Effects of Non-Adiabatic Electromagnetic Vacuum Fluctuations on Internal Conversion.

To explore non-adiabatic effects caused by electromagnetic (EM) vacuum fluctuations in molecules, we develop a general theory of internal conversion (IC) in the framework of quantum electrodynamics and propose a new mechanism, "quantum electrodynamic internal conversion" (QED-IC). The theory allows us to compute the rates of the conventional IC and QED-IC processes at the first-principles level. Our simulations manifest that, under experimentally feasible weak light-matter coupling conditions, EM vacuum fluctuations can significantly affect IC rates by an order of magnitude. Moreover, our theory elucidates three key factors in the QED-IC mechanism: the effective mode volume, coupling-weighted normal mode alignment, and molecular rigidity. The theory successfully captures the nucleus-photon interaction in the factor "coupling-weighted normal mode alignment". In addition, we find that molecular rigidity plays a totally different role in conventional IC versus QED-IC rates. Our study provides applicable design principles for exploiting QED effects on IC processes.

Laminin Receptor-Mediated Nanoparticle Uptake by Tumor Cells: Interplay of Epigallocatechin Gallate and Magnetic Force at Nano-Bio Interface.

Epigallocatechin gallate (EGCG), a major tea catechin, enhances cellular uptake of magnetic nanoparticles (MNPs), but the mechanism remains unclear. Since EGCG may interact with the 67-kDa laminin receptor (67LR) and epidermal growth factor receptor (EGFR), we investigate whether a receptor and its downstream signaling may mediate EGCG's enhancement effects on nanoparticle uptake. As measured using a colorimetric iron assay, EGCG induced a concentration-dependent enhancement effect of MNP internalization by LN-229 glioma cells, which was synergistically enhanced by the application of a magnetic field. Transmission electron microscopy demonstrated that EGCG increased the number, but not the size, of internalized vesicles, whereas EGCG and the magnet synergistically increased the size of vesicles. EGCG appears to enhance particle-particle interaction and thus aggregation following a 5-min magnet application. An antibody against 67LR, knockdown of 67LR, and a 67LR peptide (amino acid 161-170 of 67LR) attenuated EGCG-induced MNP uptake by 35%, 100%, and 45%, respectively, suggesting a crucial role of 67LR in the effects of EGCG. Heparin, the 67LR-binding glycosaminoglycan, attenuated EGCG-induced MNP uptake in the absence, but not presence, of the magnet. Such enhancement effects of EGCG were attenuated by LY294002 (a phosphoinositide 3-kinase inhibitor) and Akt inhibitor, but not by agents affecting cGMP levels, suggesting potential involvement of signaling downstream of 67LR. In contrast, the antibody against EGFR exerted no effect on EGCG-enhanced internalization. These results suggest that 67LR may be potentially amenable to tumor-targeted therapeutics.

TEAD4 as an Oncogene and a Mitochondrial Modulator.

TEAD4 (TEA Domain Transcription Factor 4) is well recognized as the DNA-anchor protein of YAP transcription complex, which is modulated by Hippo, a highly conserved pathway in Metazoa that controls organ size through regulating cell proliferation and apoptosis. To acquire full transcriptional activity, TEAD4 requires co-activator, YAP (Yes-associated protein) or its homolog TAZ (transcriptional coactivator with PDZ-binding motif) the signaling hub that relays the extracellular stimuli to the transcription of target genes. Growing evidence suggests that TEAD4 also exerts its function in a YAP-independent manner through other signal pathways. Although TEAD4 plays an essential role in determining that differentiation fate of the blastocyst, it also promotes tumorigenesis by enhancing metastasis, cancer stemness, and drug resistance. Upregulation of TEAD4 has been reported in several cancers, including colon cancer, gastric cancer, breast cancer, and prostate cancer and serves as a valuable prognostic marker. Recent studies show that TEAD4, but not other members of the TEAD family, engages in regulating mitochondrial dynamics and cell metabolism by modulating the expression of mitochondrial- and nuclear-encoded electron transport chain genes. TEAD4's functions including oncogenic activities are tightly controlled by its subcellular localization. As a predominantly nuclear protein, its cytoplasmic translocation is triggered by several signals, such as osmotic stress, cell confluency, and arginine availability. Intriguingly, TEAD4 is also localized in mitochondria, although the translocation mechanism remains unclear. In this report, we describe the current understanding of TEAD4 as an oncogene, epigenetic regulator and mitochondrial modulator. The contributing mechanisms will be discussed.

