensitivity of 2.104μA/fmol with a response time of 16s. The cDNA/CHIT-co-PANI/ITO electrode had a shelf life of about six months, even when stored at room temperature. [Copyright &y& Elsevier]

Abstract: A novel thiolated carboxymethyl chitosan-g-β-cyclodextrin (CMC-g-β-CD) drug delivery carrier was synthesized and characterized. Thiolated CMC-g-β-CD was synthesized using two steps. First, carboxymethyl β-cyclodextrin (CM β-CD) was grafted onto carboxymethyl chitosan (CMC) using water-soluble 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS) as the condensing agents. Next, the resultant product was further grafted with cysteine methyl ester hydrochloride (CMEH). Its structure was confirmed by FT-IR and 1H NMR spectral analysis. X-ray diffraction (XRD) analysis on the resulting product showed that the peaks at 2θ =10° and 20° decreased greatly in thiolated polymers, indicating that these polymers are more amorphous in nature. The swelling study showed that the water uptake of thiolated CMC-g-β-CD was higher than that of the unmodified chitosan control. The adhesive properties of thiolated CMC-g-β-CD were evaluated in vitro on a freshly excised mouse mucosa, and a fivefold increase in the adhesion time was found in thiolated CMC-g-β-CD when compared with the unmodified chitosan control. The drug release profile showed that thiolated CMC-g-β-CD tablets provided a slower release of the entrapped hydrophobic model drug, ketoprofen, than the chitosan control, and the release behavior was influenced by the amounts of thiol groups present on the polymer chains. These results suggest that thiolated CMC-g-β-CD with improved mucoadhesive properties may potentially become an effective hydrophobic drug delivery system with controlled drug release capability. [Copyright &y& Elsevier]

A simple and sensitive immunosensor for the detection of cancer biomarker prostate specific antigen (PSA) has been developed. Around the percolation threshold of the graphene film, the conductivity of the graphene film varies significantly with the surface adsorption of molecules, which can be used for the detection of proteins based on antibody–antigen binding. [ABSTRACT FROM AUTHOR]

This paper presents a simplified analytical model and balanced design approach for modeling light-weight wood-based structural panels in bending. Because many design parameters are required to input for the model of finite element analysis (FEA) during the preliminary design process and optimization, the equivalent method was developed to analyze the mechanical performance of panels based on experimental results. The bending deflection, normal strain and shear strain of the panels with various configurations were investigated using four point bending test. The results from the analytical model matched well with the experimental data, especially, the prediction for maximum deflection of the panels under failure load. The normal strain and shear strain calculated by the model also agreed with the experimental data. The failure criterion was determined by the failure modes using a 3-dimensional diagram with apparent normal and shear strain. For demonstration, panels 1 and 2 with a fixed core were modeled using the balanced design approach for optimal face thickness. The results showed that both the 3-dimensional diagram and analytical model provided similar thickness results, which were verified by the FEA for wood-based structural panels. [ABSTRACT FROM AUTHOR]

Abstract: Quantum dot (QD) functionalized graphene sheets (GS) were prepared and used as labels for the preparation of sandwich-type electrochemical immunosensors for the detection of a cancer biomarker (i.e., prostate specific antigen (PSA)). The primary anti-PSA antibody was also immobilized onto the GS. The immunosensor displayed a wide range of linear response (0.005–10ng/mL), low detection limit (3pg/mL), and good reproducibility, selectivity and stability. The immunosensor was used to detect PSA in patient serum samples with satisfactory results. Thus, this unique immunosensor may provide many applications in clinical diagnosis. [Copyright &y& Elsevier]

Abstract: Poly(trimethylene carbonate)-block-poly(ethylene glycol)-block-poly(trimethylene carbonate) (PTMC–PEG–PTMC) triblock copolymers were synthesized successfully by the microwave-assisted ring-opening copolymerization of trimethylene carbonate (TMC) and poly(ethylene glycol) (PEG). The polymerizations were carried out in a single-mode microwave oven in the absence of any metallic compound catalyst. In the presence of PEG600, PTMC–PEG–PTMC triblock copolymer with a number-average molar mass of 16,600g/mol and a TMC conversion of 97% could be synthesized after the TMC/PEG600 reaction mixture was irradiated at 120°C for 60min. Both the molar mass of the resulting triblock copolymer and TMC conversion produced by the microwave method were higher than those produced by the conventional method. Thermal properties of the resulting polymers were studied by differential scanning calorimetry. [Copyright &y& Elsevier]

Abstract: Poly(trimethylene carbonate) (PTMC) was synthesized successfully by microwave-assisted ring-opening polymerization of trimethylene carbonate. The polymerizations were carried out in a single-mode microwave oven using ethylene glycol (EG) as the initiator in the absence of any metallic compound catalyst. The temperature–time profiles of the reaction mixture were investigated at different power levels and EG concentrations. The molar mass of the resulting PTMC and TMC monomer conversion by the microwave method is higher than those by the conventional method. Thermal properties of the resulting polymers were studied by differential scanning calorimetry. Microwave irradiation proved to be an effective and efficient method for the preparation of PTMC. [Copyright &y& Elsevier]

The long-term success of endovascular intervention has long been overshadowed by vessel re-occlusion, also known as restenosis. Mainstream anti-restenotic devices, such as drug-eluting stent (DES) and drug-coated balloon (DCB), were recently shown with suboptimal performances and life-threatening complications, thereby underpinning the urgent need for alternative strategies with enhanced efficacy and safety profile. In our current study, we engineered a multimodal nanocluster formed by self-assembly of unimolecular nanoparticles and surface coated with platelet membrane, specifically tailored for precision drug delivery in endovascular applications. More specifically, it incorporates the combined merits of platelet membrane coating (lesion targetability and biocompatibility), reactive oxygen species (ROS)-detonable "cluster-bomb" chemistry (to trigger the large-to-small size transition at the target site, thereby achieving longer circulation time and higher tissue penetration), and sustained drug release. Using RVX-208 (an emerging anti-restenotic drug under clinical trials) as the model payload, we demonstrated the superior performances of our nanocluster over conventional poly(lactic- co -glycolic acid) (PLGA) nanoparticle. In cultured vascular smooth muscle cell (VSMC), the drug-loaded nanocluster induced effective inhibition of proliferation and protective gene expression (e.g., APOA-I) with a significantly reduced dosage of RVX-208 (1 μM). In a rat model of balloon angioplasty, intravenous injection of Cy5.5-tagged nanocluster led to greater lesion targetability, improved biodistribution, and deeper penetration into injured vessel walls featuring enriched ROS. Moreover, in contrast to either free drug solution or drug-loaded PLGA nanoparticle formulation, a single injection with the drug-loaded nanocluster (10 mg/kg of RVX-208) was sufficient to substantially mitigate restenosis. Additionally, this nanocluster also demonstrated biocompatibility according to in vitro cytotoxicity assay and in vivo histological and tissue qPCR analysis. Overall, our multimodal nanocluster offers improved targetability, tissue penetration, and ROS-responsive release over conventional nanoparticles, therefore making it a highly promising platform for development of next-generation endovascular therapies. [Display omitted] [ABSTRACT FROM AUTHOR]

