Near-infrared-II photoacoustic imaging and photo-triggered synergistic treatment of thrombosis via fibrin-specific homopolymer nanoparticles.

The formation of an occlusive thrombus in the blood vessel is the main culprit for numerous life-threatening cardiovascular diseases that represent the leading cause of morbidity and mortality worldwide. Herein, we develop a polymer nanoplatform that integrates long-wavelength second near-infrared (NIR-II) photoacoustic imaging-based thrombosis detection and antithrombotic activity. We design and synthesize a semiconducting homopolymer with strong absorption in the NIR-II region and molecular motion that boosts photothermal conversion and photoacoustic signal. We dope the homopolymer with a thermosensitive nitric oxide donor to formulate a nanoplatform, on which a fibrin-specific ligand is functionalized to ensure selective thrombus targeting. We show that with strong NIR-II light harvesting capability, bright photoacoustic signal and active thrombus accumulation ability, the NIR-II photoacoustic nanoprobes are able to sensitively and selectively delineate thrombi. We find that the nanoplatform also displays rapid and efficient blood clot removal activity with nearly complete blood flow restoration in both carotid thrombosis models and low extremity arterial thrombosis models under NIR-II light trigger by integrating a thrombus-localized photothermal effect and on-demand nitric oxide release. This nanoplatform offers a versatile approach for the diagnosis and treatment of life-threatening diseases caused by various thrombotic disorders.

Highly Bright AIE Nanoparticles by Regulating the Substituent of Rhodanine for Precise Early Detection of Atherosclerosis and Drug Screening.

Fluorescent probes capable of precise detection of atherosclerosis (AS) at an early stage and fast assessment of anti-AS drugs in animal level are particularly valuable. Herein, a highly bright aggregation-induced emission (AIE) nanoprobe is introduced by regulating the substituent of rhodanine for early detection of atherosclerotic plaque and screening of anti-AS drugs in a precise, sensitive, and rapid manner. With dicyanomethylene-substituted rhodanine as the electron-withdrawing unit, the AIE luminogen named TPE-T-RCN shows the highest molar extinction coefficient, the largest photoluminescence quantum yield, and the most redshifted absorption/emission spectra simultaneously as compared to the control compounds. The nanoprobes are obtained with an amphiphilic copolymer as the matrix encapsulating TPE-T-RCN molecules, which are further surface functionalized with anti-CD47 antibody for specifically binding to CD47 overexpressed in AS plaques. Such nanoprobes allow efficient recognition of AS plaques at different stages in apolipoprotein E-deficient (apoE-/- ) mice, especially for the recognition of early-stage AS plaques prior to micro-computed tomography (CT) and magnetic resonance imaging (MRI). These features impel to apply the nanoprobes in monitoring the therapeutic effects of anti-AS drugs, providing a powerful tool for anti-AS drug screening. Their potential use in targeted imaging of human carotid plaque is further demonstrated.

PolyTLR7/8a-conjugated, antigen-trapping gold nanorods elicit anticancer immunity against abscopal tumors by photothermal therapy-induced in situ vaccination.

Nanovaccine can elicit antigen-specific immune responses against tumor cells expressing homologous antigens and has attracted enormous attention in cancer immunotherapy. However, tumor heterogeneity remarkably hinders the development of nanovaccines. Here we demonstrate that PTT-induced in situ vaccination cancer therapy can elicit potent antitumor immunity against disseminated and metastatic tumors. Gold nanorods (AuNRs) covalently coupled with amphiphilic polyTLR7/8a and MMP-2-sensitive R9-PEG conjugate (AuNRs-IMQD-R9-PEG) were developed as a new biocompatible PTT agent with favorable photothermal efficiency and stability. Importantly, AuNRs-IMQD-R9-PEG can effectively absorb tumor-derived protein antigens, forming nanovaccines directly in vivo and enhance the activation of host dendritic cells (DCs), thereby amplifying adaptive antitumor T-cell responses, triggering effector memory immune responses, and activating innate antitumor immunity. Remarkably, peri-tumoral administration of low-dose multifunctional AuNRs followed by non-invasive near-infrared (NIR) laser irradiation enables efficient tandem PTT-vaccination treatment modality that can inhibit local as well as untreated distant and metastatic tumors in mice inoculated with poorly immunogenic, highly metastatic 4T1 tumors. Our findings indicate that AuNRs-IMQD-R9-PEG-mediated in situ cancer vaccination provides a powerful immunotherapy characterized by markedly increased infiltration of effector CD8+ T, natural killer T (NKT) cells in tumors and long-term animal survival, thus, offering a promising therapeutic strategy for advanced, disseminated cancers.