Arginine Signaling and Cancer Metabolism.

Arginine is an amino acid critically involved in multiple cellular processes including the syntheses of nitric oxide and polyamines, and is a direct activator of mTOR, a nutrient-sensing kinase strongly implicated in carcinogenesis. Yet, it is also considered as a non- or semi-essential amino acid, due to normal cells' intrinsic ability to synthesize arginine from citrulline and aspartate via ASS1 (argininosuccinate synthase 1) and ASL (argininosuccinate lyase). As such, arginine can be used as a dietary supplement and its depletion as a therapeutic strategy. Strikingly, in over 70% of tumors, ASS1 transcription is suppressed, rendering the cells addicted to external arginine, forming the basis of arginine-deprivation therapy. In this review, we will discuss arginine as a signaling metabolite, arginine's role in cancer metabolism, arginine as an epigenetic regulator, arginine as an immunomodulator, and arginine as a therapeutic target. We will also provide a comprehensive summary of ADI (arginine deiminase)-based arginine-deprivation preclinical studies and an update of clinical trials for ADI and arginase. The different cell killing mechanisms associated with various cancer types will also be described.

Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes.

Rationale: One of the most common metabolic defects in cancers is the deficiency in arginine synthesis, which has been exploited therapeutically. Yet, challenges remain, and the mechanisms of arginine-starvation induced killing are largely unclear. Here, we sought to demonstrate the underlying mechanisms by which arginine starvation-induced cell death and to develop a dietary arginine-restriction xenograft model to study the in vivo effects. Methods: Multiple castration-resistant prostate cancer cell lines were treated with arginine starvation followed by comprehensive analysis of microarray, RNA-seq and ChIP-seq were to identify the molecular and epigenetic pathways affected by arginine starvation. Metabolomics and Seahorse Flux analyses were used to determine the metabolic profiles. A dietary arginine-restriction xenograft mouse model was developed to assess the effects of arginine starvation on tumor growth and inflammatory responses. Results: We showed that arginine starvation coordinately and epigenetically suppressed gene expressions, including those involved in oxidative phosphorylation and DNA repair, resulting in DNA damage, chromatin-leakage and cGAS-STING activation, accompanied by the upregulation of type I interferon response. We further demonstrated that arginine starvation-caused depletion of α-ketoglutarate and inactivation of histone demethylases are the underlying causes of epigenetic silencing. Significantly, our dietary arginine-restriction model showed that arginine starvation suppressed prostate cancer growth in vivo, with evidence of enhanced interferon responses and recruitment of immune cells. Conclusions: Arginine-starvation induces tumor cell killing by metabolite depletion and epigenetic silencing of metabolic genes, leading to DNA damage and chromatin leakage. The resulting cGAS-STING activation may further enhance these killing effects.

Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells.

Arginine plays diverse roles in cellular physiology. As a semi-essential amino acid, arginine deprivation has been used to target cancers with arginine synthesis deficiency. Arginine-deprived cancer cells exhibit mitochondrial dysfunction, transcriptional reprogramming and eventual cell death. In this study, we show in prostate cancer cells that arginine acts as an epigenetic regulator to modulate histone acetylation, leading to global upregulation of nuclear-encoded oxidative phosphorylation (OXPHOS) genes. TEAD4 is retained in the nucleus by arginine, enhancing its recruitment to the promoter/enhancer regions of OXPHOS genes and mediating coordinated upregulation in a YAP1-independent but mTOR-dependent manner. Arginine also activates the expression of lysine acetyl-transferases and increases overall levels of acetylated histones and acetyl-CoA, facilitating TEAD4 recruitment. Silencing of TEAD4 suppresses OXPHOS functions and prostate cancer cell growth in vitro and in vivo. Given the strong correlation of TEAD4 expression and prostate carcinogenesis, targeting TEAD4 may be beneficially used to enhance arginine-deprivation therapy and prostate cancer therapy.