The rapid development of gene therapy and genome editing techniques brings up an urgent need to develop safe and efficient nanoplatforms for nucleic acids and CRISPR genome editors. Herein we report a stimulus-responsive silica nanoparticle (SNP) capable of encapsulating biomacromolecules in their active forms with a high loading content and loading efficiency as well as a well-controlled nanoparticle size (~50 nm). A disulfide crosslinker was integrated into the silica network, endowing SNP with glutathione (GSH)-responsive cargo release capability when internalized by target cells. An imidazole-containing component was incorporated into the SNP to enhance the endosomal escape capability. The SNP can deliver various cargos, including nucleic acids (e.g., DNA and mRNA) and CRISPR genome editors (e.g., Cas9/sgRNA ribonucleoprotein (RNP), and RNP with donor DNA) with excellent efficiency and biocompatibility. The SNP surface can be PEGylated and functionalized with different targeting ligands. In vivo studies showed that subretinally injected SNP conjugated with all- trans -retinoic acid (ATRA) and intravenously injected SNP conjugated with GalNAc can effectively deliver mRNA and RNP to murine retinal pigment epithelium (RPE) cells and liver cells, respectively, leading to efficient genome editing. Overall, the SNP is a promising nanoplatform for various applications including gene therapy and genome editing. [Display omitted] [ABSTRACT FROM AUTHOR]

Flexible electronics incorporating built-in thin-film semiconductors with soft substrates allow devices or systems to conform to desired shapes, creating opportunities for various novel applications. High radio-frequency (RF) power flexible devices play significant roles in flexible wireless communication and other miniaturized microwave systems in the future. However, high power operations of devices generate a massive amount of heat, and if not dissipated effectively, the excessive heat can degrade the performance of flexible active devices and even cause irreversible damage to the systems. In this work, we present a hybrid heat dissipation structure that can be used in flexible electronics where significant heat dissipation is needed. The structure was designed with finite element method-based simulations with the goal of achieving both high heat dissipation efficiency and mechanical flexibility. The structure was fabricated using a phase transition technique, greatly simplifying the fabrication process without need of handling liquid in the fabrication process, and was tested on an ultra-thin flexible AlGaN/GaN high electron mobility transistor (HEMT). The maximum power handled by the heat-managed HEMT measured from the IDS–VDS curve was 2.33 times larger than a reference HEMT without the heat dissipation structure. This demonstration opens new prospects for expanding the applications of flexible electronics toward high-power radio frequency regime in the future. [ABSTRACT FROM AUTHOR]

Versatile wood cellulose, the most prototypical abundant polymer on earth, is considered a promising natural material for the fabrication of biodegradable electronics. The development of biodegradable electronics may help alleviate the adverse environmental impact caused by the fast‐growing electronic waste (e‐waste). The focus of this review is to discuss recent major advances in biodegradable electronics with versatile wood cellulose in terms of supporting substrates and functional components. First, the biological biodegradation and structural hierarchy of versatile wood cellulose is briefly introduced, followed by highlighting three types of cellulose substrates (opaque and hazy cellulose paper, transparent and clear cellulose film, and transparent and hazy cellulose film) for biodegradable electronics. Then, recent progress and research achievements in the use of versatile wood cellulose with multiscale dimensions in biodegradable electronics as a functional component (e.g., advanced light management layer, high capacitance dielectric, and ionic conductor) or even smart materials (e.g., mechanochromic layer, humidity sensing layer, adaptable adhesive layer, and piezoelectric component) are summarized in detail. Finally, an overview of challenges and perspectives for biodegradable electronics with versatile cellulose is provided. [ABSTRACT FROM AUTHOR]

Microwave electronics have evolved from bulky waveguide and vacuum tube‐based format to smaller and lighter board‐based electronics, and then to the highly miniaturized, chip‐based solid‐state form. Spurred by the advent of high‐performance flexible inorganic single‐crystalline semiconductors, a new opportunity of technology evolution from rigid microwave electronics to flexible and/or stretchable microwave electronics has emerged. The new forms of microwave electronics are expected to provide novel functions to be achieved with advanced materials, device, and system design considerations and innovative fabrication methods. Over the last years, some microwave components, modules, and systems with operation frequency greater than or equal to 1 GHz in the flexible/stretchable form factors are demonstrated. These demonstrations have alluded to the prospects of the new stage of microwave electronics evolution. Herein, a comprehensive review of the microwave/flexible microwave electronics that are demonstrated up to date is provided. An introduction to the need of flexible/stretchable microwave electronics emphasizes the motivation and potential influences of this new growing field. This review also highlights important developments in transistors, diodes, various passives, antennas, circuits, and system demonstrations, all in flexible or stretchable forms. Finally, an outlook for specific technical gaps at both the fundamental and applications levels is presented. [ABSTRACT FROM AUTHOR]

An urgent need for developing new antimicrobial approaches has emerged due to the imminent threat of antimicrobial‐resistant (AMR) pathogens. Bacterial infection can induce a unique microenvironment with low pH, which can be employed to trigger drug release and activation. Here, a pH‐responsive polymer–drug conjugate (PDC) capable of combating severe infectious diseases and overcoming AMR is reported. The PDC is made of a unique biodegradable and biocompatible cationic polymer Hex‐Cys‐DET and streptomycin, a model antibiotic. The two components show strong antimicrobial synergy since the polymer can induce pores on the bacterial wall/membrane, thus significantly enhancing the transport of antibiotics into the bacteria and bypassing the efflux pump. The PDC is neutralized for enhanced biocompatibility under physiological conditions but becomes positively charged while releasing the antibiotic in infected tissues due to the low pH. Additionally, the polymer contains disulfide bonds in its main chain, which makes it biodegradable in mammalian cells and thus reducing the cytotoxicity. The PDC can effectively penetrate bacterial biofilms and be taken up by mammalian cells, thereby minimizing biofilm‐induced AMR and intracellular infections. The PDC exhibits remarkable antimicrobial activity in three in vivo infection models, demonstrating its broad‐spectrum antimicrobial capability and great potency in eliminating AMR infections. [ABSTRACT FROM AUTHOR]

Efficient delivery of hydrophilic drugs, nucleic acids, proteins, and any combination thereof is essential for various biomedical applications. Herein, we report a straightforward, yet versatile approach to efficiently encapsulate and deliver various hydrophilic payloads using a pH-responsive silica–metal–organic framework hybrid nanoparticle (SMOF NP) consisting of both silica and zeolitic imidazole framework (ZIF). This unique SMOF NP offers a high loading content and efficiency, excellent stability, and robust intracellular delivery of a variety of payloads, including hydrophilic small molecule drugs (e.g., doxorubicin hydrochloride), nucleic acids (e.g., DNA and mRNA), and genome-editing machineries (e.g., Cas9-sgRNA ribonucleoprotein (RNP), and RNP together with donor DNA (e.g., RNP + ssODN)). The superior drug delivery/gene transfection/genome-editing efficiencies of the SMOF NP are attributed to its pH-controlled release and endosomal escape capabilities due to the proton sponge effect enabled by the imidazole moieties in the SMOF NPs. Moreover, the surface of the SMOF NP can be easily customized (e.g., PEGylation and ligand conjugation) via various functional groups incorporated into the silica component. RNP-loaded SMOF NPs induced efficient genome editing in vivo in murine retinal pigment epithelium (RPE) tissue via subretinal injection, providing a highly promising nanoplatform for the delivery of a wide range of hydrophilic payloads. Unlabelled Image [ABSTRACT FROM AUTHOR]

