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Vascular embolization provides an effective approach for the treatment of hemorrhage, aneurysms, and other vascular abnormalities. However, current embolic materials, such as metallic coils and liquid embolic agents, are limited by their inability to provide safe, consistent, and controlled embolization. Here, we report an injectable hydrogel that can remain at the injection site and subsequently undergo in situ covalent crosslinking, leading to the formation of a dual-crosslinking network (DCN) hydrogel for endovascular embolization. The DCN hydrogel is simple to prepare, easy to deploy via needles and catheters, and mechanically stable at the target injection site, thereby avoiding embolization of nontarget vessels. It possesses efficient hemostatic activity and good biocompatibility. The DCN hydrogel is also clearly visible under X-ray imaging, thereby allowing for targeted embolization. In vivo tests in a rabbit artery model demonstrates that the DCN hydrogel is effective in achieving immediate embolization of the target artery with long-term occlusion by inducing luminal fibrosis. Collectively, the DCN hydrogel provides a viable, biocompatible, and cost-effective alternative to existing embolic materials with clinical translation potential for endovascular embolization.

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.

Occlusion of blood vessel caused by thrombus is the major pathogenesis of various catastrophic cardiovascular diseases. Thrombus can be prevented or treated by antithrombotic drugs. However, free antithrombotic drugs often have relatively low therapeutic efficacy due to a number of limitations such as short half-life, unexpected bleeding complications, low thrombus targeting capability, and negligible hydrogen peroxide (H(2)O(2))-scavenging ability. Inspired by the abundance of H(2)O(2) and the active thrombus-targeting property of platelets, a H(2)O(2)-responsive platelet membrane-cloaked argatroban-loaded polymeric nanoparticle (PNP(Arg)) was developed for thrombus therapy. Poly(vanillyl alcohol-co-oxalate) (PVAX), a H(2)O(2)-degradable polymer, was synthesized to form an argatroban-loaded nanocore, which was further coated with platelet membrane. The PNP(Arg) can effectively target the blood clots due to the thrombus-homing property of the cloaked platelet membrane, and subsequently exert combined H(2)O(2)-scavenging effect via the H(2)O(2)-degradable nanocarrier polymer and antithrombotic effect via argatroban, the released payload. The PNP(Arg) effectively scavenged H(2)O(2) and protected cells from H(2)O(2)-induced cellular injury in RAW 264.7 cells and HUVECs. The PNP(Arg) rapidly targeted the thrombosed vessels and remarkably suppressed thrombus formation, and the levels of H(2)O(2) and inflammatory cytokine in the ferric chloride-induced carotid arterial thrombosis mouse model. Safety assessment indicated good biocompatibility of the PNP(Arg). Taken together, the biomimetic PNP(Arg) offers multifunctionalities including thrombus-targeting, antioxidation, and H(2)O(2)-stimulated antithrombotic action, thereby making it a promising therapeutic nanomedicine for thrombosis diseases.

Visual Abstract, Highlights • Drug-eluting stents impede neointimal smooth muscle cell hyperplasia but exacerbate endothelial cell dysfunction and thrombogenicity. It has been a challenge to identify a common target to inhibit both. Findings in this study suggest PERK as such a target. • A PERK inhibitor administered either via an endovascular (in biomimetic nanocarriers) or perivascular (in hydrogel) route effectively mitigated neointimal hyperplasia in rats. • Oral gavage of the PERK inhibitor partially preserved the normal blood flow in a mouse model of induced thrombosis. • Dampening PERK activity inhibited STAT3 while activating SRF in smooth muscle cells, and also reduced prothrombogenic tissue factor and growth impairment of endothelial cells., Summary Developing endothelial-protective, nonthrombogenic antirestenotic treatments has been a challenge. A major hurdle to this has been the identification of a common molecular target in both smooth muscle cells and endothelial cells, inhibition of which blocks dysfunction of both cell types. The authors’ findings suggest that the PERK kinase could be such a target. Importantly, PERK inhibition mitigated both restenosis and thrombosis in preclinical models, implicating a low-thrombogenic antirestenotic paradigm.