A Bacteria-Inspired Morphology Genetic Biomedical Material: Self-Propelled Artificial Microbots for Metastatic Triple Negative Breast Cancer Treatment.

Morphology genetic biomedical materials (MGBMs), referring to fabricating materials by learning from the genetic morphologies and strategies of natural species, hold great potential for biomedical applications. Inspired by the cargo-carrying-bacterial therapy (microbots) for cancer treatment, a MGBM (artificial microbots, AMBs) was constructed. Rather than the inherent bacterial properties (cancerous chemotaxis, tumor invasion, cytotoxicity), AMBs also possessed ingenious nitric oxide (NO) generation strategy. Mimicking the bacterial construction, the hyaluronic acid (HA) polysaccharide was induced as a coating capsule of AMBs to achieve long circulation in blood and specific tissue preference (tumor tropism). Covered under the capsule-like polysaccharide was the combinatorial agent, the self-assembly constructed by the amphiphilic dendrons with abundant l-arginine residues peripherally (as endogenous NO donor) and hydrophobic chemotherapeutic drugs at the core stacking on the surface of SWNTs (the photothermal agent) for a robust chemo-photothermal therapy (chemo-PTT) and the elicited immune therapy. Subsequently, the classic inducible nitric oxide synthase (iNOS) pathway aroused by immune response was revolutionarily utilized to oxidize the l-arginine substrates for NO production, the process for which could also be promoted by the high reactive oxygen species level generated by chemo-PTT. The NO generated by AMBs was intended to regulate vasodilation and cause a dramatic invasion (as the microbots) to disperse the therapeutic agents throughout the solid tumor for a much more enhanced curative effect, which we defined as "self-propulsion". The self-propelled AMBs exhibiting impressive primary tumor ablation, as well as the distant metastasis regression to conquer the metastatic triple negative breast cancer, provided pioneering potential therapeutic opportunities, and enlightened broad prospects in biomedical application.

ICG/l-Arginine Encapsulated PLGA Nanoparticle-Thermosensitive Hydrogel Hybrid Delivery System for Cascade Cancer Photodynamic-NO Therapy with Promoted Collagen Depletion in Tumor Tissues.

Photodynamic therapy (PDT) is promising for clinical cancer therapy; however, the efficacy was limited as an individual treatment regimen. Here, an approach synergistically combining PDT and nitric oxide (NO) gas therapy along with destruction of the tumor extracellular matrix (ECM) was presented to eliminate cancer. Specifically, the NO donor l-arginine (l-Arg) and the photosensitizer indocyanine green (ICG) were co-encapsulated in poly(lactic-glycolic acid) (PLGA) nanoparticles and then loaded into the poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) hydrogel to develop an injectable, thermosensitive dual drug delivery system (PLGA@ICG@l-Arg/Gel). Significantly, reactive oxygen species (ROS) produced by PLGA@ICG@l-Arg/Gel under near-infrared (NIR) light irradiation could not only result in the apoptosis of cancer cells but also oxidize l-Arg to generate NO, which could suppress the proliferation of cancer cells. Moreover, ROS could further oxidize NO to generate peroxynitrite anions (ONOO-). ONOO- could activate matrix metalloproteinases (MMPs), which notably degraded collagen in ECM so as to damage the tumor microenvironment. PLGA@ICG@l-Arg/Gel significantly increased the antitumor efficacy against highly malignant 4T1 tumors in mice. Taken together, PLGA@ICG@l-Arg/Gel is a multifunctional platform that provides a novel strategy for cancer treatment with cascade amplification of the ROS oxidation effect, which holds great potential in clinical translation.

Nitric-Oxide-Releasing Biomaterial Regulation of the Stem Cell Microenvironment in Regenerative Medicine.

Stem cell therapy has proven to be an attractive solution for the treatment of degenerative diseases or injury. However, poor cell engraftment and survival within injured tissues limits the successful use of stem cell therapy within the clinical setting. Nitric oxide (NO) is an important signaling molecule involved in various physiological processes. Emerging evidence supports NO's diverse roles in modulating stem cell behavior, including survival, migration, differentiation, and paracrine secretion of proregenerative factors. Thus, there has been a shift in research focus to concentrate efforts on the delivery of therapeutic concentration ranges of NO to the target tissue sites. Combinatory therapies utilizing biomaterials that control NO generation and support stem cell delivery can be holistic and synergistic approaches to significantly improve tissue regeneration. Here, the focus is on recent developments of various therapeutic platforms, engineered to both transport NO and to enhance stem-cell-mediated regeneration of damaged tissues. New and emerging revelations of how the stem cell microenvironment can be regulated by NO-releasing biomaterials are also highlighted.