Purpose: Retinopathy of prematurity (ROP) is a condition of abnormal retinal vascularization with reduced levels of vascular endothelial growth factor (VEGF) causing vaso-obliteration (Phase I), followed by abnormal neovascularization from increased VEGF (Phase II). We hypothesized that intravitreal pro-angiogenic VEGF-A in microparticle form would promote earlier retinal revascularization in an oxygen-induced ischemic retinopathy (OIR) mouse model. Materials and Methods: Wildtype mice (39) were exposed to 77% oxygen from postnatal day 7 (P7) to P12. VEGF-A165-loaded poly(lactic-co-glycolic acid) (PLGA) (n = 15) or empty PLGA (n = 14) microparticles were fabricated using a water-in-oil-in-water double emulsion method, and injected intravitreally at P13 into mice right eyes (RE). Left eyes (LE) were untreated. At P20, after retinal fluorescein angiography, vascular parameters were quantified. Retinal VEGF levels at P13 and flatmounts at P20 were performed separately. Results: VEGF-A165-loaded microparticles had a mean diameter of 4.2 μm. with a loading level of 8.6 weight.%. Retinal avascular area was reduced in VEGF-treated RE (39.5 ± 9.0%) compared to untreated LE (52.6 ± 6.1%, p < 0.0001) or empty microparticle-treated RE (p < 0.001) and untreated LEs (p = 0.001). Retinal arteries in VEGF-treated RE were less tortuous than untreated LE (1.08 ± 0.05 vs. 1.18 ± 0.08, p < 0.001) or empty-microparticles-treated RE (p = 0.02). Retinal arterial tortuosity was similar in the LE of VEGF and empty microparticle-treated mice (P > 0.05). Retinal vein width was similar in VEGF-treated and empty microparticle-treated RE (P > 0.9), which were each less dilated than their contralateral LE (p < 0.01). VEGF levels were higher in P13 OIR mice than RA mice (p < 0.0001). Retinal flatmounts showed vaso-obliteration and neovascularization. Conclusions: Endogenous retinal VEGF is suppressed in OIR mice. Exogenous intravitreal VEGF-A165-loaded microparticles in OIR mice reduced retinal vaso-obliteration and accelerated recovery from vein dilation and arterial tortuosity. This may be beneficial in preventing Phase II ROP without systemic effects. [ABSTRACT FROM AUTHOR]

Open vascular reconstructions such as bypass are common treatments for cardiovascular disease. Unfortunately, neointimal hyperplasia (IH) follows, leading to treatment failure for which there is no approved therapy. Here we combined the strengths of tailoring nanoplatforms for open vascular reconstructions and targeting new epigenetic mechanisms. We produced adhesive nanoparticles (ahNP) that could be pen-brushed and immobilized on the adventitia to sustainably release pinometostat, an inhibitor drug selective to the epigenetic writer DOT1L that catalyzes histone-3 lysine-79 dimethylation (H3K79me2). This treatment not only reduced IH by 76.8% in injured arteries mimicking open reconstructions in obese Zucker rats with human-like diseases but also avoided the shortcoming of endothelial impairment in IH management. In mechanistic studies, chromatin immunoprecipitation (ChIP) sequencing revealed co-enrichment of the histone mark H3K27ac(acetyl) and its reader BRD4 at the gene of aurora kinase B (AURKB), where H3K79me2 was also enriched as indicated by ChIP-qPCR. Accordingly, DOT1L co-immunoprecipitated with H3K27ac. Furthermore, the known IH driver BRD4 governed the expression of DOT1L which controlled AURKB's protein level, revealing a BRD4- > DOT1L- > AURKB axis. Consistently, AURKB-selective inhibition reduced IH. Thus, this study presents a prototype nanoformulation suited for open vascular reconstructions, and the new insights into chromatin modulators may aid future translational advances. [Display omitted] • Bioadhesive nanoparticle is pen-brushed on arteries for adventitia-localized delivery. • A DOT1L inhibitor drug (Pino) so delivered abates neointima in obese Zucker rats. • Unlike rapamycin, Pino does not impair the recovery of injured endothelium in vivo. • The epigenetic axis BRD4->DOT1L->AURKB regulates smooth muscle cell phenotype. • AURKB-selective inhibition hampers neointimal hyperplasia in injured rat arteries. [ABSTRACT FROM AUTHOR]

Drug-eluting stents are the most commonly employed method to control post-angioplasty restenosis. Unfortunately, they exacerbate life-threatening stent thrombosis because of endothelium damage caused by both drug and stenting. To solve this major medical problem, an endothelium-protective and stent-free anti -restenotic method is highly desirable. Here we have generated a biomimetic intravenous delivery system using dendritic polymer-based nanoclusters, which were coated with platelet membranes for targeting to the injured arterial wall where restenosis occurs. These nanoclusters were loaded with an endothelium-protective epigenetic inhibitor (JQ1) or an endothelium-toxic status quo drug (rapamycin), and compared for their ability to mitigate restenosis without hindering the process of re-endothelialization. Fluorescence imaging of Cy5-tagged biomimetic nanoclusters indicated their robust homing to injured, but not uninjured arteries. Two weeks after angioplasty, compared to no-drug control, both rapamycin- and JQ1-loaded biomimetic nanoclusters substantially reduced (by >60%) neointimal hyperplasia, the primary cause of restenosis. However, whereas the rapamycin formulation impaired the endothelial re-coverage of the denuded inner arterial wall, the JQ1 formulation preserved endothelial recovery. In summary, we have created an endothelium-protective anti -restenotic system with biomimetic nanoclusters containing an epigenetic inhibitor. This system warrants further development for a non-thrombogenic and stent-free method for clinical applications. [ABSTRACT FROM AUTHOR]

Spatiotemporal control over the release or activation of biomacromolecules such as siRNA remains a significant challenge. Light-controlled release has gained popularity in recent years; however, a major limitation is that most photoactivable compounds/systems respond only to UV irradiation, but not near-infrared (NIR) light that offers a deeper tissue penetration depth and better biocompatibility. This paper reports a simple NIR-to-UV upconversion nanoparticle (UCNP)-based siRNA nanocarrier for NIR-controlled gene silencing. siRNA is complexed onto a NaYF 4 :Yb/Tm/Er UCNP through an azobenzene (Azo)–cyclodextrin (CD) host–guest interaction. The UV emission generated by the NIR-activated UCNP effectively triggers the trans -to- cis photoisomerization of azobenzene, thus leading to the release of siRNA due to unmatched host − guest pairs. The UCNP-siRNA complexes are also functionalized with PEG (i.e., UCNP-(CD/Azo)-siRNA/PEG NPs), targeting ligands (i.e., EGFR-specific GE11 peptide), acid-activatable cell-penetrating peptides (i.e., TH peptide), and imaging probes (i.e., Cy5 fluorophore). The UCNP-(CD/Azo)-siRNA/PEG NPs with both GE11 and TH peptides display a high level of cellular uptake and an excellent endosomal/lysosomal escape capability. More importantly, NIR-controlled spatiotemporal knockdown of GFP expression is successfully achieved in both a 2D monolayer cell model and a 3D multicellular tumor spheroid model. Thus, this simple and versatile nanoplatform has great potential for the selective activation or release of various biomacromolecules. [ABSTRACT FROM AUTHOR]

Polymeric unimolecular nanoparticles (NPs) exhibiting a core-shell structure and formed by a single multi-arm molecule containing only covalent bonds have attracted increasing attention for numerous biomedical applications. This unique single-molecular architecture provides the unimolecular NP with superior stability both in vitro and in vivo, a high drug loading capacity, as well as versatile surface chemistry, thereby making it a desirable nanoplatform for therapeutic and diagnostic applications. In this review, we surveyed the architecture of various types of polymeric unimolecular NPs, including water-dispersible unimolecular micelles and water-soluble unimolecular NPs used for the delivery of hydrophobic and hydrophilic agents, respectively, as well as their diverse biomedical applications. Future opportunities and challenges of unimolecular NPs were also briefly discussed. [ABSTRACT FROM AUTHOR]