A major medical problem is the persistent lack of approved therapeutic methods to prevent postoperative intimal hyperplasia (IH) which leads to high-rate failure of open vascular reconstructions such as bypass grafting. Hydrogel has been widely used in preclinical trials for perivascular drug administration to mitigate postoperative IH. However, bulky hydrogel is potentially pro-inflammatory, posing a significant hurdle to clinical translation. Here we developed a new modality of directly "painting" drug-loaded unimolecular micelles (UM) to the adventitia thus obviating the need for a hydrogel. To render tissue adhesion, we generated amine-reactive unimolecular micelles with N-hydroxysuccinimide ester (UM-NHS) terminal groups to form stable amide bonds with the adventitia. To test periadventitial application, we either soaked balloon-injured rat carotid arteries in crosslinked UM-NHS (Mode-1) or non-crosslinked UM-NHS (Mode-2), or painted the vessel surface with non-crosslinked UM-NHS (Mode-3). The UM-NHS were loaded with or without a model drug (rapamycin) known to be IH inhibitory. We found that Mode-1 produced a marked IH-mitigating drug effect but also caused severe tissue damage. Mode-2 resulted in lower tissue toxicity yet less drug effect on IH. However, the painting method, Mode-3, demonstrated a pronounced therapeutic effect (75% inhibition of IH) without obvious toxicity. In summary, we present a simple painting modality of periadventitial local drug delivery using tissue-adhesive UM. Given the robust IH-abating efficacy and low tissue toxicity, this prototype merits further development towards an effective anti-stenosis therapy suitable for open vascular reconstructions.

Scaffold microfabrication strategies for high-density, layered, and organized photoreceptor cell replacement are presented., Polymeric scaffolds are revolutionizing therapeutics for blinding disorders affecting the outer retina, a region anatomically and functionally defined by light-sensitive photoreceptors. Recent engineering advances have produced planar scaffolds optimized for retinal pigment epithelium monolayer delivery, which are being tested in early-stage clinical trials. We previously described a three-dimensional scaffold supporting a polarized photoreceptor monolayer, but photoreceptor somata typically occupy multiple densely packed strata to maximize light detection. Thus, patients with severe photoreceptor degeneration are expected to extract greater benefits from higher-density photoreceptor delivery. Here, we describe the microfabrication of a biodegradable scaffold patterned for high-density photoreceptor replacement. The “ice cube tray” structure optimizes mechanical properties and cell-to-biomaterial load, enabling production of a multicellular photoreceptor layer designed for outer retinal reconstruction. Our approach may also be useful in the production of a multitude of micro- and nanoscale structures for multilayered cell delivery in other tissues.

An abdominal aortic aneurysm (AAA) is a localized dilatation of the aorta that plagues millions. Its rupture incurs high mortality rates (~80-90%), pressing an urgent need for therapeutic methods to prevent this deadly outcome. Judiciously designed nanoparticles (NPs) have displayed a unique potential to fulfill this need. Aneurysms feature excessive inflammation and extracellular matrix (ECM) degradation. As such, typically inflammatory cells and exposed ECM proteins have been targeted with NPs for therapeutic, diagnostic, or theranostic purposes in experimental models. NPs have been used not only for encapsulation and delivery of drugs and biomolecules in preclinical tests, but also for enhanced imaging to monitor aneurysm progression in patients. Moreover, they can be readily modified with various molecules to improve lesion targeting, detectability, biocompatibility, and circulation time. This review updates on the progress, limitations, and prospects of NP applications in the context of AAA.

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 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-A(165)-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-A(165)-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-A(165)-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.

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.

Cancer remains a major threat to human health due to low therapeutic efficacies of currently available cancer treatment options. Nanotheranostics, capable of simultaneous therapy and diagnosis/monitoring of diseases, has attracted increasing amounts of attention, particularly for cancer treatment. In this study, CuS-based theranostic micelles capable of simultaneous combination chemotherapy and photothermal therapy (PTT), as well as photoacoustic imaging, were developed for targeted cancer therapy. The micelle was formed by a CuS nanoparticle (NP) functionalized by thermosensitive amphiphilic poly(acrylamide-acrylonitrile)–poly(ethylene glycol) block copolymers. CuS NPs under near-infrared (NIR) irradiation induced a significant temperature elevation, thereby enabling NIR-triggered PTT. Moreover, the hydrophobic core formed by poly(acrylamide-acrylonitrile) segments used for drug encapsulation exhibited an upper critical solution temperature (UCST; ~38 °C), which underwent a hydrophobic-to-hydrophilic transition once the temperature rose above the UCST induced by NIR-irradiated CuS NPs, thereby triggering a rapid drug release and enabling NIR-controlled chemotherapy. The CuS-based micelles conjugated with GE11 peptides were tested in an epidermal growth factor receptor-overexpressing triple-negative breast cancer model. In both two-dimensional monolayer cell and three-dimensional multicellular tumor spheroid models, GE11-tagged CuS-based micelles under NIR irradiation, enabling the combination chemotherapy and PTT, exhibited the best therapeutic outcome due to a synergistic effect. These CuS-based micelles also displayed a good photoacoustic imaging ability under NIR illumination. Taken together, this multifunctional CuS-based micelle could be a promising nanoplatform for targeted cancer nanotheranostics.

Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions.

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.

This paper presents the experimental behavior of low-energy impact and quasi-static compression test of shifted-tri-axial structural wood-fiber-based composite panels made from laminated paper. The experimental results were analyzed based on design parameters and configurations of panels for the further design and optimization. The results showed that the face stiffness and strength was a significant factor to improve both impact performance and compressive performance. The panels made with additional carbon fiber fabric composite faces had higher energy absorption compared with the same panels made without it. The core configuration also affected the impact behavior of the panels, the foam filled core integrated with the shifted-tri-axial rib structure improved the impact load and absorbed more energy than the same panels without the foam. Further, the structure and size of the element in the core influenced the impact performance and energy absorption. The location for both compression and impact at the triangular lattice element center of the ribs had higher absorbed energy than the location at the hexagonal lattice element center of the ribs. A 3D contour surface map of maximum energy absorption was made based on the experimental data, the contour shows localized energy absorption based on the impact location on the core, the small triangular lattice element of the core had highest maximum energy absorption of panels. For both the quasi-static compression tests and the low-velocity impact tests, the panels with the same core configuration had similar compressive load–displacement trends during the early contact phase. However, the peak load was higher in compression than the peak load for the low-velocity impact for panels with the same configuration.

Medullary thyroid cancer (MTC) is often resistant to standard therapies, emphasizing the need for the development of other treatments. A new histone deacetylase inhibitor, AB3, can effectively inhibit MTC cell proliferation in vitro. However, its poor aqueous solubility and stability, fast clearance, and lack of tumor targeting ability limit its in vivo application. Therefore, multifunctional unimolecular micelles were developed for targeted delivery of AB3 for MTC therapy. The unimolecular micelles exhibited a spherical core–shell structure, uniform size distribution, and excellent stability. AB3 was encapsulated into the hydrophobic core of the unimolecular micelles, thus significantly enhancing its aqueous solubility and stability. KE108, a somatostatin analog possessing high affinity to all five subtypes of SSTR, was used as an MTC-targeting ligand. In vitro cellular uptake analyses demonstrated that the KE108 exhibited superior targeting ability in MTC cells compared to octreotide, the first clinically used somatostatin analog. Moreover, the AB3-loaded and KE108-conjugated unimolecular micelles exhibited the best efficacy in suppressing MTC cell growth and tumor marker expression in vitro. Furthermore, AB3-loaded, KE108-conjugated micelles demonstrated the best anticancer efficacy in vivo without any apparent systemic toxicity, thereby offering a promising approach for targeted MTC therapy.

BackgroundDrug-eluting stents (DES) represent the main-stream management of restenosis following treatments of occlusive cardiovascular diseases. However, DES cannot eliminate instent restenosis yet exacerbate thrombogenic risks. To achieve dual inhibition of restenotic smooth muscle cell (SMC) de-differentiation/proliferation and thrombogenic endothelial cell (EC) dysfunction, a common target in both cell types, has been long-sought after. We evaluated the potential of protein kinase RNA-like endoplasmic reticulum kinase (PERK) as such a target for low-thrombogenic anti-restenotic intervention.Methods and ResultsWe used a rat angioplasty model of restenosis and a FeCl3-induced mouse model of thrombosis. Loss-or gain-of-function was achieved by PERK inhibition (GSK2606414, siRNA) or overexpression (adenovirus). Restenosis was robustly mitigated by GSK2606414 administered either via injected (i.v.) lesion-homing platelet membrane-coated nanoclusters or a perivascular hydrogel; it was enhanced by PERK transgene. Whereas PERK inhibition blocked, its overexpression exacerbated PDGF-induced human aortic SMC de-differentiation (reduced smooth muscle α-actin or αSMA) and proliferation (BrdU incorporation). Further, PERK activity promoted STAT3 activation but inhibited SRF transcriptional (luciferase) activity; its protein co-immunoprecipitated with STAT3 and also MRTF-A, the SRF activator for αSMA transcription. Importantly, PERK inhibition also prevented TNFα-induced impairment of human EC growth and upregulation of thrombogenic tissue factor, both in vitro and ex vivo. In vivo, oral gavage of GSK2606414 preserved ~50% of the normal blood flow 60 min after FeCl3-induced vascular injury.ConclusionsPERK inhibition is dual beneficial in mitigating restenosis and thrombosis, thus implicating a potential design for anti-restenotic intervention to overcome the thrombogenicity of DES.