A Dual-Model Imaging Theragnostic System Based on Mesoporous Silica Nanoparticles for Enhanced Cancer Phototherapy.

Mesoporous silica nanoparticles (MSNs) show great promise to be exploited as versatile multifunctional nanocarriers for effective cancer diagnosis and treatment. In this work, perfluorohexane (PFH)-encapsulated MSNs with indocyanine green (ICG)-polydopamine (PDA) layer and poly(ethylene glycol)-folic acid coating (designated as MSNs-PFH@PDA-ICG-PEG-FA) are successfully fabricated to achieve tumor ultrasonic (US)/near-infrared fluorescence (NIRF) imaging as well as photothermal therapy (PTT)/photodynamic therapy (PDT). MSNs-PFH@PDA-ICG-PEG-FA exhibits good monodispersity with high ICG loading, significantly enhances ICG photostability, and greatly improves cellular uptake. Upon single 808 nm NIR irradiation, the nanocarrier not only efficiently generates hyperthermia to realize PTT, but also produces reactive oxygen species (ROS) for effective PDT. Meanwhile, NIR irradiation can trigger PFH to undergo vaporization and provide a super-resolution US image. Thus, the PTT/PDT combination therapy can be dually guided by PFH-induced US imaging and ICG-induced NIRF imaging. In vivo antitumor studies demonstrate that PTT/PDT from MSNs-PFH@PDA-ICG-PEG-FA significantly inhibits tumor growth and achieves a cure rate of 60% (three out of five mice are completely cured). Hence, the multifunctional MSNs appear to be a promising theragnostic nanoplatform for multimodal cancer imaging and therapy.

Fluorescence imaging guided CpG nanoparticles-loaded IR820-hydrogel for synergistic photothermal immunotherapy.

As synergistic photothermal immunotherapy has developed as one of the most attractive strategies for cancer therapy, it is crucial to design an effective photothermal immunotherapy system to enhance the synergistic anti-tumor effect and reveal the essential role of each treatment. In this study, we designed CpG self-crosslinked nanoparticles-loaded IR820-conjugated hydrogel with dual self-fluorescence to exert the combined photothermal-immunotherapy. IR820-hydrogel can be effective for hyperthermia to eliminate the primary tumor based on its comprehensive coverage and generated photothermal-induced tumor antigens for assisted immunotherapy. CpG self-crosslinked nanoparticles improved the immune response of adjuvant against melanoma without extra nano-carriers. The synergistic photothermal immunotherapy was achieved by the merging of CpG self-crosslinked nanoparticles and IR820-hydrogel. A possible mechanism of combined antitumor effect was further revealed by analyzing immune cells including CD8 +T cells, DCs, B cells, Treg and MDSC in tumor microenvironment. The specific antitumor immunity was provoked to remove the tumor residues and ultimately the combined treatment mode achieved more effective systemic therapeutic effect than either photothermal therapy or immunotherapy alone. Furthermore, self-fluorescent IR820-hydrogel and CpG nanoparticles exerted the imaging-guided combined photothermal-immunotherapy by the dual fluorescence imaging method without additional fluorescent labeling. This visible combined photothermal-immunotherapy offers a potential for precise cancer treatment.

A dual fluorescent reverse targeting drug delivery system based on curcumin-loaded ovalbumin nanoparticles for allergy treatment.

A reverse targeting drug delivery based on antigen-modified nanoparticles provided an innovative strategy for effectively alleviating or inhibiting immune response. In this study, a dual fluorescent reverse targeting drug delivery system based on curcumin-loaded ovalbumin nanoparticles is developed for allergy treatment. The self-crosslinked ovalbumin nanoparticles achieved the double function of reverse targeting and sustained delivery carriers to maximize the anti-allergy of curcumin. Using a murine model of ovalbumin-induced allergy, this drug delivery system suppressed antigen-specific IgG1 and IgE production, inhibited CD4+ T activity, and decreased the level of ovalbumin-sensitized memory B cells. The curcumin-loaded ovalbumin nanoparticles exert stronger and more effective treatment on the immunomodulatory role. Furthermore, fluorescence imaging in vivo can reveal the precise delivery process for the effective allergy immunotherapy. The dual fluorescent reverse targeting delivery system provided a significant potential for the visible treatment of allergy with the merged functions of targeting, vehicles and fluorescence.