Comparative Studies of CPEs Modified with Distinctive Metal Nanoparticle-Decorated Electroactive Polyimide for the Detection of UA.

In this present work, an electrochemical sensor was developed for the sensing of uric acid (UA). The sensor was based on a carbon paste electrode (CPE) modified with electroactive polyimide (EPI) synthesized using aniline tetramer (ACAT) decorated with reduced nanoparticles (NPs) of Au, Pt, and Ag. The initial step involved the preparation and characterization of ACAT. Subsequently, the ACAT-based EPI synthesis was performed by chemical imidization of its precursors 4,4'-(4.4'-isopropylidene-diphenoxy) bis (phthalic anhydride) BPADA and ACAT. Then, EPI was doped with distinctive particles of Ag, Pt and Au, and the doped EPIs were abbreviated as EPIS, EPIP and EPIG, respectively. Their structures were characterized by XRD, XPS, and TEM, and the electrochemical properties were determined by cyclic voltammetry and chronoamperometry. Among these evaluated sensors, EPI with Au NPs turned out the best with a sensitivity of 1.53 uA uM-1 UA, a low limit of detection (LOD) of 0.78 uM, and a linear detection range (LDR) of 5-50 uM UA at a low potential value of 310 mV. Additionally, differential pulse voltammetric (DPV) analysis showed that the EPIG sensor showed the best selectivity for a tertiary mixture of UA, dopamine (DA), and ascorbic acid (AA) as compared to EPIP and EPIS.

Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation.

PKM2 is a key metabolic enzyme central to glucose metabolism and energy expenditure. Multiple stimuli regulate PKM2's activity through allosteric modulation and post-translational modifications. Furthermore, PKM2 can partner with KDM8, an oncogenic demethylase and enter the nucleus to serve as a HIF1α co-activator. Yet, the mechanistic basis of the exon-10 region in allosteric regulation and nuclear translocation remains unclear. Here, we determined the crystal structures and kinetic coupling constants of exon-10 tumor-related mutants (H391Y and R399E), showing altered structural plasticity and reduced allostery. Immunoprecipitation analysis revealed increased interaction with KDM8 for H391Y, R399E, and G415R. We also found a higher degree of HIF1α-mediated transactivation activity, particularly in the presence of KDM8. Furthermore, overexpression of PKM2 mutants significantly elevated cell growth and migration. Together, PKM2 exon-10 mutations lead to structure-allostery alterations and increased nuclear functions mediated by KDM8 in breast cancer cells. Targeting the PKM2-KDM8 complex may provide a potential therapeutic intervention.

The FLT3 inhibitor midostaurin selectively resensitizes ABCB1-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic agents.

The occurrence of multidrug resistance (MDR) associated with the overexpression of the ATP-binding cassette (ABC) protein ABCB1 in cancer cells remains a significant obstacle to successful cancer chemotherapy. Therefore, discovering modulators that are capable of inhibiting the drug efflux function or expression of ABCB1 and re-sensitizing multidrug-resistant cancer cells to anticancer agents is of great clinical importance. Regrettably, due to potential adverse events associated with drug-drug interactions and toxicity in patients, researchers have struggled to develop a synthetic inhibitor of ABCB1 that is clinically applicable to improve the effectiveness of chemotherapy. Alternatively, through drug repositioning of approved drugs, we discovered that the FMS-like tyrosine kinase-3 (FLT3) inhibitor midostaurin blocks the drug transport function of ABCB1 and re-sensitizes ABCB1-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic drugs. Our findings were further supported by results demonstrating that midostaurin potentiates drug-induced apoptosis in ABCB1-overexpressing cancer cells and inhibits the ATPase activity of ABCB1. Considering that midostaurin is a clinically approved anticancer agent, our findings revealed an additional action of midostaurin and that patients with multidrug-resistant tumors may benefit from a combination therapy of midostaurin with standard chemotherapy, which should be further investigated.

KDM8/JMJD5 as a dual coactivator of AR and PKM2 integrates AR/EZH2 network and tumor metabolism in CRPC.