Abstract: A novel class of high performance polymer porous aerogel film‐based triboelectric nanogenerators (A‐NGs) is demonstrated. The A‐NGs, made of a pair of highly porous polymer films, exhibit much higher triboelectric outputs than the corresponding dense polymer film‐based triboelectric nanogenerators (D‐NGs) under the same mechanical stress. The triboelectric outputs of the A‐NGs increase significantly with increasing porosity, which can be attributed to the increase in contact area and the electrostatic induction in the porous structure, thereby leading to additional charges on the porous surface. Remarkably, the A‐NG fabricated using porous chitosan aerogel film paired with the most porous polyimide (with a porosity of 92%) aerogel film demonstrates a very high voltage of 60.6 V and current of 7.7 µA, corresponding to a power density of 2.33 W m−2, which is sufficient to power 22 blue light‐emitting‐diodes (LEDs). This is the first report on triboelectric nanogenerators (TENGs) employing porous polymer aerogel films as both positive and negative materials to enhance triboelectric outputs. Furthermore, enhancing the tribopositive polarity of the cellulose aerogel film via silanization using aminosilane can dramatically improve the triboelectric performance. Therefore, this study provides new insights into investigating porous materials with tunable triboelectric polarities for high performance TENGs. [ABSTRACT FROM AUTHOR]

As the expected life of dry cask storage installations increases, it becomes increasingly desirable to monitor the state and performance of the cask internals to ensure that they continue to safely contain the radioactive materials in the fuel. One aspect of this task is the monitoring of oxidation of the cladding. With this consideration in mind, Zircaloy-4 (Zr-4) cladding samples were exposed to air at 500C for various duration times to create thin corrosion oxide layers on the surface. The surfaces of the oxidized samples were then systematically scanned by Fourier Transform Infrared (FT-IR) spectroscopy to achieve the infrared (IR) interference spectra and study the relationship between the optical interference and the various thicknesses of the oxide layers. The profiles of the oxide layers were verified througth cross-sectional examination by Scanning Electron Microscopy. The IR interference patterns varied with oxide layer thickness, enabling the determination of oxide layer thickness of values, including half micron thick. Further analysis demonstrated that the interference oscillation period and the oscillation amplitude decreased with increasing oxide layer thickness. Combined with a physical model that describes the optical interference, the interference spectra were directly correlated to the oxide layer thickness quantitatively. The study provides the basis for an accurate, nondestructive and sensitive method to monitor the degree of zirconium-based cladding corrosion due to oxidation. Zircaloy-4 (Zr-4) cladding samples were exposed to air at 500∘C for various time-lengths to create thin corrosion oxide layers on their surface. Fourier transform infrared spectroscopy was used to quantify the oxide thickness. Interference spectra revealed the oxide thickness along with support of a physical model. The study provides an accurate, nondestructive, yet a sensitive method to monitor the degree of zirconium-based cladding corrosion due to oxidation. [ABSTRACT FROM AUTHOR]

Abstract: A novel method is developed to realize a III‐V/Si dual‐junction photovoltaic cell by combining epitaxial lift‐off (ELO) and print‐transfer‐assisted bonding methods. The adoption of ELO enables III‐V wafers to be recycled and reused, which can further lower the cost of III‐V/Si photovoltaic panels. For demonstration, high crystal quality, micrometer‐thick, GaAs/AlGaAs/GaAs films are lifted off, transferred, and directly bonded onto Si wafer without the use of any adhesive or bonding agents. The bonding interface is optically transparent and conductive both thermally and electrically. Prototype AlGaAs/Si dual‐junction tandem solar cells have been fabricated and exhibit decent performance. [ABSTRACT FROM AUTHOR]

The ability to topographically mimic the surface features of collagen fibrils is an important step in the preparation of tissue engineering scaffolds. It is important to know which kinds of surface topographies of electrospun fibers are more favorable for cell growth. In this study, fibers with three kinds of hierarchical-structured surfaces were fabricated by electrospinning to mimic collagen fibrils. By combining thermally induced phase separation (TIPS) and non-solvent induced phase separation (NIPS), polycaprolactone (PCL) fibers with a porous surface were electrospun from PCL in a chloroform (CF)/dimethyl sulfoxide (DMSO) mixed solution. In addition, two additional types of fibrous membranes, with PCL fibers being the shish and decorated by PCL kebabs on the surface, were created by two different controlled homoepitaxic crystallization methods—the solution incubation method and the solvent evaporation method. It was found that the solvent evaporation method was more effective in forming kebabs and the primary optimal processing parameters were identified. The presence of pores on the fiber surfaces contributed to a much larger surface area and a higher total volume of pores. To investigate the cellular response on such scaffolds, 3T3 fibroblast cell and human umbilical vein endothelial cell (HUVEC) assays were conducted and the results indicated that both of the nanotopographies on the surfaces of the scaffolds improved cell viability and proliferation. Furthermore, the porous surface was more beneficial for enhancing cellular responses, which suggests better biocompatibility and greater potential to mimic collagen fibrils for tissue engineering application, and especially as scaffolds for endothelial layers in blood vessels. [ABSTRACT FROM AUTHOR]

Notch signaling is minimally active in neuroendocrine ( NE) cancer cells. While histone deacetylase inhibitors ( HDACi) suppress NE cancer growth by inducing Notch, the molecular mechanism underlying this interplay has not yet been defined. NE cancer cell lines BON, H727, and MZ- CRC-1 were treated with known HDACi Thailadepsin-A ( TDP-A) and valproic acid ( VPA), and Notch1 mRNA expression was measured with RT- PCR. Truncated genomic fragments of the Notch1 promotor region fused with luciferase reporter were used to identify the potential transcription factor ( TF) binding site. The key regulatory TF was identified with the electrophoretic mobility shift assay ( EMSA). The effect of HDACi on Notch1 level was determined before and after silencing the TF. TDP-A and VPA induced Notch1 mRNA in a dose-dependent manner. A functional DNA motif at −80 to −52 from the Notch1 start codon responsible for the HDACi-dependent Notch1 induction was identified. Mutation of this core sequence failed to induce luciferase activity despite HDACi treatment. EMSA showed the greatest gel shift with AP-1 in nuclear extracts. Knockdown of AP-1 significantly attenuated the effect of HDACi on Notch1 induction. Interestingly, AP-1 transfection did not alter Notch1 level, suggesting that AP-1 is necessary but insufficient for HDACi activation of Notch1. Therefore, AP-1 is the TF that binds to a specific transcription-binding site within the Notch1 promotor region to trigger Notch1 transcription. Elucidating the HDACi activation mechanism may lead to the development of novel therapeutic options against NE cancers and facilitate the identification of clinical responders and prevent adverse effects. [ABSTRACT FROM AUTHOR]