Nanoscale Reduced Graphene Oxide-Mediated Photothermal Therapy Together with IDO Inhibition and PD-L1 Blockade Synergistically Promote Antitumor Immunity.

Despite the potential efficacy of immune checkpoint blockade for effective treatment of cancer, this therapeutic modality is not generally curative, and only a fraction of patients respond. Combination approaches provide strategies to target multiple antitumor immune pathways to induce synergistic antitumor immunity. Here, a multi-combination immunotherapy, including photothermal therapy (PTT), indoleamine-2,3-dioxygenase (IDO) inhibition, and programmed cell death-ligand 1 (PD-L1) blockade, is introduced for inducing synergistic antitumor immunity. We designed a multifunctional IDO inhibitor (IDOi)-loaded reduced graphene oxide (rGO)-based nanosheets (IDOi/rGO nanosheets) with the properties to directly kill tumor cells under laser irradiation and in situ trigger antitumor immune response. In vivo experiments further revealed that the triggered immune response can be synergistically promoted by IDO inhibition and PD-L1 blockade; the responses included the enhancement of tumor-infiltrating lymphocytes, including CD45+ leukocytes, CD4+ T cells, CD8+ T cells, and NK cells; the inhibition of the immune suppression activity of regulator T cells (Tregs); and the production of INF-γ. We also demonstrate that the three combinations of PTT, IDO inhibition, and PD-L1 blockade can effectively inhibit the growth of both irradiated tumors and tumors in distant sites without PTT treatment. This work can be thought of as an important proof of concept to target multiple antitumor immune pathways to induce synergistic antitumor immunity.

NaoXinTong Capsules inhibit the development of diabetic nephropathy in db/db mice.

NaoXinTong Capsule (NXT), a Chinese medicine, is currently used to treat patients with cardiovascular and cerebrovascular diseases. Clinical observations indicate its anti-diabetic functions with unclear mechanisms. Herein, we report the effect of NXT on diabetic nephropathy (DN). Type 2 diabetic db/db mice were treated with NXT for 14 weeks. In the course of treatment, NXT reduced diabetes-increased glucose levels and improved renal functions. At the end of treatment, we found that NXT ameliorated serum lipid profiles and other biochemical parameters. In the kidney, NXT inhibited mesangial matrix expansion, expression of vascular endothelial growth factor A, fibronectin, advanced glycation end product and its receptor. Meanwhile, it reduced the diabetes-induced podocyte injury by increasing WT1 and nephrin expression. In addition, NXT inhibited accumulation of extracellular matrix proteins by increasing MMP2/9 expression through inactivation of TGFß/Smad pathway and CTGF expression. Mechanically, NXT activated insulin signaling pathway by increasing expression of INSR, IRS and FGF21, phosphorylation of Akt and AMPKα in the liver, INSR phosphorylation in the kidney, and FGF21 and GLUT4 expression in adipose tissue and skeletal muscle. Taken together, our study demonstrates that NXT inhibits DN by ameliorating glucose/lipid metabolism, maintaining tissue structure integrity, and correcting diabetes-induced renal dysfunctions.

Dual pH/reduction-responsive hybrid polymeric micelles for targeted chemo-photothermal combination therapy.

The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed new pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs exhibited nano-sized structure (∼100 nm) with good monodispersity, high encapsulation efficiency of both ICG and DOX, triggered DOX release in response to acid pH and reduction environment, and excellent temperature conversion with laser irradiation. In vitro cellular uptake study indicated FA Co-PMs achieved significant targeting to BEL-7404 cells via folate receptor-mediated endocytosis, and laser-induced hyperthermia further enhanced drug accumulation into cancer cells. In vivo biodistribution study indicated that FA Co-PMs prolonged drug circulation and enhanced drug accumulation into the tumor via EPR effect and FA targeting. Furthermore, the ICG-based photo-triggered hyperthermia combined with DOX-based chemotherapy synergistically induced the BEL-7404 cell death and apoptosis, and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs were promising theranostic nanocarriers for versatile antitumor drug delivery and imaging-guided cancer chemo-photothermal combination therapy. STATEMENT OF SIGNIFICANCE: The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed novel pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs triggered DOX release in response to acid pH and reduction environment and exhibited excellent temperature conversion with laser irradiation. The results indicated FA Co-PMs achieved significant targeting to BEL-7404 cells in vitro and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs displayed great potential in imaging-guided cancer chemo-photothermal combination therapy as theranostic nanocarriers.

