CD44-Targeted and Enzyme-Responsive Photo-Cross-Linked Nanogels with Enhanced Stability for In Vivo Protein Delivery.

One of the biggest challenges of the protein delivery system is to realize stable and high protein encapsulation efficiency in blood circulation and rapid release of protein in the targeted tumor cells. To overcome these hurdles, we fabricated enzyme-responsive photo-cross-linked nanogels (EPNGs) through UV-triggered chemical cross-linking of cinnamyloxy groups in the side chain of PEGylation hyaluronic acid (HA) for CD44-targeted transport of cytochrome c (CC). The EPNGs showed high loading efficiency and excellent stability in different biological media. Notably, CC leakage effectively suppressed under physiological conditions but accelerated release in the presence of hyaluronidase, an overexpressed enzyme in tumor cells. Moreover, thiazolylblue tetrazolium bromide (MTT) results indicated that the vacant EPNGs showed excellent nontoxicity, while CC-loaded EPNGs exhibited higher killing efficiency to CD44-positive A549 cells than to CD44-negative HepG2 cells and free CC. Confocal images confirmed that CC-loaded EPNGs could effectively be internalized by CD44-mediated endocytosis pathway and rapidly escape from the endo/lysosomal compartment. Human lung tumor-bearing mice imaging assays further revealed that CC-loaded EPNGs actively target tumor locations. Remarkably, CC-loaded EPNGs also exhibited enhanced antitumor activity with negligible systemic toxicity. These results implied that these EPNGs have appeared as stable and promising nanocarriers for tumor-targeting protein delivery.

A Case Report of Immune Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.

Immune thrombocytopenia (ITP) is an autoimmune condition characterized by platelet destruction through antibody-mediated mechanism. ITP is one of the manifestations of a coronavirus disease, as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several cases of ITP have been described after vaccination with two mRNA-based vaccines-BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-against SARS-CoV-2. Herein, we report a case of ITP occurring after vaccination with ChAdOx1 adenovirus vector nCoV-19 (AstraZeneca) vaccine in Korea. A 66-year-old woman presented with multiple ecchymoses on both upper and lower extremities and gingival bleeding, appearing 3 days after receiving the first dose of ChAdOx1 nCoV-19. Her laboratory results showed isolated severe thrombocytopenia without evidence of combined coagulopathy. She was diagnosed with ITP and successfully treated with high-dose dexamethasone and intravenous immunoglobulin. Clinical suspicion to identify vaccine-related ITP is important to promptly initiate appropriate treatment.

Biocompatible and Biodegradable Fe3+-Melanoidin Chelate as a Potentially Safe Contrast Agent for Liver MRI.

Currently, most MRI probes available for clinical use contain gadolinium, which is a high-risk paramagnetic metal that can cause severe side effects (e.g., nephrogenic systemic fibrosis). To limit such side effects and improve diagnostic efficacy, we developed a novel biocompatible MRI contrast agent using glucose, glycine, and paramagnetic iron ion. Glucose and glycine were polymerized into melanoidin by the nonenzymatic Maillard reaction, and Fe3+ was chelated stably with the melanoidin during polymerization. The Fe3+-melanoidin chelate had biocompatibility, biodegradability, and unique contrast effects on both T1- and T2-weighted MRI, depending on the pH and oxidative environments. The administration of the Fe3+-melanoidin chelate to a mouse model of liver cancer showed highly enhanced liver-to-tumor contrasts on both T1- and T2-weighted MRI.

Tumor-targeted delivery of paclitaxel using low density lipoprotein-mimetic solid lipid nanoparticles.

Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous administration, we developed biocompatible anticancer therapeutic solid lipid nanoparticles (SLNs), mimicking the structure and composition of natural particles, low-density lipoproteins (LDLs), for tumor-targeted delivery of paclitaxel. These therapeutic nanoparticles contained water-insoluble paclitaxel in the core with tumor-targeting ligand covalently conjugated on the polyethylene glycol (PEG)-modified surface (targeted PtSLNs). In preclinical human cancer xenograft mouse model studies, the paclitaxel-containing tumor-targeting SLNs exhibited pronounced in vivo stability and enhanced biocompatibility. Furthermore, these SLNs had superior antitumor activity to in-class nanoparticular therapeutics in clinical use (Taxol and Genexol-PM) and yielded long-term complete responses. The in vivo targeted antitumor activities of the SLN formulations in a mouse tumor model suggest that LDL-mimetic SLN formulations can be utilized as a biocompatible, tumor-targeting platform for the delivery of various anticancer therapeutics.