A unique pH/redox dual-sensitive cationic unimolecular nanoparticle (NP) enabling excellent endosomal/lysosomal escape and efficient siRNA decomplexation inside the target cells was developed for tumor-targeted delivery of siRNA. siRNA was complexed into the cationic core of the unimolecular NP through electrostatic interactions. The cationic core used for complexing siRNA contained reducible disulfide bonds that underwent intracellular reduction owing to the presence of high concentrations of reduced glutathione (GSH) inside the cells, thereby facilitating the decomplexation of siRNA from the unimolecular NPs. The cationic polymers were conjugated onto the hyperbranched core (H40) via a pH-sensitive bond, which further facilitated the decomplexation of siRNA from the NPs. In vitro studies on the siRNA release behaviors showed that dual stimuli (pH = 5.3, 10 mM GSH) induced the quickest release of siRNA from the NPs. In addition, the imidazole groups attached to the cationic polymer segments enhanced the endosomal/lysosomal escape of NPs via the proton sponge effect. Intracellular tracking studies revealed that siRNA delivered by unimolecular NPs was efficiently released to the cytosol. Moreover, the GE11 peptide, an anti-EGFR peptide, enhanced the cellular uptake of NPs in MDA-MB-468, an EFGR-overexpressing triple negative breast cancer (TNBC) cell line. The GE11-conjugated, GFP-siRNA-complexed NPs exhibited excellent GFP gene silencing efficiency in GFP-MDA-MB-468 TNBC cells without any significant cytotoxicity. Therefore, these studies suggest that this smart unimolecular NP could be a promising nanoplatform for targeted siRNA delivery to EFGR-overexpressing cancer cells. [ABSTRACT FROM AUTHOR]

Although neuroendocrine tumors (NETs) are slow growing, they are frequently metastatic at the time of discovery and no longer amenable to curative surgery, emphasizing the need for the development of other treatments. In this study, multifunctional upconversion nanoparticle (UCNP)-based theranostic micelles are developed for NET-targeted and near-infrared (NIR)-controlled combination chemotherapy and photodynamic therapy (PDT), and bioimaging. The theranostic micelle is formed by individual UCNP functionalized with light-sensitive amphiphilic block copolymers poly(4,5-dimethoxy-2-nitrobenzyl methacrylate)-polyethylene glycol (PNBMA-PEG) and Rose Bengal (RB) photosensitizers. A hydrophobic anticancer drug, AB3, is loaded into the micelles. The NIR-activated UCNPs emit multiple luminescence bands, including UV, 540 nm, and 650 nm. The UV peaks overlap with the absorption peak of photocleavable hydrophobic PNBMA segments, triggering a rapid drug release due to the NIR-induced hydrophobic-to-hydrophilic transition of the micelle core and thus enabling NIR-controlled chemotherapy. RB molecules are activated via luminescence resonance energy transfer to generate 1O2 for NIR-induced PDT. Meanwhile, the 650 nm emission allows for efficient fluorescence imaging. KE108, a true pansomatostatin nonapeptide, as an NET-targeting ligand, drastically increases the tumoral uptake of the micelles. Intravenously injected AB3-loaded UCNP-based micelles conjugated with RB and KE108-enabling NET-targeted combination chemotherapy and PDT-induce the best antitumor efficacy. [ABSTRACT FROM AUTHOR]

Glaucoma is a common blinding disease characterized by loss of retinal ganglion cells (RGCs). To date, there is no clinically available treatment directly targeting RGCs. We aim to develop an RGC-targeted intraocular drug delivery system using unimolecular micelle nanoparticles (unimNPs) to prevent RGC loss. The unimNPs were formed by single/individual multi-arm star amphiphilic block copolymer poly(amidoamine)–polyvalerolactone–poly(ethylene glycol) (PAMAM–PVL–PEG). While the hydrophobic PAMAM–PVL core can encapsulate hydrophobic drugs, the hydrophilic PEG shell provides excellent water dispersity. We conjugated unimNPs with the cholera toxin B domain (CTB) for RGC-targeting and with Cy5.5 for unimNP-tracing. To exploit RGC-protective sigma-1 receptor (S1R), we loaded unimNPs with an endogenous S1R agonist dehydroepiandrosterone (DHEA) as an FDA-approved model drug. These unimNPs produced a steady DHEA release in vitro for over two months at pH 7.4. We then co-injected (mice, intraocular) unimNPs with the glutamate analog N -methyl- d -aspartate (NMDA), which is excito-toxic and induces RGC death. The CTB-conjugated unimNPs (i.e., targeted NPs) accumulated at the RGC layer and effectively preserved RGCs at least for 14 days, whereas the unimNPs without CTB (i.e., non-targeted NPs) showed neither accumulation at nor protection of NMDA-treated RGCs. Consistent with S1R functions, targeted NPs relative to non-targeted NPs showed markedly better inhibitory effects on apoptosis and oxidative/inflammatory stresses in the RGC layer. Hence, the DHEA-loaded, CTB-conjugated unimNPs represent an RGC/S1R dual-targeted nanoplatform that generates an efficacious template for further development of a sustainable intraocular drug delivery system to protect RGCs, which may be applicable to treatments directed at glaucomatous pathology. [ABSTRACT FROM AUTHOR]

Genome editing of somatic cells via clustered regularly interspaced short palindromic repeats (CRISPR) offers promise for new therapeutics to treat a variety of genetic disorders, including neurological diseases. However, the dense and complex parenchyma of the brain and the post-mitotic state of neurons make efficient genome editing challenging. In vivo delivery systems for CRISPR-Cas proteins and single guide RNA (sgRNA) include both viral vectors and non-viral strategies, each presenting different advantages and disadvantages for clinical application. We developed non-viral and biodegradable PEGylated nanocapsules (NCs) that deliver preassembled Cas9-sgRNA ribonucleoproteins (RNPs). Here, we show that the RNP NCs led to robust genome editing in neurons following intracerebral injection into the healthy mouse striatum. Genome editing was predominantly observed in medium spiny neurons (>80%), with occasional editing in cholinergic, calretinin, and parvalbumin interneurons. Glial activation was minimal and was localized along the needle tract. Our results demonstrate that the RNP NCs are capable of safe and efficient neuronal genome editing in vivo. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer for which there is no available targeted therapy. TNBC cases contribute disproportionately to breast cancer-related mortality, thus the need for novel and effective therapeutic methods is urgent. We have previously shown that a National Cancer Institute (NCI) investigational drug aminoflavone (AF) exhibits strong growth inhibitory effects in TNBC cells. However, in vivo pulmonary toxicity resulted in withdrawal or termination of several human clinical trials for AF. Herein we report the in vivo efficacy of a nanoformulation of AF that enhances the therapeutic index of AF in TNBC. We engineered a unique unimolecular micelle nanoparticle (NP) loaded with AF and conjugated with GE11, a 12 amino acid peptide targeting epidermal growth factor receptor (EGFR), since EGFR amplification is frequently observed in TNBC tumors. These unimolecular micelles possessed excellent stability and preferentially released drug payload at endosomal pH levels rather than blood pH levels. Use of the GE11 targeting peptide resulted in enhanced cellular uptake and strong growth inhibitory effects in TNBC cells. Further, AF-loaded, GE11-conjugated (targeted) unimolecular micelle NPs significantly inhibit orthotopic TNBC tumor growth in a xenograft model, compared to treatment with AF-loaded, GE11-lacking (non-targeted) unimolecular micelle NPs or free AF. Interestingly, the animals treated with AF-loaded, targeted NPs had the highest plasma and tumor level of AF among different treatment groups yet exhibited no increase in plasma aspartate aminotransferase (AST) activity level or observable tissue damage at the time of sacrifice. Together, these results highlight AF-loaded, EGFR-targeted unimolecular micelle NPs as an effective therapeutic option for EGFR-overexpressing TNBC. [ABSTRACT FROM AUTHOR]