Bubble-generating polymersomes loaded with both indocyanine green and doxorubicin for effective chemotherapy combined with photothermal therapy.

The combination of chemotherapy and photothermaltherapy (PTT) via stimuli-responsive nanovesicles has great potential in tumor treatment. In the present study, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug and photosensitizing agent for the synergistic chemo-photothermal tumor therapy. Photosensitizer indocyanine green (ICG) was encapsulated into the bilayer of polymersomes formed by amphiphilic triblock copolymer PCL8000-PEG8000-PCL8000 through thin film re-hydration method, while chemotherapeutic doxorubicin (DOX) was loaded into the hydrophilic lumen using a transmembrane ammonium bicarbonate gradient loading procedure. Under acidic condition or laser irradiation, the ammonium bicarbonate (NH4HCO3) encapsulated in the bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would decompose to produce CO2 bubbles, resulting in destruction of vesicle structure and rapid drug release. In vitro drug release study confirmed that acidic environment and NIR laser irradiation could accelerate DOX release from the BG-DIPS. Cellular uptake study indicated that laser-induced hyperthermia highly enhanced endocytosis of BG-DIPS into 4T1-Luc cancer cells. In vitro cytotoxicity study demonstrated that BG-DIPS exhibited much higher cytotoxicity than free drugs under laser irradiation. In vivo biodistribution study indicated that BG-DIPS could accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. Furthermore, in vivo antitumor study showed that BG-DIPS with laser irradiation efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy. STATEMENT OF SIGNIFICANCE: The combination of chemotherapy and photothermaltherapy via stimuli-responsive nanovesicles has great potential in tumor treatment. Herein, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug (DOX) and photosensitizing agent (ICG) for the synergistic chemo-photothermal tumor therapy. The results in vitro and in vivo demonstrated that bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would accelerate DOX release from the BG-DIPS and accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. BG-DIPS with laser irradiation could efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy.

Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer.

Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff's base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff's base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.

Synthesis, biodistribution, and imaging of PEGylated-acetylated polyamidoamine dendrimers.

Polyamidoamine (PAMAM) dendrimers have been widely used as drug carriers, non-viral gene vectors and imaging agents. However, the use of dendrimers in biological system is constrained because of inherent toxicity and organ accumulation. In this study, the strategy of acetylation and PEGylation-acetylation was used to minimize PAMAM dendrimers toxicities and to improve their biodistribution and pharmacokinetics for medical application. PEGylated-acetylated PAMAM (G4-Ac-PEG) dendrimers were synthesized by PEGylation of acetylated PAMAM dendrimer of generation 4 (G4) with acetic anhydride and polyethylene glycol (PEG) 3.4 k. To investigate the cytotoxicity and in vivo biodistribution of the conjugates, in vitro cell viability analysis, Iodine-125 (125I) imaging, tissue distribution and hematoxylin-eosin (HE) staining were performed. We find that acetylation and PEGylation-acetylation essentially eliminates the inherent dendrimer cytotoxicity in vitro. Planar gamma (gamma) camera imaging revealed that all the conjugates were slowly eliminated from the body, and higher abdominal accumulation of acetylation PAMAM dendrimer was observed. Tissue distribution analysis showed that PEGylated-acetylated dendrimers have longer blood retention and lower accumulation in organs such as the kidney and liver than the non-PEGylated-acetylated dendrimers, but acetylation only can significantly increase the accumulation of G4 in the kidney and decrease the concentration in blood. Histology results reveal that no obvious damage was observed in all groups after high dose administration. This study indicates that PEGylation-acetylation could improve the blood retention, decrease organ accumulation, and improve pharmacokinetic profile, which suggests that PEGylation-acetylation provides an alternative method for PAMAM dendrimers modification.

Switchable catalytic activity: selenium-containing peptides with redox-controllable self-assembly properties.

Mimicking nature: The reversible formation of self-assembled nanostructures of selenium-containing peptides can be controlled by redox triggers (see scheme, VC = vitamin C). As a consequence, the catalytic activity of these peptides is switchable. These results should lead to the development of nature-mimicking smart materials with promising properties.