Antimicrobial resistant (AMR) infections are a growing threat to public health and there is a general lack of development in new antibiotics. Here, a dextran-coated stimuli-responsive nanoparticle (NP) that encapsulates the hydrophobic antibiotic, rifampicin, and specifically binds bacteria to overcome AMR infections is reported. The NP shows a strong affinity with a variety of pathogens in vitro and effectively accumulates in the bacterial infected tissues. The NP is activated by either low pH or high reactive oxygen species in the infectious microenvironment, and releases both cationic polymer and rifampicin that display synergistic activity against AMR pathogens. The NP carrier also enables the antibiotic to penetrate both bacterial biofilms and mammalian cells, thus allowing the elimination of biofilm and intracellular infections. The NP formulation demonstrates both safety and efficacy in two animal infection models against either Gram-negative or Gram-positive AMR pathogens.

Thrombosis is a principle cause of various life-threatening cardiovascular diseases. However, current antithrombotic treatments using drugs only offer limited efficacy due to short half-life, low targeting ability to the thrombus site, and unexpected bleeding complications. Taking into account of the biological characteristics of thrombus including upregulation of hydrogen peroxide (H2O2) and abundance of fibrin, we engineered a H2O2-responsive nanocarrier for thrombus-targeting delivery of an antithrombotic agent (i.e., tirofiban). The nanocarrier was composed of a drug-conjugated dextran nanocore and a red blood cell (RBC) membrane shell, and its surface was functionalized with a fibrin-targeting peptide, CREKA. Tirofiban was conjugated to dextran through a H2O2-cleavable phenylboronic ester linkage. The fibrin-targeting RBC membrane-cloaked dextran-tirofiban conjugate nanoparticles (i.e., T-RBC-DTC NPs) can scavenge H2O2 and provide controlled release of tirofiban to achieve site-specific antithrombotic effects. In RAW 264.7 cells and HUVECs, the T-RBC-DTC NPs effectively scavenged H2O2 and protected cells from H2O2-induced cytotoxicity. In the ferric chloride-induced carotid thrombosis mouse model, the T-RBC-DTC NPs efficiently accumulated at the injured carotid artery and exhibited significantly enhanced antithrombotic activity compared to free drug. The T-RBC-DTC NPs also exhibited good biocompatibility according to histology analysis. Overall, our results indicated that this bioengineered nanocarrier offers a promising therapeutic strategy for thrombotic disorders.

Fully biobased chemically crosslinked anisotropic carboxymethyl cellulose (CMC)/cellulose nanofibril (CNF) aerogels were prepared using an environmentally friendly directional freeze-drying method. The resulting cellulose aerogels were characterized using various techniques. It was found that the CMC/CNF aerogel exhibited a honeycomb structure, and thus possessed anisotropic properties. Moreover, the fully biobased crosslinked organic aerogel possessed excellent mechanical properties based on both compression and three-point bending tests. For instance, it exhibited a remarkable compressive modulus (up to 10 MPa) along the vertical direction (parallel to the freezing direction) as well as a high flexural modulus (up to 54 MPa) perpendicular to the freezing direction. The effects of different aerogel densities and CNF contents on the mechanical properties of CMC/CNF aerogels have been studied. With increasing aerogel density or CNF content, the modulus and strength of the CMC/CNF aerogel increased in both compression and three-point bending tests. In addition, these cellulose aerogels also exhibited relatively low thermal conductivities (

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.

Adipocyte-cancer cell crosstalk plays a key role in tumorigenesis and metastasis. In this issue of Matter, Gu and colleagues applied adipocytes as a drug depot for effective chemotherapy and tumor microenvironment modulation.

A quantum-dot (QD)-based micelle conjugated with an anti-epidermal growth factor receptor (EGFR) nanobody (Nb) and loaded with an anticancer drug, aminoflavone (AF), has been engineered for EGFR-overexpressing cancer theranostics. The near-infrared (NIR) fluorescence of the indium phosphate core/zinc sulfide shell QDs (InP/ZnS QDs) allowed for in vivo nanoparticle biodistribution studies. The anti-EGFR nanobody 7D12 conjugation improved the cellular uptake and cytotoxicity of the QD-based micelles in EGFR-overexpressing MDA-MB-468 triple-negative breast cancer (TNBC) cells. In comparison with the AF-encapsulated nontargeted (i.e., without Nb conjugation) micelles, the AF-encapsulated Nb-conjugated (i.e., targeted) micelles accumulated in tumors at higher concentrations, leading to more effective tumor regression in an orthotopic triple-negative breast cancer xenograft mouse model. Furthermore, there was no systemic toxicity observed with the treatments. Thus, this QD-based Nb-conjugated micelle may serve as an effective theranostic nanoplatform for EGFR-overexpressing cancers such as TNBCs.

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.

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.