Superhydrophobic and crosslinked poly(vinyl alcohol) (PVA)/cellulose nanofibril (CNF) aerogel microspheres were prepared via a combination of the water-in-oil (W/O) emulsification process with the freeze-drying process, followed by thermal chemical vapor deposition of methyltrichlorosilane. The oil phase and the cooling agent were judiciously selected to ensure that the frozen ice microspheres can be easily separated from the emulsion system. The silanized microspheres were highly porous with a bulk density ranging from 4.66 to 16.54 mg/cm 3 . The effects of the solution pH, stirring rate, and emulsifier concentration on the morphology and microstructure of the aerogel microspheres were studied. The highly porous structure of the ultralight aerogel microspheres demonstrated an ultrahigh crude oil absorption capacity (up to 116 times its own weight). This study provides a novel approach for the large-scale preparation of polymeric aerogel microspheres with well-controlled particle sizes that can be used for various applications including oil and chemical spill/leak clean-up. [ABSTRACT FROM AUTHOR]

Neuroendocrine (NE) cancers can cause significant patient morbidity. Besides surgery, there are no curative treatments for NE cancers and their metastases, emphasizing the need for the development of other forms of therapy. In this study, multifunctional unimolecular micelles were developed for targeted NE cancer therapy. The unimolecular micelles were formed by multi-arm star amphiphilic block copolymer poly(amidoamine)–poly(valerolactone)–poly(ethylene glycol) conjugated with KE108 peptide and Cy5 dye (abbreviated as PAMAM–PVL–PEG–KE108/Cy5). The unimolecular micelles with a spherical core–shell structure exhibited a uniform size distribution and excellent stability. The hydrophobic drug thailandepsin-A (TDP-A), a recently discovered HDAC inhibitor, was physically encapsulated into the hydrophobic core of the micelles. KE108 peptide, a somatostatin analog possessing high affinity for all five subtypes of somatostatin receptors (SSTR 1–5), commonly overexpressed in NE cancer cells, was used for the first time as an NE cancer targeting ligand. KE108 exhibited superior targeting abilities compared to other common somatostatin analogs, such as octreotide, in NE cancer cell lines. The in vitro assays demonstrated that the TDP-A-loaded, KE108-targeted micelles exhibited the best capabilities in suppressing NE cancer cell growth. Moreover, the in vivo near-infrared fluorescence imaging on NE-tumor-bearing nude mice showed that KE108-conjugated micelles exhibited the greatest tumor accumulation due to their passive targeting and active targeting capabilities. Finally, TDP-A-loaded and KE108-conjugated micelles possessed the best anticancer efficacy without detectable systemic toxicity. Thus, these novel TDP-A-loaded and KE108-conjugated unimolecular micelles offer a promising approach for targeted NE cancer therapy. [ABSTRACT FROM AUTHOR]

Stretchable electrical interconnects based on serpentines combined with elastic materials are utilized in various classes of wearable electronics. However, such interconnects are primarily for direct current or low-frequency signals and incompatible with microwave electronics that enable wireless communication. In this paper, design and fabrication procedures are described for stretchable transmission line capable of delivering microwave signals. The stretchable transmission line has twisted-pair design integrated into thin-film serpentine microstructure to minimize electromagnetic interference, such that the line's performance is minimally affected by the environment in close proximity, allowing its use in thin-film bioelectronics, such as the epidermal electronic system. Detailed analysis, simulations, and experimental results show that the stretchable transmission line has negligible changes in performance when stretched and is operable on skin through suppressed radiated emission achieved with the twisted-pair geometry. Furthermore, stretchable microwave low-pass filter and band-stop filter are demonstrated using the twisted-pair structure to show the feasibility of the transmission lines as stretchable passive components. These concepts form the basic elements used in the design of stretchable microwave components, circuits, and subsystems performing important radio frequency functionalities, which can apply to many types of stretchable bioelectronics for radio transmitters and receivers. [ABSTRACT FROM AUTHOR]

Background Intimal hyperplasia (IH) remains a major cause of poor patient outcomes after surgical revascularization to treat atherosclerosis. A multitude of drugs have been shown to prevent the development of IH. Moreover, endovascular drug delivery following angioplasty and stenting has been achieved with a marked diminution in the incidence of restenosis. Despite advances in endovascular drug delivery, there is currently no clinically available method of periadventitial drug delivery suitable for open vascular reconstructions. Herein we provide an overview of the recent literature regarding innovative polymer platforms for periadventitial drug delivery in preclinical models of IH as well as insights about barriers to clinical translation. Methods A comprehensive PubMed search confined to the past 15 years was performed for studies of periadventitial drug delivery. Additional searches were performed for relevant clinical trials, patents, meeting abstracts, and awards of NIH funding. Results Most of the research involving direct periadventitial delivery without a drug carrier was published prior to 2000. Over the past 15 years there have been a surge of reports utilizing periadventitial drug-releasing polymer platforms, most commonly bioresorbable hydrogels and wraps. These methods proved to be effective for the inhibition of IH in various animal models (e.g. balloon angioplasty, wire injury, and vein graft), but very few have advanced to clinical trials. There are a number of barriers that may account for this lack of translation. Promising new approaches including the use of nanoparticles will be described. Conclusions No periadventitial drug delivery system has reached clinical application. For periadventitial delivery, polymer hydrogels, wraps, and nanoparticles exhibit overlapping and complementary properties. The ideal periadventitial delivery platform would allow for sustained drug release yet exert minimal mechanical and inflammatory stresses to the vessel wall. A clinically applicable strategy for periadventitial drug delivery would benefit thousands of patients undergoing open vascular reconstruction each year. [ABSTRACT FROM AUTHOR]

Due to the overexpression of somatostatin receptors in neuroendocrine (NE) cancers, drug nanocarriers conjugated with somatostatin analogs, such as octreotide (OCT), for targeted NE cancer therapy may offer increased therapeutic efficacies and decreased adverse effects. In this study, OCT-functionalized unimolecular micelles were prepared using individual hyperbranched polymer molecules consisting of a hyperbranched polymer core (Boltorn ® H40) and approximately 25 amphiphilic polylactide-poly(ethlyene glycol) (PLA-PEG) block copolymer arms (H40-PLA-PEG-OCH 3 /OCT). The resulting micelles, exhibiting a uniform core-shell shape and an average hydrodynamic diameter size of 66 nm, were loaded with thailandepsin-A (TDP-A), a relatively new naturally produced histone deacetylase (HDAC) inhibitor. In vitro studies using flow cytometry and confocal laser scanning microscopy (CLSM) demonstrated that OCT conjugation enhanced the cellular uptake of the unimolecular micelles. Consequently, TDP-A-loaded and OCT-conjugated micelles exhibited the highest cytotoxicity and caused the highest reduction of NE tumor markers. Finally, the in vivo studies on NE cancer bearing nude mice demonstrated that TDP-A-loaded and OCT-conjugated micelles possessed superior anticancer activity in comparison with other TDP-A formulations or drug alone, while showing no detectable systemic toxicity. Thus, these TDP-A-loaded and OCT-conjugated micelles offer a promising approach for targeted NE cancer therapy. [ABSTRACT FROM AUTHOR]