Long-term survival of methanogens of an anaerobic digestion sludge under starvation and temperature variation.

To investigate starvation effect on methanogen community, two identical membrane reactors were continuously operated for 84 consecutive days, with a temperature change from 50 degrees C to 20 degrees C. Continuous feeding washed out 97% biomass from reactors during the experimental period. Quantitative PCR, using mcrA genes, indicated that the methanogen abundance decreased from 7.0 x 10(7) to 1.2 x 10(7) mcrA copies ml(-1) (volume basis) at 50 degrees C, and then increased to 4.4 x 10(7) mcrA copies ml(7) at 20 degrees C (p<0.05). Correspondence analysis indicated that methanogen communities were distinctly grouped by each temperature. Canonical correspondence analysis indicated that temperature showed a significant correlation with the methanogen community composition. These results suggest that methanogens can survive for a long time (at least more than 84 days) under starvation conditions, and that temperature could be a primary factor determining the density and community of methanogens.

P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy After Deployment of a Drug-Eluting Stent: The SHARE Randomized Clinical Trial.

Importance: P2Y12 inhibitor monotherapy after dual antiplatelet therapy (DAPT; a P2Y12 inhibitor plus aspirin) for a brief duration has recently emerged as an attractive alternative for patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent. Objective: To investigate whether P2Y12 inhibitor monotherapy after 3 months of DAPT was noninferior to 12 months of DAPT following PCI with a drug-eluting stent. Design, Setting, and Participants: The Short-Term Dual Antiplatelet Therapy After Deployment of Bioabsorbable Polymer Everolimus-Eluting Stent (SHARE) open-label, noninferiority randomized clinical trial was conducted from December 15, 2017, through December 14, 2020. Final 1-year clinical follow-up was completed in January 2022. This study was a multicenter trial that was conducted at 20 hospitals in South Korea. Patients who underwent successful PCI with bioabsorbable polymer everolimus-eluting stents were enrolled. Interventions: Patients were randomly assigned to receive P2Y12 inhibitor monotherapy after 3 months of DAPT (n = 694) or 12 months of DAPT (n = 693). Main Outcomes and Measures: The primary outcome was a net adverse clinical event, a composite of major bleeding (based on Bleeding Academic Research Consortium type 3 or type 5 bleeding) and major adverse cardiac and cerebrovascular events (cardiac death, myocardial infarction, stent thrombosis, stroke, or ischemia-driven target lesion revascularization) between 3 and 12 months after the index PCI. The major secondary outcomes were major adverse cardiac and cerebrovascular events and major bleeding. The noninferiority margin was 3.0%. Results: Of the total 1452 eligible patients, 65 patients were excluded before the 3-month follow-up, and 1387 patients (mean [SD] age, 63.0 [10.7] years; 1055 men [76.1%]) were assigned to P2Y12 inhibitor monotherapy (n = 694) or DAPT (n = 693). Between 3 and 12 months of follow-up, the primary outcome (using Kaplan-Meier estimates) occurred in 9 patients (1.7%) in the P2Y12 inhibitor monotherapy group and in 16 patients (2.6%) in the DAPT group (absolute difference, -0.93 [1-sided 95% CI, -2.64 to 0.77] percentage points; P < .001 for noninferiority). For the major secondary outcomes (using Kaplan-Meier estimates), major adverse cardiac and cerebrovascular events occurred in 8 patients (1.5%) in the P2Y12 inhibitor monotherapy group and in 12 patients (2.0%) in the DAPT group (absolute difference, -0.49 [95% CI, -2.07 to 1.09] percentage points; P = .54). Major bleeding occurred in 1 patient (0.2%) in the P2Y12 inhibitor monotherapy group and in 5 patients (0.8%) in the DAPT group (absolute difference, -0.60 [95% CI, -1.33 to 0.12] percentage points; P = .10). Conclusions and Relevance: In patients with coronary artery disease undergoing PCI with the latest generation of drug-eluting stents, P2Y12 inhibitor monotherapy after 3-month DAPT was not inferior to 12-month DAPT for net adverse clinical events. Considering the study population and lower-than-expected event rates, further research is required in other populations. Trial Registration: ClinicalTrials.gov Identifier: NCT03447379.

Bio-inspired, melanin-like nanoparticles as a highly efficient contrast agent for T1-weighted magnetic resonance imaging.