Films of polyvinylpyrrolidone (PVP)-stabilized silver nanowire (AgNW)/thermoplastic polyurethane (TPU) elastomer nanocomposites were fabricated and characterized. With increasing loading levels of AgNW, the transparency of the nanocomposite films was reduced, but their crystallization temperatures increased, suggesting that AgNW could serve as crystallization nucleating agents. The addition of AgNW also enhanced both the Young’s moduli and storage moduli of the nanocomposite films, but caused a reduction in their strain-at-break (from 536% to 304% with 1.5 vol.% AgNW) and ultimate strength (from 12.7 to 9.8 MPa with 1.5 vol.% AgNW). The specific toughness was the highest for nanocomposites with AgNW loading levels of 0.03 vol.% and 0.05 vol.%. In addition, the dielectric constant of the nanocomposite films with 1.5 vol.% AgNW was 9 times higher than that of pure TPU at 1 kHz, while the dielectric loss of all nanocomposite films studied was less than 0.2. Thus, AgNW/TPU elastomer nanocomposites with varying mechanical, dielectric, and thermal properties can be engineered by adding a small amount of AgNW. These nanocomposites can potentially be used for a wide range of applications including dielectric materials.

Neoantigens induced by random mutations and specific to an individual’s cancer are the most important tumor antigens recognized by T cells. Among immunologically “cold” tumors, limited recognition of tumor neoantigens results in the absence of a de novo anti-tumor immune response. These “cold” tumors present a clinical challenge as they are poorly responsive to most immunotherapies, including immune checkpoint inhibitors (ICIs). Radiation therapy (RT) can enhance immune recognition of “cold” tumors, resulting in a more diversified anti-tumor T cell response. Yet RT alone rarely results in a systemic anti-tumor immune response. Therefore, a multifunctional bacterial membrane-coated nanoparticle (BNP) comprised of an immune activating PC7A/CpG polyplex core coated with bacterial membrane and imide groups to enhance antigen retrieval was developed. This BNP can capture cancer neoantigens following RT, enhance their uptake in dendritic cells (DCs), and facilitate their cross presentation to stimulate an anti-tumor T cell response. In mice bearing syngeneic melanoma or neuroblastoma, treatment with BNP+RT results in activation of DCs and effector T cells, marked tumor regression, and tumor-specific anti-tumor immune memory. This BNP facilitates in situ immune recognition of a radiated tumor, enabling a novel personalized approach to cancer immunotherapy using off-the-shelf therapeutics.

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.

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-loadedloaded, GE11-lacking, 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.

A multifunctional gold nanorod (GNR)-based nanoplatform for targeted anticancer drug delivery and positron emission tomography (PET) imaging of tumors was developed and characterized. An anti-cancer drug (i.e., doxorubicin (DOX)) was covalently conjugated onto PEGylated (PEG: polyethylene glycol) GNR nanocarriers via a hydrazone bond to achieve pH-sensitive controlled drug release. Tumor-targeting ligands (i.e., the cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides, cRGD) and (64)Cu-chelators (i.e., 1,4,7-triazacyclononane-N, N', N''-triacetic acid (NOTA)) were conjugated onto the distal ends of the PEG arms to achieve active tumor-targeting and PET imaging, respectively. Based on flow cytometry analysis, cRGD-conjugated nanocarriers (i.e., GNR-DOX-cRGD) exhibited a higher cellular uptake and cytotoxicity than non-targeted ones (i.e., GNR-DOX) in vitro. However, GNR-DOX-cRGD and GNR-DOX nanocarriers had similar in vivo biodistribution according to in vivo PET imaging and biodistribution studies. Due to the unique optical properties of GNRs, this multifunctional GNR-based nanoplatform can potentially be optimized for combined cancer therapies (chemotherapy and photothermal therapy) and multimodality imaging (PET, optical, X-ray computed tomography (CT), etc.).

Blinding disorders of the outer retina involve dysfunction and degeneration of photoreceptors. One potential approach to treat these forms of blindness is to repopulate the outer retina via a simple bolus injection of donor photoreceptors. However, this may not be ideal due to the highly polarized organization of photoreceptors that include apical light sensing photopigments and basal axon terminals. Furthermore, bolus injections create uncertainty with regard to the area, density, and retention of donor cells. Here, a novel and robust microfabrication process is developed to create 3D, micrometer-sized complex structures in ultrathin and biocompatible elastomer films (nonbiodegradable polydimethylsiloxane and biodegradable poly(glycerol-sebacate)) that can serve as polarizable photoreceptor delivery scaffolds, consisting of an array of cup-shaped photoreceptor capture wells that funnel into a microchannel. This "wine glass" scaffold design promotes efficient capture of human pluripotent stem-cell-derived photoreceptor cell bodies and guidance of basal axon extensions, ultimately achieving a uniform level of organization and polarization that is not possible with bolus injections or previously described scaffolds. In addition to future therapeutic applications, our scaffold design and materials provide a platform to generate reproducible and scalable in vitro models of photoreceptor-based diseases.

Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions Citation Format: Fabao Liu, Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Yidan Wang, Peng Liu, Irene M. Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, Lingjun Li, Wei Xu. PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2418.

The effects of adding epoxy-functionalized chain-extender (CE) and processing conditions such as die temperature on the cell morphology, volume expansion ratio (VER), open cell content (OCC), and crystallization of microcellular extruded polylactide (PLA) were investigated. When compared with pure PLA, the addition of talc decreased the average cell size and increased the cell density. Moreover, the simultaneous addition of talc and CE led to denser and more uniform cell structure up until 1.0% CE content. In general, the volume expansion ratio and open cell content of all the formulations decreased with the die temperature. The addition of talc decreased both VER and OCC, whereas the addition of CE increased both. The die temperature did not affect the degree of crystallinity significantly. The addition of talc increased the crystallinity, but the addition of CE decreased it. Finally, the molecular weight of PLA increased significantly with the addition of CE. POLYM. ENG. SCI., 2009. © 2009 Society of Plastics Engineers

New amphiphilic polymer networks were synthesized by the free-radical copolymerization of α,ω-diacryl polycaprolactone (DAPCL) and N-vinylpyrrolidone (NVP), which was initiated by 0.5% azobisisobutyronitrile at 70°C. The chemical structures of the networks were characterized by proton nuclear magnetic resonance spectrometry. The NVP/DAPCL feed ratio played an important role in the crosslinking process. The synthesized amphiphilic polymer networks exhibited controlled swelling properties in water and organic solvents (ethanol, acetones, and toluene). A porous structure was observed for the amphiphilic polymer networks under a scanning electron microscope. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007

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.

The solubilities of carbon dioxide and nitrogen in a polylactide melt were determined at temperatures from 180 to 200 °C and pressures up to 28 MPa using a magnetic suspension balance (MSB). Both Sanchez–Lacombe (SL) and Simha–Somcynsky (SS) equations-of-state (EOS) were applied to predict the amount of volume swelling in the polylactide (PLA)/gas mixture due to gas dissolution. With the proper prediction of volume swelling from both SS-EOS and SL-EOS, the “corrected solubility” was determined based on the experimentally measured “apparent solubility” from the MSB. After measurement of the gas sorption curve in the PLA melt, the theoretical sorption model based on Fick's second law was adopted to extract the diffusion coefficients of carbon dioxide and nitrogen in polylactide at both 180 and 200 °C.

Photo detection of ultraviolet (UV) light remains a challenge since the penetration depth of UV light is limited to the nanometer scale. Therefore, the doping profile and electric field in the top nanometer range of the photo detection devices become critical. Traditional UV photodetectors usually use a constant doping profile near the semiconductor surface, resulting in a negligible electric field, which limits the photo-generated carrier collection efficiency of the photodetector. Here, we demonstrate, via the use of an optimized gradient boron doping technique, that the carrier collection efficiency and photo responsivity under the UV wavelength region have been enhanced. Furthermore, the ultrathin p+-i-n junction shows an avalanche gain of 2800 and an ultra-low junction capacitance (sub pico-farad), indicating potential applications in the low timing jitter single photon detection area.

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.

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.

Platinum-based chemotherapy has been widely used to treat cancers including ovarian cancer; however, it suffers from dose-limiting toxicity. Judiciously designed drug nanocarriers can enhance the anticancer efficacy of platinum-based chemotherapy while reducing its systemic toxicity. Herein the authors report a stable and water-soluble unimolecular nanoparticle constructed from a hydrophilic multi-arm star block copolymer poly(amidoamine)-b-poly(aspartic acid)-b-poly(ethylene glycol) (PAMAM-PAsp-PEG) conjugated with both cRGD (cyclo(Arg-Gly-Asp-D-Phe-Cys) peptide and cyanine5 (Cy5) fluorescent dye as a platinum-based drug nanocarrier for targeted ovarian cancer therapy. Carboplatin is complexed to the poly(aspartic acid) inner shell via pH-responsive ion-dipole interactions between carboplatin and the carboxylate groups of poly(aspartic acid). Based on flow cytometry and confocal laser scanning microscopy analyses, cRGD-conjugated unimolecular nanoparticles exhibit much higher cellular uptake by ovarian cancer cells overexpressing αv β3 integrin than nontargeted (i.e., cRGD-lacking) ones. Carboplatin-complexed cRGD-conjugated nanoparticles also exhibit higher cytotoxicity than nontargeted nanoparticles as well as free carboplatin, while empty unimolecular nanoparticles show no cytotoxicity. These results indicate that stable unimolecular nanoparticles made of individual hydrophilic multi-arm star block copolymer molecules conjugate with tumor-targeting ligands and dyes (i.e., PAMAM-PAsp-PEG-cRGD/Cy5) are promising nanocarriers for platinum-based anticancer drugs for targeted cancer therapy.