During the evolution into castration or therapy resistance, prostate cancer cells reprogram the androgen responses to cope with the diminishing level of androgens, and undergo metabolic adaption to the nutritionally deprived and hypoxia conditions. AR (androgen receptor) and PKM2 (pyruvate kinase M2) have key roles in these processes. We report in this study, KDM8/JMJD5, a histone lysine demethylase/dioxygnase, exhibits a novel property as a dual coactivator of AR and PKM2 and as such, it is a potent inducer of castration and therapy resistance. Previously, we showed that KDM8 is involved in the regulation of cell cycle and tumor metabolism in breast cancer cells. Its role in prostate cancer has not been explored. Here, we show that KDM8's oncogenic properties in prostate cancer come from its direct interaction (1) with AR to affect androgen response and (2) with PKM2 to regulate tumor metabolism. The interaction with AR leads to the elevated expression of androgen response genes in androgen-deprived conditions. They include ANCCA/ATAD2 and EZH2, which are directly targeted by KDM8 and involved in sustaining the survival of the cells under hormone-deprived conditions. Notably, in enzalutamide-resistant cells, the expressions of both KDM8 and EZH2 are further elevated, so are neuroendocrine markers. Consequently, EZH2 inhibitors or KDM8 knockdown both resensitize the cells toward enzalutamide. In the cytosol, KDM8 associates with PKM2, the gatekeeper of pyruvate flux and translocates PKM2 into the nucleus, where the KDM8/PKM2 complex serves as a coactivator of HIF-1α to upregulate glycolytic genes. Using shRNA knockdown, we validate KDM8's functions as a regulator for both androgen-responsive and metabolic genes. KDM8 thus presents itself as an ideal therapeutic target for metabolic adaptation and castration-resistance of prostate cancer cells.

Resveratrol Mitigates High-Fat Diet-Induced Vascular Dysfunction by Activating the Akt/eNOS/NO and Sirt1/ER Pathway.

We investigated whether resveratrol (RSV) can attenuate obesity and diabetes progression and improve diabetes-induced vascular dysfunction, and we attempted to delineate its underlying mechanisms. Male C57Bl/6 mice were administered a high-fat diet (HFD) for 17 weeks. Mice developed type 2 diabetes with increased body weight, hyperglycemia, hyperinsulinemia, and hyperlipidemia. Oral gavage with RSV significantly reversed the symptoms induced by the HFD. Insulin sensitivity likewise improved after the RSV intervention in these mice. Phenylephrine-induced cremaster arteriolar constriction was impaired, whereas RSV treatment significantly mitigated the vessel responsiveness to phenylephrine. The obese diabetic mice exhibited increased leukocyte rolling, adhesion, and transmigration in the postcapillary venules of the cremaster muscle. By contrast, RSV treatment significantly attenuated HFD-induced extravasation. RSV significantly recovered phosphorylated Akt and eNOS expression in the thoracic aorta. In addition, activated adenosine monophosphate-activated protein kinase in the thoracic aorta was involved in the improvement of epithelial function after RSV intervention. RSV considerably upregulated the plasma NO level in HFD mice. Moreover, RSV-enhanced human umbilical vein endothelial cells healing through Sirt1/ER pathway may be involved in the prevention of leukocyte extravasation. Collectively, RSV attenuates diabetes-induced vascular dysfunction by activating Akt/eNOS/NO and Sirt1/ER pathway. Our mechanistic study provides a potential RSV-based therapeutic strategy against cardiovascular disease.

Role of dysfunctional adipocytes in cholesterol-induced nonobese metabolic syndrome.