The development of nontoxic and biocompatible imaging agents will create new opportunities for potential applications in clinical MRI diagnosis. Synthetic melanin-like nanoparticles (MelNPs), analogous to natural sepia melanin (a major component of the cuttlefish ink), can be used as contrast agent for MRI. MelNPs complexed with paramagnetic Fe(3+) ions show much higher relaxivity values than existing MRI T1 contrast agents based on gadolinium (Gd) or manganese (Mn); MelNP values at 3T were r1 = 17 and r2 = 18 mM(-1) s(-1) (r2/r1 value of 1.1). With significant enhancement to MRI contrast, this biomimetic approach using MelNPs functionalized with paramagnetic Fe(3+) ions and surface-modified with biocompatible poly(ethylene glycol) units, could provide new insight into how melanin-based bioresponsive and therapeutic imaging probes integrate with their various biological functions.

Oxygen-Generating Organic/Inorganic Self-Assembled Nanocolloids for Tumor-Activated Dual-Model Imaging-Guided Photodynamic Therapy.

Tumor phototheranostics is usually compromised by the hypoxic tumor microenvironment and poor theranostic efficiency. The interplay between organic polymers and inorganic nanoparticles in novel nanocomposites has proven to be advantageous, overcoming previous limitations and harnessing their full potential through activation via the tumor microenvironment. This study successfully fabricated hypoxia-activated nanocolloids called HOISNDs through a process of self-assembly involving superparamagnetic iron oxide nanoparticles (SPIONs) and an organic polymer ligand called tetrakis(4-carboxyphenyl) porphyrin (TCPP)-engineered organic polymer ligand [methoxy poly(ethyleneglycol)-block-poly(dopamine-ethylenediamine-conjugated-4-nitrobenzyl chloroformate)-l-glutamate, mPEG-b-P(Dopa-EDA-co-NBCF)LG-TCPP)]. The SPIONs act as an oxygen generator to overcome the challenges posed by hypoxic tumors and enable the use of hypoxic-activatable MR/fluorescence dual-modal imaging-guided photodynamic therapy (PDT). The colloid stability of these HOISNDs proved to be exceptional in diverse biomimetic environments. Furthermore, they not only augment T2-weighted contrast capability as an MRI contrast agent but also function as an oxygen-producing device to amplify the generation and release of reactive oxygen species (ROS). The HOISNDs can significantly target to tumor sites through the enhanced permeability and retention (EPR) effect with prolonged blood circulation time and subsequently are effectively endocytosed into a hypoxic intracellular environment that "turn on" the imaging function and photodynamic activity. Moreover, HOISNDs possess the ability to effectively decompose naturally occurring H2O2 into oxygen (O2) within the tumor utilizing the Fenton reaction. This method can mitigate the impact of hypoxia on oxygen-dependent PDT. The outcomes of in vivo diagnostic and therapeutic evaluations indicated that HOISNDs are a highly promising tool for dual-model imaging-guided cancer theranosis by ameliorating hypoxic conditions and augmenting PDT efficiency.

CD44-mediated tumor homing of hyaluronic acid nanogels for hypoxia-activated photodynamic therapy against tumor.

In this study, unique hypoxia-activated hyaluronic acid nanogels (HANGs) were reported for CD44-targeted delivery of photosensitizers (chlorin e6, Ce6) for diagnostic imaging and photodynamic therapy (PDT) of cancers. Through the use of a hypoxia-responsive cross-linker (AZO-CDI), the HANGs were prepared by chemically cross-linking primary amine groups-functionalized hyaluronic acid (HA). Under normoxic condition, fluorescence of Ce6 conjugated on the HANGs was highly quenched, and level of reactive oxygen species (ROS) generated from the HANGs was rather low after laser irradiation. However, under hypoxic condition, the HANGs underwent rapid disassociation, and fluorescence of Ce6 conjugated on the HANGs was recovered, triggering high-level singlet oxygen generation after laser irradiation. Due to the presence of HA, the HANGs showed much higher cellular uptake by CD44-positive cancer cells (A549 cells) than that by CD44-negative cancer cells (HepG2 cells). In addition, the HANGs could generate higher level of ROS in A549 cells because of improved cancer cell uptake. This excellent tumor-targeting and singlet oxygen-generating ability of the HANGs was favorable to hypoxia-activated PDT of CD44-positive cancers with significant inhibition of tumor growth within the whole treatment period. Taken together, the HANGs are safe and effective tools in treating CD44-positive cancers.

Effectiveness and Feasibility of Injectable Escherichia coli-Derived Recombinant Human Bone Morphogenetic Protein-2 for Anterior Lumbar Interbody Fusion at the Lumbosacral Junction in Adult Spinal Deformity Surgery: A Clinical Pilot Study.