Improved mesenchymal stem cell survival in ischemic heart through electroacupuncture.

OBJECTIVE: To investigate whether electroacupuncture (EA) can promote cell survival and enhance heart function of mesenchymal stem cells (MSCs) therapy. METHODS: MSCs were isolated from bone marrow and expanded in Minimum Essential Medium Alpha (α-MEM). MI was induced in 72 Sprague-Dawley (S-D) rats by ligation of the left anterior descending coronary artery (LAD) for 30 min and reperfusion. MI rats randomly received injection of 1×10(6) DiI-labeled MSCs alone (n =24, MSC group), or plus electroacupuncture (EA) at Neiguan (PC6, n=24, EA+MSC group), or saline (n =24, saline group). EA treatment was performed for 4 days. Another 24 rats were subjected to chest-open surgery without LAD occlusion and treatment (sham group). Three time points, 4, 14 and 28 days (n =8 for each group) were included in this study. The survival of transplanted MSCs and the protective gene expression were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot at day 4 and 14. Left ventricular remodeling, cardiac function, infarction area, fibrosis and capillary density were analyzed at day 28. RESULTS: EA can enhance MSC survival (2.6-fold up) at day 4. Big capillary density was 53% higher in EA+MSC treated group than MSC alone group. Furthermore, the rats treated by EA reduced the fibrosis and had 36% smaller infarct size comparing to MSC alone. EA also attenuated left ventricular remodeling and enhanced the functional recovery of infarcted hearts at week 4. CONCLUSION: EA at Neiguan acupoint can promote the stem cell survival and improve ischemic heart function. EA could become a useful approach in stem cell therapy for ischemia heart diseases.

Small-diameter tissue engineered vascular graft made of electrospun PCL/lecithin blend.

In this study, natural lecithin was incorporated into cholesterol-poly(ε-caprolactone) (Chol-PCL) by solution blending in order to modify the performance of the hydrophobic and bio-inert PCL. The fibrous Chol-PCL/lecithin membranes were fabricated by electrospinning, and the surface morphology and properties were characterized by scanning electron microscopy, X-ray photoelectron spectroscopy, static water contact angle, and mechanical tensile testing. The blood compatibility of the scaffolds was evaluated by in vitro hemolysis assay. The cytocompatibility of the scaffolds was investigated by cell adhesion and proliferation using bone-marrow mesenchymal stem cells (MSCs). Subcutaneous implantation was also performed to evaluate the in vivo inflammatory reaction. The tubular tissue-engineered vascular graft (TEVG) was further constructed by rolling cell sheet comprising fibrous membrane and MSCs. Furthermore, endothelial cells (ECs) were seeded onto the lumen of the graft with the aim to form vascular endothelium. The preliminary results indicate that electrospun Chol-PCL/lecithin scaffolds show improved hemocompatibility and cytocompatibility compared with neat Chol-PCL, and combining the Chol-PCL/lecithin fibrous scaffold with MSCs and ECs with well controlled distribution is a promising strategy for constructing TEVGs.

Construction of ureteral grafts by seeding urothelial cells and bone marrow mesenchymal stem cells into polycaprolactone-lecithin electrospun fibers.

The aim of the present study was to investigated the construction of polycaprolactone-lecithin (PCL-L) electrospun fibers as a novel scaffold material for a tissue-engineered ureter. The effect of bone marrow mesenchymal stem cells (BM-MSCs) on the neovascularization of the scaffolds and the viability of planted urothelial cells (UCs) on PCL-L were also studied. UCs were obtained from New Zealand rabbit bladders, cultured and then seeded onto the lumen of the tubular scaffolds before being subcutaneously transplanted into the space of nude mice. The cultured UCs showed vacuolar degeneration after 7 days of transplantation and they gradually degraded thereafter. To facilitate the regeneration of the tissue-engineered ureter and the survival of UCs in the implant, MSCs were seeded into the tubular grafts by rolling up the nanofibrous membrane, followed by the seeding of UCs. This facilitated the survival of the UCs, which formed several cellular layers after 30 days. The mean microvessel density was significantly increased in tissues seeded with MSCs. Cell-tracking experiments revealed that the transplanted MSCs did not integrate directly into capillaries for angiogenesis. Our results demonstrated that the PCL-L electrospun fibrous scaffold has a high potential for a tissue-engineered ureter especially when seeded with BM-MSCs, which enhanced angiogenesis.