Tissue engineering and advanced manufacturing of human stem cells requires a suite of tools to control gene expression spatiotemporally in culture. Inducible gene expression systems offer cell-extrinsic control, typically through addition of small molecules, but small molecule inducers typically contain few functional groups for further chemical modification. Doxycycline (DXC), a potent small molecule inducer of tetracycline (Tet) transgene systems, was conjugated to a hyperbranched dendritic polymer (Boltorn H40) and subsequently reacted with polyethylene glycol (PEG). The resulting PEG–H40–DXC nanoparticle exhibited pH-sensitive drug release behavior and successfully controlled gene expression in stem-cell-derived fibroblasts with a Tet-On system. While free DXC inhibited fibroblast proliferation and matrix metalloproteinase (MMP) activity, PEG–H40–DXC nanoparticles maintained higher fibroblast proliferation levels and MMP activity. The results demonstrate that the PEG–H40–DXC nanoparticle system provides an effective tool to controlling gene expression in human stem cell derivatives.

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.

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.

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.

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.

Foamed poly(lactide) (PLA)/poly(butylene adipate-co-terephthalate) (PBAT) blends were processed via the microcellular extrusion process using CO2 as a blowing agent. Talc has been added to promote heterogeneous nucleation. Two types of PLA/PBAT blend systems were investigated: Ecovio, which is a commercially available compatibilized PLA/PBAT blend; and a non-compatibilized PLA/PBAT blend at the same PLA/PBAT ratio (i.e., 45:55 by weight percent). Six different formulations were investigated: pure PLA, PLA-talc, Ecovio, Ecovio-talc, non-compatibilized PLA/PBAT blend, and non-compatibilized PLA/PBAT-talc. The effects of various processing parameters such as die temperature, talc and compatibilization on various foaming properties such as cell morphology, volume expansion ratio (VER), open cell content (OCC) and crystallinity were investigated. As per the DSC thermograms, it was observed that compatibilization has merged the two distinctive melting peaks of PLA and PBAT into a single peak while lowering the peak temperature. In general, the addition of talc has decreased the average cell size and VER and increased the cell density and crystallinity; however, it has varying effects on the open cell content. Compatibilization has reduced the average cell size and volume expansion but increased the cell density and had varying and no effects on the OCC and crystallinity, respectively. Similar to compatibilization, the die temperature was found to have varying and no effects on the OCC and crystallinity, respectively. Except for PLA and non-compatibilized PLA/PBAT blend, the cell size and VER of all other formulations did not vary much throughout the entire temperature range (130-150°C). The cell density was found to be insensitive to die temperatures except for Ecovio and Ecovio-talc.

We, the named authors, hereby wholly retract this Molecular BioSystems article. Signed: Xiaoqiang Yang, Jamison J. Grailer, Srikanth Pilla, Douglas A. Steeber, Shaoqin Gong, Yinghua Chen and Guihua Chen, Milwaukee, USA, August 2009. Retraction endorsed by Michael Smith, Commissioning Editor. Retraction published 24th August 2009.

This paper presented construction and strain distributions for light-weight wood-fiber-based structural panels with tri-grid core made from phenolic impregnated laminated paper composites under bending. A new fastening configuration of slots in the faces and tabs on the core was applied to the face/core interfaces of the sandwich panel in addition to epoxy resin. Both normal strain gages and shear strain gages were attached on these panels to analyze inside strain distributions by third point load bending test. The purpose of the bending test was to investigate the various strain distributions of panels with different face/core configurations that identified the critical failure modes for future design. In this research, four panels with different configurations were constructed to analyze the influence of strain distributions for bending behavior. Either maximum localized normal strain or shear strain were used to judge failures and associated failure modes through observation. Test results of strain distribution showed normal strain was primarily carried by both top and bottom faces. As bending load increased, compression buckling occurred on the top surface of some panels with thinner faces. Face thickness and stiffness significantly affected the strength of the panel as evident by nonlinear strain behavior. Meanwhile, the shear strain was primarily taken by the ribs in the structural core, and shear failure always occurred in the longitudinal linear ribs of core with thicker faces. The shear strain in the cross ribs was approximately half that of the longitudinal linear ribs in the same section of shear zone, which was consistent with the geometric formula. The problem of panel imperfections resulting in either face compression buckling or rib shear buckling could be overcome by further design optimization, and the analytical modeling for bending design and evaluation was presented.