OBJECTIVE: To explore the effectiveness and feasibility of injectable Escherichia coli-derived recombinant human bone morphogenetic protein-2 (injectable E-rhBMP-2, a combination of E. coli-derived recombinant human bone morphogenic protein-2 and a hydrogel type beta-tricalcium phosphate carrier) as a bone substitute for anterior lumbar interbody fusion (ALIF) of the lumbosacral junction in adult spinal deformity (ASD) patients. METHODS: A prospective single-institution therapeutic exploratory trial was conducted. Twenty patients (average age: 69.1 years; 19 female and one male; average fusion level: 7.95) diagnosed with ASD with sagittal imbalance who underwent surgical treatment including ALIF at the lumbosacral junction from December 2017 to January 2019 were evaluated. Injectable E-rhBMP-2 was prepared by dissolving 3 mg of E. coli-derived recombinant human bone morphogenetic protein-2 in 1.5 ml H2 O and mixing in situ with 9 g hydrogel type beta-tricalcium phosphate. This bone graft substitute was loaded onto a metal ALIF cage and L5 -S1 ALIF was performed in routine manner. Then posterior column osteotomy with multilevel oblique lumbar interbody fusion or pedicle subtraction osteotomy with accessory rod technique was performed to restore sagittal balance. Patients were followed up for 12 months. CT-based fusion rates were examined at 6 and 12 months after surgery. Also, clinical outcomes (Oswestry Disability Index [ODI], Visual Analog Scale [VAS] score of the back and leg) were evaluated at 6 and 12 months after surgery. All postoperative adverse events were evaluated for the association with injectable E.BMP-2. RESULTS: Of the 20 patients, loss to follow-up occurred with one patient at 6 months after surgery and one patient at 12 months after surgery, resulting in a total of 18 patients who were available for follow-up. Six months after surgery, 68.4% patients achieved solid fusion. Twelve months after surgery, 100% fusion rate was achieved. Compared to baseline values, ODI scores improved to 45.8% and 63.7%, VAS (back) improved to 69.2% and 72.8%, and VAS (leg) improved to 49.2% and 64.8%, respectively, at 6 and 12 months after surgery (p < 0.001 for all). Ten cases of adverse events occurred. But no adverse events were associated with injectable E-rhBMP-2. CONCLUSION: Injectable E-rhBMP-2 will be an effective bone graft substitute when achieving solid interbody fusion in the lumbosacral junction.

pH-responsive dynamically cross-linked nanogels with effective endo-lysosomal escape for synergetic cancer therapy based on intracellular co-delivery of photosensitizers and proteins.

Co-delivery of photosensitizers (PSs) and protein drugs represents great potentiality for enhancing the efficiency of synergistic cancer therapy. However, the intricate tumor-microenvironment and the lack of nanoplatforms to co-deliver both into cancer cells and activate their functions significantly hinder the clinical translation of this combined approach for cancer treatment. Herein, a chlorine e6 (Ce6)-functionalized and pH-responsive dynamically cross-linked nanogel (Ce6@NG) is fabricated by formation of benzoic imine linkages between Ce6-modified methoxy poly (ethyleneglycol)-block-poly (diethylenetriamine)-L-glutamate-Ce6 [MPEG-b-P(Deta)LG-Ce6] and terephthalaldehyde as cross-linkers for effective intracellular co-delivery of Ce6 and cytochrome c (CC), which could form a novel combination therapy system (CC/Ce6@NGs). The pH-sensitive benzoic imine bonds in the CC/Ce6@NGs endow them with excellent systemic stability under normal physiological environment while this nanosystem can be further cationized to enhance cell uptake in acidic extracellular environment. Upon cellular internalization, CC/Ce6@NGs can rapidly escape from the endo/lysosomal compartments and subsequently activate Ce6 to generate cytotoxic singlet oxygen upon laser irradiation and release of CC to induce programmed cell death by complete cleavage of benzoic imines at more acidic intracellular environments. Importantly, the catalase-like activity of CC can decompose H2O2 to produce O2 for hypoxia alleviation and improvement of the photodynamic therapy (PDT) of cancer. Moreover, this enhanced synergistic anticancer activity is confirmed both in vitro and in vivo. In view of the versatile chemical conjugation, this research offers a promising and smart nanosystem for intracellular co-delivery of PSs and therapeutic proteins.

Bifidobacterium longum HY8004 attenuates TNBS-induced colitis by inhibiting lipid peroxidation in mice.