A novel type of self-fluorescent unimolecular micelle nanoparticle (NP) formed by multi-arm star amphiphilic block copolymer, Boltron ® H40 (H40, a 4th generation hyperbranched polymer)- b iodegradable p hoto- l uminescent p olymer (BPLP)-poly(ethylene glycol) (PEG) conjugated with cRGD peptide (i.e., H40-BPLP-PEG-cRGD) was designed, synthesized, and characterized. The hydrophobic BPLP segment was self-fluorescent, thereby making the unimolecular micelle NP self-fluorescent. cRGD peptides, which can effectively target α v β 3 integrin-expressing tumor neovasculature and tumor cells, were selectively conjugated onto the surface of the micelles to offer active tumor-targeting ability. This unique self-fluorescent unimolecular micelle exhibited excellent photostability and low cytotoxicity, making it an attractive bioimaging probe for NP tracking for a variety of microscopy techniques including fluorescent microscopy, confocal laser scanning microscopy (CLSM), and two-photon microscopy. Moreover, this self-fluorescent unimolecular micelle NP also demonstrated excellent stability in aqueous solutions due to its covalent nature, high drug loading level, pH-controlled drug release, and passive and active tumor-targeting abilities, thereby making it a promising nanoplatform for targeted cancer theranostics. [ABSTRACT FROM AUTHOR]

Polyamidoamine (PAMAM) dendrimer was conjugated with both carboxymethyl-β-cyclodextrin (βCD) and poly(ethylene glycol) (PEG). Cyclic RGD peptide, used as a tumor targeting ligand, was then selectively conjugated onto the distal ends of the PEG arms. The resulting βCD-PAMAM-PEG-cRGD polymer was able to form stable and uniform nanoparticles (NPs) in aqueous solution. Doxorubicin (Dox), a model hydrophobic anticancer drug, was effectively encapsulated in the NPs via an inclusion complex formed between the drug and βCD. The Dox loading level was 16.8 wt%. The cellular uptake of cRGD-conjugated Dox-loaded NPs in the U87MG cell line was much higher than that of non-targeted NPs. Furthermore, the anti-proliferative effect of the cRGD-conjugated NPs was superior to that of free drug and non-targeted NPs. These results suggest that NPs formed by βCD-PAMAM-PEG-cRGD with a high drug payload may significantly improve the anticancer efficacy by tumor-targeted delivery and enhanced cellular uptake. [ABSTRACT FROM AUTHOR]

Highlights: [•] Young’s moduli and crystallinity of the AgNW/TPU nanocomposite films increased with AgNW content. [•] Higher AgNW content induced higher dielectric constant while maintaining a low dielectric loss. [•] The PVP AgNW coating affected the thermal and mechanical properties of the AgNW/TPU nanocomposites. [Copyright &y& Elsevier]

Open vascular reconstructions frequently fail due to the development of recurrent disease or intimal hyperplasia (IH). This paper reports a novel drug delivery method using a rapamycin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs)/pluronic gel system that can be applied periadventitially around the carotid artery immediately following the open surgery. In vitro studies revealed that rapamycin dispersed in pluronic gel was rapidly released over 3 days whereas release of rapamycin from rapamycin-loaded PLGA NPs embedded in pluronic gel was more gradual over 4 weeks. In cultured rat vascular smooth muscle cells (SMCs), rapamycin-loaded NPs produced durable (14 days versus 3 days for free rapamycin) inhibition of phosphorylation of S6 kinase (S6K1), a downstream target in the mTOR pathway. In a rat balloon injury model, periadventitial delivery of rapamycin-loaded NPs produced inhibition of phospho-S6K1 14 days after balloon injury. Immunostaining revealed that rapamycin-loaded NPs reduced SMC proliferation at both 14 and 28 days whereas rapamycin alone suppressed proliferation at day 14 only. Moreover, rapamycin-loaded NPs sustainably suppressed IH for at least 28 days following treatment, whereas rapamycin alone produced suppression on day 14 with rebound of IH by day 28. Since rapamycin, PLGA, and pluronic gel have all been approved by the FDA for other human therapies, this drug delivery method could potentially be translated into human use quickly to prevent failure of open vascular reconstructions. [ABSTRACT FROM AUTHOR]

Abstract: Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)–poly(l-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N′, N-triacetic acid (NOTA, a macrocyclic chelator for 64Cu) (abbreviated as PAMAM–PLA-b-PEG–TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti-cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physical encapsulation. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. TRC105-conjugated unimolecular micelles showed a CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with non-targeted unimolecular micelles, which was further validated by cellular uptake in CD105-negative MCF-7 cells. In 4T1 murine breast tumor-bearing mice, 64Cu-labeled targeted micelles exhibited a much higher level of tumor accumulation than 64Cu-labeled non-targeted micelles, measured by serial non-invasive positron emission tomography (PET) imaging and confirmed by biodistribution studies. These unimolecular micelles formed by dendritic amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics. [Copyright &y& Elsevier]

Abstract: In the absence of effective therapy for prostate cancer, there is an immense need for developing improved therapeutic options for the management of this disease. This study has demonstrated that aptamer-conjugated unimolecular micelles can improve the in vivo tumor biodistribution of systemically administered anti-cancer drugs in prostate cancer expressing prostate-specific membrane antigen (PSMA). The aptamer-conjugated unimolecular micelles were formed by individual hyperbranched polymer molecules consisting of a hyperbranched H40 polymer core and approximately 25 amphiphilic polylactide–poly(ethlyene glycol) (PLA–PEG) block copolymer arms (H40-PLA-PEG-Apt). The unimolecular micelles with an average hydrodynamic diameter of 69 nm exhibited a pH-sensitive and controlled drug release behavior. The targeted unimolecular micelles (i.e., DOX-loaded H40-PLA-PEG-Apt) exhibited a much higher cellular uptake in PSMA positive CWR22Rν1 prostate carcinoma cells than non-targeted unimolecular micelles (i.e., DOX-loaded H40-PLA-PEG), thereby leading to a significantly higher cytotoxicity. The DOX-loaded unimolecular micelles up-regulated the cleavage of PARP and Caspase 3 proteins and increased the protein expression of Bax along with a concomitant decrease in Bcl2. These micelles also increased the protein expression of cell cycle regulation marker P21 and P27. In CWR22Rν1 tumor-bearing mice, DOX-loaded H40-PLA-PEG-Apt micelles (i.e., targeted) also exhibited a much higher level of DOX accumulation in the tumor tissue than DOX-loaded H40-PLA-PEG micelles (i.e., non-targeted). These findings suggest that aptamer-conjugated unimolecular micelles may potentially be an effective drug nanocarrier to effectively treat prostate cancer. [Copyright &y& Elsevier]

Abstract: A multifunctional unimolecular micelle made of a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for cancer-targeted drug delivery and non-invasive positron emission tomography (PET) imaging in tumor-bearing mice. The hyperbranched amphiphilic block copolymer, Boltorn® H40-poly(L-glutamate-hydrazone-doxorubicin)-b-poly(ethylene glycol) (i.e., H40-P(LG-Hyd-DOX)-b-PEG), was conjugated with cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides (cRGD, for integrin αvβ3 targeting) and macrocyclic chelators (1,4,7-triazacyclononane-N, N’, N’’-triacetic acid [NOTA], for 64Cu-labeling and PET imaging) (i.e., H40-P(LG-Hyd-DOX)-b-PEG-OCH3/cRGD/NOTA, also referred to as H40-DOX-cRGD). The anti-cancer drug, doxorubicin (DOX) was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms (i.e., PLG) via a pH-labile hydrazone linkage to enable pH-controlled drug release. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. cRGD-conjugated unimolecular micelles (i.e., H40-DOX-cRGD) exhibited a much higher cellular uptake in U87MG human glioblastoma cells due to integrin αvβ3-mediated endocytosis than non-targeted unimolecular micelles (i.e., H40-DOX), thereby leading to a significantly higher cytotoxicity. In U87MG tumor-bearing mice, H40-DOX-cRGD-64Cu also exhibited a much higher level of tumor accumulation than H40-DOX-64Cu, measured by non-invasive PET imaging and confirmed by biodistribution studies and ex vivo fluorescence imaging. We believe that unimolecular micelles formed by hyperbranched amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics. [Copyright &y& Elsevier]