Introduction: Carcinoids are neuroendocrine (NE) tumors that secrete hormones causing the carcinoid syndrome. Metastatic carcinoids are not amenable to curative surgery. Our previous research has shown that Notch signaling has a tumor suppressor role in NE tumors. In the present study, we sought to examine Thailandepsin A (TDP-A), a newly discovered HDAC inhibitor as a Notch activating drug and carcinoid cancer agent. Methods: TDP-A is a bacterial natural product isolated from the fermentation broth of Burkholderia thailandensis E264. The cytotoxicity of TDP-A on human pancreatic (BON) carcinoid cells was measured by determining the IC50 value.The antiproliferative effect of TDP-A on BON cells growth was assessed by the methylthiazolyldiphenyl-tetrazolium bromide (MTT) rapid colorimetric assay.The mechanism of growth inhibition was determined for cell cycle and apoptosis markers by Western blot and flow cytometry analyses. Expression of Notch isoforms 1-3 was assessed at the transcriptional level (real time RT-PCR) and protein level (Western blot) from parental and TDP-A treated BON cells. Functional analysis of Notch Intracellular Domain (NICD) was done by measuring the degree of luciferase activity by CBF1 binding assay. The gene expression of HES and HEY (Notch signaling mediators) was quantified by real time RT-PCR. Effect of TDP-A on NE markers -chromogranin A (CgA) and achaete-scute complex-like1 (ASCL1) - was assessed by Western blot analysis. Results: The IC50 value for TDP-A treatment of BON cells was determined to be 7 nM. TDP-A treatment decreased cell proliferation in a dose and time dependent manner. Western blot analysis and flow cytometry experiments indicated that the growth inhibition was due to cell cycle arrest (at G2/M phase) followed by apoptosis.Treatment of BON cells with TDP-A led to an induction of Notch isoforms in a dose-dependent manner. Functional Notch signaling was demonstrated by an increase in the CBF1 binding activity and upregualtion of transcriptional levels of HES and HEY families. More importantly, Notch activation led to a dose dependent reduction of NE markers ASCL1 and CgA. Conclusions: We demonstrated that TDP-A is a potent Notch pathway activator and an inhibitor of BON carcinoid cell proliferation at low nanomolar concentrations. TDP-A suppressed carcinoid cell growth by promoting cell cycle arrest and apoptosis and decreased NET marker expression (ASCL1 and CgA). These results indicate that TDP-A has therapeutic potential for carcinoid cancer. Citation Format: Renata Jaskula-Sztul, Ajitha Dammalapati, Colin Korlesky, Shaoqin Gong, Yi-Qiang Cheng, Herbert Chen. Thailandepsin A, a new HDAC inhibitor, reduces cellular proliferation and activates the Notch pathway in human carcinoids cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1014. doi:10.1158/1538-7445.AM2013-1014

A multifunctional gold (Au) nanorod (NR)-based nanocarrier capable of co-delivering small interfering RNA (siRNA) against achaete-scute complex-like 1 (ASCL1) and an anticancer drug (doxorubicin (DOX)) specifically to neuroendocrine (NE) cancer cells was developed and characterized for combined chemotherapy and siRNA-mediated gene silencing. The Au NR was conjugated with (1) DOX, an anticancer drug, via a pH-labile hydrazone linkage to enable pH-controlled drug release, (2) polyarginine, a cationic polymer for complexing siRNA, and (3) octreotide (OCT), a tumor-targeting ligand, to specifically target NE cancer cells with overexpressed somatostatin receptors. The Au NR-based nanocarriers exhibited a uniform size distribution as well as pH-sensitive drug release. The OCT-conjugated Au NR-based nanocarriers (Au-DOX-OCT, targeted) exhibited a much higher cellular uptake in a human carcinoid cell line (BON cells) than non-targeted Au NR-based nanocarriers (Au-DOX) as measured by both flow cytometry and confocal laser scanning microscopy (CLSM). Moreover, Au-DOX-OCT-ASCL1 siRNA (Au-DOX-OCT complexed with ASCL1 siRNA) resulted in significantly higher gene silencing in NE cancer cells than Au-DOX-ASCL1 siRNA (non-targeted Au-DOX complexed with ASCL1 siRNA) as measured by an immunoblot analysis. Additionally, Au-DOX-OCT-ASCL1 siRNA was the most efficient nanocarrier at altering the NE phenotype of NE cancer cells and showed the strongest anti-proliferative effect. Thus, combined chemotherapy and RNA silencing using NE tumor-targeting Au NR-based nanocarriers could potentially enhance the therapeutic outcomes in treating NE cancers.