Many studies have reported the causes of obese metabolic syndrome (MS); however, the causes of nonobese MS (NMS) remain unknown. In this study, we demonstrated that inflamed dysfunctional adipose tissue plays a crucial role in cholesterol-induced NMS. Control (C), high cholesterol (HC) and HC with 10% fructose in drinking water (HCF) diets were fed to Sprague-Dawley rats for 12 weeks. After 12 weeks, the body weights of the C- and HC-fed rats were comparable, but the weights of the HCF-fed rats were relatively low. Cholesterol caused metabolic problems such as high blood pressure, hypercholesterolemia and hypoinsulinemia. The HCF-fed rats exhibited whole-body insulin resistance with low circulating high-density lipoprotein levels. Increases in the tumor necrosis factor α level in the plasma, the number of CD68+ macrophages and the free nuclear factor-κB level in gonadal white adipose tissue (gWAT) resulted in local inflammation, which appeared as inflamed dysfunctional gWAT. Reduced superoxide dismutases (SODs) deteriorate natural antioxidant defense systems and induce reactive oxygen species in gWAT. Dysregulation of plasma levels of catecholamine, adipokines (leptin and adiponectin), hormone-sensitive lipase and perilipin in cholesterol-induced inflamed adipose tissue contributed to increased lipolysis and increased circulating nonesterified fatty acids. Cholesterol activated inflammation, lipolysis and cell death in 3T3-L1 adipocytes. Moreover, Chol-3T3-CM reduced the population of M2-type Raw264.7 macrophages, indicating that the macrophage polarization is mediated by cholesterol. Together, our findings indicate that inflamed dysfunctional adipocytes are critical in NMS, supporting the development of anti-inflammatory agents as potential therapeutic drugs for treating NMS.

Optimization of reprogramming culture conditions for the generation of induced pluripotent stem cells from Col1a1 4F2A-Oct4-GFP mice with high efficiency.

A reprogrammable transgenic mouse strain, called Col1a1 4F2A-Oct4-GFP, was bred for the present study. Because the somatic cells of this mouse strain contain only two copies of each Yamanaka factor, these animals are inefficient at producing induced pluripotent stem cells (iPSCs; approx. 0.005%) under traditional culture conditions. With an optimized culture condition, the iPSC production rate of mouse embryonic fibroblasts (MEFs) of Col1a1 4F2A-Oct4-GFP mice (MEFCol1a14F2A-Oct4-GFP ) was increased to approximately 8%. Further, promotion of cell proliferation by serum supplementation did not enhance iPSC production. Inhibition of transforming growth factor ß (TGF-ß) in the serum by SB431542 neither affected the growth rate of MEFCol1a14F2A-Oct4-GFP nor promoted iPSC production. However, the use of the gamma-irradiated STO-NEO-LIF (γSNL) cells to serve as feeders for iPSC production resulted in a 5-fold higher rate of iPSC production than the use of γMEFICR feeders. Interestingly, the use of SB431542 with the γMEFICR -adopted system could eliminate this difference. RT-PCR-based comparative analysis further demonstrated that TGF-ß expression was 10-fold higher in γMEFICR than in γSNL cells. Consistent with previous reports, mesenchymal to epithelial transition was found to participate in the initial steps of reprogramming in the specific context of MEFCol1a14F2A-Oct4-GFP . Moreover, we found that the initial seeding density is one of the pivotal factors for determining a high efficiency of iPSC generation. The iPSCs efficiently generated from our MEFCol1a14F2A-Oct4-GFP resembled mouse embryonic stem cells (mESCs) in aspects of teratoma formation and germline transmission. Depending on the culture conditions, our Col1a1 4F2A-Oct4-GFP mouse system can generate bona fide iPSCs with variable efficiencies, which can serve as a tool for interrogating the route taken by cells during somatic reprogramming.

Human ATP-Binding Cassette Transporter ABCB1 Confers Resistance to Volasertib (BI 6727), a Selective Inhibitor of Polo-like Kinase 1.

The overexpression of the serine/threonine specific polo-like kinase 1 (Plk1) is associated with poor prognosis in many types of cancer. Consequently, Plk1 has emerged as a valid therapeutic target for anticancer drug design. Volasertib is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting cell cycle arrest at nanomolar concentrations. However, the risk of developing drug resistance, which is often associated with the overexpression of the ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein), can present a therapeutic challenge for volasertib and many other therapeutic drugs. Although volasertib is highly effective against the proliferation of numerous cancer cell lines, we found that the overexpression of ABCB1 in cancer cells leads to cellular resistance to volasertib and reduces the level of volasertib-stimulated G2/M cell cycle arrest and subsequent onset of apoptosis. Furthermore, we demonstrate that volasertib competitively inhibits the function of ABCB1 and stimulates the basal ATPase activity of ABCB1 in a concentration-dependent manner, which is consistent with substrate transport by ABCB1. More importantly, we discovered that the coadministration of an inhibitor or drug substrate of ABCB1 restored the anticancer activity of volasertib in ABCB1-overexpressing cancer cells. In conclusion, the results of our study reveal that ABCB1 negatively affects the efficacy of volasertib and supports its combination with a modulator of ABCB1 to improve clinical responses.