Abstract: Multifunctional and water-soluble superparamagnetic iron oxide (SPIO) nanocarriers were developed for targeted drug delivery and positron emission tomography/magnetic resonance imaging (PET/MRI) dual-modality imaging of tumors with integrin αvβ3 expression. An anticancer drug was conjugated onto the PEGylated SPIO nanocarriers via pH-sensitive bonds. Tumor-targeting ligands, cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)) peptides, and PET 64Cu chelators, macrocyclic 1,4,7-triazacyclononane-N, N′, N″-triacetic acid (NOTA), were conjugated onto the distal ends of the PEG arms. The effectiveness of the SPIO nanocarriers as an MRI contrast agent was evaluated via an in vitro r2 MRI relaxivity measurement. cRGD-conjugated SPIO nanocarriers exhibited a higher level of cellular uptake than cRGD-free ones in vitro. Moreover, cRGD-conjugated SPIO nanocarriers showed a much higher level of tumor accumulation than cRGD-free ones according to non-invasive and quantitative PET imaging, and ex vivo biodistribution studies. Thus, these SPIO nanocarriers demonstrated promising properties for combined targeted anticancer drug delivery and PET/MRI dual-modality imaging of tumors. [Copyright &y& Elsevier]

Abstract: Stable and tumor-targeting multifunctional wormlike polymer vesicles simultaneously loaded with superparamagnetic iron oxide (SPIO) nanoparticles (NPs) as magnetic resonance imaging (MRI) contrast agent and anticancer drug doxorubicin (DOX) were developed for targeted cancer therapy and ultrasensitive MR imaging. These multifunctional wormlike polymer vesicles were formed by heterobifunctional amphiphilic triblock copolymers R (R = methoxy or folate (FA))-PEG114-PLA x -PEG46-acrylate using a double emulsion method. The long PEG segments bearing methoxy/folate groups (CH3O/FA-PEG114) were mostly segregated to the outer hydrophilic PEG layers of the wormlike vesicles thereby providing active tumor-targeting ability, while the short PEG segments bearing acrylate groups (PEG46-acrylate) were mostly segregated onto the inner hydrophilic PEG layers of the wormlike vesicles thereby allowing the inner PEG layers to be crosslinked via free radical polymerization for enhanced in vivo stability. The hydrophobic anticancer drug, DOX, was loaded into the hydrophobic membrane of the wormlike vesicles. Meanwhile, a cluster of hydrophilic SPIO NPs was encapsulated into the aqueous cores of the stable wormlike vesicles with crosslinked inner PEG layers for ultrasensitive MRI detection. Cellular uptake of the FA-conjugated wormlike vesicles facilitated by the folate receptor-mediated endocytosis process was higher than that of the FA-free vesicles thereby leading to high cytotoxicity against the HeLa human cervical tumor cell line. Moreover, the SPIO/DOX-loaded wormlike vesicles with crosslinked inner PEG layers demonstrated a much higher r 2 relaxivity value than Feridex®, a commercially available T2 agent, which can be attributed to the high SPIO NPs loading level as well as the SPIO clustering effect. These unique stable and tumor-targeting multifunctional SPIO/DOX-loaded wormlike polymer vesicles would make targeted cancer theranostics possible thereby paving the road for personalized medicine. [Copyright &y& Elsevier]

Abstract: An ultrasensitive electrochemical immunosensor based on graphene sheet (GS) has been developed. GS was used to immobilize mediator thionine (TH), horseradish peroxidase (HRP) and secondary anti-prostate-specific antigen (PSA) antibody (Ab2) and the resulting nanostructure (GS-TH-HRP-Ab2) was used as the label for the immunosensor. With primary anti-PSA antibody (Ab1) also immobilized onto the GS, the immunosensor displayed a wide range of linear response (0.002–10ng/mL), low detection limit (1pg/mL), good reproducibility, selectivity and stability. The good performance of the immunosensor is attributed to the graphene sheet''s high surface-to-volume ratio which allows the immobilization of a high-level of Ab1, Ab2, TH and HRP and its good electrical conductivity which can improve the electron transfer among TH, HRP, H2O2 and electrode. The immunosensor was used to detect the PSA contents in serum samples from patients and satisfactory test results were obtained in comparison with the ELISA test results. Thus, graphene-based labels may provide many potential applications for the detection of different cancer biomarkers. [Copyright &y& Elsevier]

Abstract: A pH-sensitive molecularly imprinted polymer (MIP) nanospheres/hydrogel composite exhibiting controlled release of dexamethasone-21 phosphate disodium (DXP) was developed as a potential coating for implantable biosensors to improve their biocompatibility. The molecularly imprinted pH-sensitive nanospheres were prepared by UV-initiated precipitation polymerization using DXP as the template molecule. The DXP loading and release experiments showed that the MIP nanospheres exhibited a higher loading level and slower release rate than non-imprinted polymer (NIP) nanospheres due to the interaction of DXP with the DXP-imprinted cavities within the MIP nanospheres. Furthermore, the MIP nanospheres exhibited a faster DXP release rate at a lower pH value within the pH range tested (i.e., 6.0–7.4), which is desirable for suppressing inflammation because inflammation induces an acidic microenvironment. In contrast, the NIP nanospheres did not show a notable pH-responsive DXP release behavior. The hydrogel poly(2-hydroxyethyl methacrylate (HEMA) -N-vinyl-2-pyrrolidinone (NVP) -2-methacryloyloxyethyl phosphorylcholine (MPC)) was prepared by UV polymerization. The MIP nanospheres were successfully incorporated into the hydrogel. The equilibrium water content and swelling kinetics of the MIP nanospheres/hydrogel composite were similar to those of pure hydrogel. The MIP nanospheres/hydrogel composite exhibited a much better controlled DXP release profile than the pure hydrogel. This pH-sensitive MIP nanospheres/hydrogel composite designed as a coating for implantable biosensors can potentially suppress the inflammation response of the implanted biosensors efficiently thereby effectively improving their lifetime. [Copyright &y& Elsevier]

Abstract: Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)/coir fiber composites were prepared via both conventional and microcellular injection-molding processes. The surface of the hydrophilic coir fiber was modified by alkali- and silane-treatment to improve its adhesion with PHBV. The morphology, thermal, and mechanical properties were investigated. The addition of coir fiber (treated and untreated) reduced cell size and increased cell density. Further decrease in cell size and increase in cell density was observed for treated fibers compared with PHBV/untreated-fiber composites. Mechanical properties such as specific toughness and strain-at-break improved for both solid and microcellular specimens with the addition of coir fibers (both treated and untreated); however, the specific modulus remained essentially the same statistically while the specific strength decreased slightly. The silane-treated coir fiber composites showed the greatest improvement in specific toughness and strain-at-break among the treated-fiber composites. In addition, adding coir fibers (treated and untreated) also increased the degree of crystallinity of the PHBV composites. PHBV with treated coir fibers showed a higher degree of crystallinity compared with untreated coir fibers. [Copyright &y& Elsevier]