Enhanced Therapeutic Epidermal Growth Factor Receptor (EGFR) Antibody Delivery via Pulsed Ultrasound with Targeting Microbubbles for Glioma Treatment.

Pulsed-mode ultrasound (pUS) in combination with intravenously (IV) administered microbubbles (MBs) can enhance local drug delivery by temporarily enhancing capillary permeability. This study evaluates the use of epidermal growth factor receptor (EGFR)-targeting MBs after pUS treatment to enhance the effects of therapeutic-EGFR antibody delivery to glioma tumor cells in mice. Three animal groups were compared: (1) IV-injected non-targeting MBs, (2) IV-injected targeting MBs, and (3) IV-injected targeting MBs combined with pUS treatment. All animals were analyzed using high-frequency small-animal US imaging. The mean halftime of circulating targeting MBs was significantly increased from 3.13 min of targeting bubble alone to 5.86 min by targeting MBs combined with pUS treatment, compared to 2.34 min for non-targeting MBs. Compared to targeting bubble administration alone, pUS exposure prior to injection of targeting MBs was also significantly better at suppressing tumor growth when monitored for up to 35 days (p < 0.05). The final relative tumor volumes were 2664, 700, and 188 mm3 for non-targeting MBs, targeting MBs, and targeting MBs combined with pUS treatment, respectively. pUS treatment prolonged the mean circulatory halftime of targeting MBs and enhanced the anti-tumor effect of EGFR antibodies in a human glioma model in mice. Targeting MBs combined with pUS treatment thus has potential for enhanced therapeutic antibody delivery for facilitating anti-glioma treatment.

Involvement of dopamine D2 receptor in the diurnal changes of tuberoinfundibular dopaminergic neuron activity and prolactin secretion in female rats.

BACKGROUND: An endogenous dopaminergic (DA) tone acting on D3 receptors has been shown to inhibit tuberoinfundibular (TI) DA neuron activity and stimulate prolactin (PRL) surge in the afternoon of estrogen-primed ovariectomized (OVX+E2) rats. Whether D2 receptor (D2R) is also involved in the regulation of TIDA and PRL rhythms was determined in this study. RESULTS: Intracerebroventricular (icv) injection of PHNO, a D2R agonist, in the morning inhibited TIDA and midbrain DA neurons' activities, and stimulated PRL secretion. The effects of PHNO were significantly reversed by co-administration of raclopride, a D2R antagonist. A single injection of raclopride at 1200 h significantly reversed the lowered TIDA neuron activity and the increased serum PRL level at 1500 h. Dopamine D2R mRNA expression in medial basal hypothalamus (MBH) exhibited a diurnal rhythm, i.e., low in the morning and high in the afternoon, which was opposite to that of TIDA neuron activity. The D2R rhythm was abolished in OVX+E2 rats kept under constant lighting but not in OVX rats with regular lighting exposures. Pretreatment with an antisense oligodeoxynucleotides (AODN, 10 µg/3 µl/day, icv) against D2R mRNA for 2 days significantly reduced D2R mRNAs in central DA neurons, and reversed both lowered TIDA neuron activity and increased serum PRL level in the afternoon on day 3. A diurnal rhythm of D2R mRNA expression was also observed in midbrain DA neurons and the rhythm was significantly knocked down by the AODN pretreatment. CONCLUSIONS: We conclude that a diurnal change of D2R mRNA expression in MBH may underlie the diurnal rhythms of TIDA neuron activity and PRL secretion in OVX+E2 rats.

In situ gelation of PEG-PLGA-PEG hydrogels containing high loading of hydroxyapatite: in vitro and in vivo characteristics.

Thermosensitive hydrogels are renowned carriers that are used to deliver a variety of drugs with the aim of combating diseases. In this study, the injectability of thermosensitive hydrogels comprised of poly(ethylene glycol)-poly(lactic acid-co-glycolic acid)-poly(ethylene glycol) (PEG-PLGA-PEG, PELGE) and hydroxyapatite (HA) were examined for their ability to deliver bone morphological protein 2 (BMP-2). The physicochemical characteristics of PELGE, HA, and PELGE/HA hydrogel composites were investigated by (1)H NMR, GPC, FTIR, XRD, SEM, and TEM. The rheological properties, injectability, in vitro degradation, and in vivo biocompatibility were investigated. The hydrogel with a weight ratio of 4:6 of polymer to HA was found to be resistant to auto-catalyzed degradation of acidic monomers (LA, GA) for a period of 70 days owing to the presence of alkaline HA. Injectability was quantitatively determined by the ejected weight of the hydrogel composite at room temperature and was a close match to the weight amount predetermined by the syringe pump. The results not only revealed that the PELGE/HA hydrogel composite presented a minor tissue response in the subcutis of ICR mice at eight weeks, but they also indicated an acceptable tolerance of the hydrogel composite in animals. Thus, PELGE/HA hydrogel composite is expected to be a promising injectable orthopedic substitute because of its desirable thermosensitivity and injectability.

Self-assembly behavior of amphiphilic poly(amidoamine) dendrimers with a shell of aniline pentamer.

A series of amphiphilic poly(amidoamine) dendrimers (PAMAM, G2-G5) composed of a hydrophilic core and a hydrophobic shell of aniline pentamer (AP) were synthesized and characterized. The modified dendrimers self-assembled to vesicular aggregates in water with the critical aggregation concentration (CAC) decreased in the order of G2 > G3 > G4 > G5. It was found that the modified dendrimers self-organized into spherical aggregates with a bilayer vesicular structures and that the dendrimers in higher generation have more order structure, which may be attributed to the crystallization induced by the compacted effect of AP segments. In addition, larger spherical vesicles were observed under acidic and alkaline conditions, as compared with sizes of aggregates in neutral medium. At low pH, the tertiary amine groups of PAMAM-AP were transformed to ammonium salts; the polarons were formed from AP units by doping with strong acids, thereby leading to the stability of vesicular aggregates being better than that in double distilled water. Nevertheless, in high pH environment, the deprotonation of PAMAM-AP caused the enhancement of π-π interactions, resulting in generation of twins or multilayered vesicles.

EGRF conjugated PEGylated nanographene oxide for targeted chemotherapy and photothermal therapy.

Low accumulation of chemotherapeutic agent in tumor tissue and multidrug resistance (MDR) present a major obstacle to curing cancer treatment. Therefore, how to combine several therapeutics in one system is a key issue to overcome the problem. Here, we demonstrate epidermal growth factor receptor (EGFR) antibody-conjugated PEGylated nanographene oxide (PEG-NGO) to carry epirubicin (EPI) for tumor targeting and triple-therapeutics (growth signal blocking, chemotherapy, photothermal therapy) in tumor treatment. This synergistic targeted treatment simultaneously enhances the local drug concentration (6.3-fold) and performs the ultra-efficient tumor suppression to significantly prolong the mice survival (over the course of 50 days).

Nanocasting technique to prepare lotus-leaf-like superhydrophobic electroactive polyimide as advanced anticorrosive coatings.

Nanocasting technique was used to obtain a biomimetic superhydrophobic electroactive polyimide (SEPI) surface structure from a natural Xanthosoma sagittifolium leaf. An electroactive polyimide (EPI) was first synthesized through thermal imidization. An impression of the superhydrophobic Xanthosoma sagittifolium leaf was then nanocasted onto the surface of the EPI so that the resulting EPI was superhydrophobic and would prevent corrosion. Polydimethylsiloxane (PDMS) was then used as a negative template to transfer the impression of the superhydrophobic surface of the biomimetic EPI onto a cold-rolled steel (CRS) electrode. The superhydrophobic electroactive material could be used as advanced coatings that protect metals against corrosion. The morphology of the surface of the as-synthesized SEPI coating was investigated using scanning electron microscopy (SEM). The surface showed numerous micromastoids, each decorated with many nanowrinkles. The water contact angle (CA) for the SEPI coating was 155°, which was significantly larger than that for the EPI coating (i.e., CA = 87°). The significant increase in the contact angle indicated that the biomimetic morphology effectively repelled water. Potentiodynamic and electrochemical impedance spectroscopic measurements indicated that the SEPI coating offered better protection against corrosion than the EPI coating did.