OBJECTIVE: To investigate the mechanisms of the preventive activity of lactic acid bacteria in colitis, the inhibitory effect of Bifidobacterium longum HY8004, which potently inhibited lipid peroxidation in vitro, was examined in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitic mice. METHODS: We measured the ability of lactic acid bacteria (LAB) to inhibit lipid peroxidation in vitro and to inhibit colitis outcomes, colon shortening, and myeloperoxidase activity in TNBS-induced colitis in C3H/HeN and C3H/HeJ mice. We also measured levels of the inflammatory markers interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha and their transcription factor, NF-kappaB, in the colon by enzyme-linked immunosorbent assay and immunoblot analysis. RESULTS: Among the LAB tested, B. logum HY8004 most potently inhibited lipid peroxidation in vitro but did not inhibit TLR-4-linked NF-kappaB activation in HEK cells. Oral administration of HY8004 inhibited TNBS-induced colon shortening and myeloperoxidase activity in the colon of C3H/HeN and C3H/HeJ mice as well as IL-1 beta and TNF-alpha expression. B. longum HY8004 also inhibited TNBS-induced lipid peroxidation, TLR-4 expression, and NF-kappaB activation in the colon of C3H/HeN and C3H/HeJ mice. CONCLUSION: B. longum HY8004 can improve colitis via the inhibition of lipid peroxidation as well as NF-kappaB activation.

Efficacy and safety of thread embedding acupuncture on knee osteoarthritis: A randomized, controlled, pilot clinical trial.

INTRODUCTION: Although there are various therapeutic methods for the treatment of knee osteoarthritis, each has its advantages and shortcomings, and a definitive treatment method is yet to be determined. This pilot study is designed to obtain basic data for a further large-scale trial as well as provide information about the feasibility of thread embedding acupuncture (TEA) with polydioxanone thread in knee osteoarthritis patients. METHODS AND ANALYSIS: This study is a clinical trial to evaluate the efficacy and safety of TEA for knee osteoarthritis. Forty participants will be recruited at the hospital and after randomization into 2 groups of 20 (experimental and control); they will be treated for 6 weeks. The experimental group will receive TEA treatment 6 times (1 time/week) in 6 weeks on 14 defined knee areas, and the control group, acupuncture treatments 12 times (2 times/week) in 6 weeks on 9 defined acupuncture points. The visual analogue scale (VAS) will be used for the primary efficacy assessment and Short-form McGill Pain Questionnaire (SF-MPQ), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) will be used for the secondary efficacy assessment. The follow-ups before clinical trial, 3 weeks after procedure, 6 weeks after procedure, and 4 weeks after the end of procedure will be done to compare the degree of pain with the control group, which received the acupuncture treatment. CONCLUSION: The trial based on this study will provide clinical information on the efficacy and safety of TEA treatment on knee osteoarthritis. TRIAL REGISTRATION NUMBER: KCT0004844.

Wrap-bake-peel process for nanostructural transformation from beta-FeOOH nanorods to biocompatible iron oxide nanocapsules.

The thermal treatment of nanostructured materials to improve their properties generally results in undesirable aggregation and sintering. Here, we report on a novel wrap-bake-peel process, which involves silica coating, heat treatment and finally the removal of the silica layer, to transform the phases and structures of nanostructured materials while preserving their nanostructural characteristics. We demonstrate, as a proof-of-concept, the fabrication of water-dispersible and biocompatible hollow iron oxide nanocapsules by applying this wrap-bake-peel process to spindle-shaped akagenite (beta-FeOOH) nanoparticles. Depending on the heat treatment conditions, hollow nanocapsules of either haematite or magnetite were produced. The synthesized water-dispersible magnetite nanocapsules were successfully used not only as a drug-delivery vehicle, but also as a T2 magnetic resonance imaging contrast agent. The current process is generally applicable, and was used to transform heterostructured FePt nanoparticles to high-temperature face-centred-tetragonal-phase FePt alloy nanocrystals.

Hierarchical tumor acidity-responsive self-assembled magnetic nanotheranostics for bimodal bioimaging and photodynamic therapy.

Nanosized self-assemblies built from inorganic nanoparticles and polymer ligands have the potential to generate personalized theranostics systems for diagnostic imaging and cancer therapy. However, most of the theranostics systems suffer from poor targeting activity, insensitive diagnosis and drug leakage, leading to poor treatment results. In this study, a hierarchical tumor acidity-responsive magnetic nanobomb (termed HTAMN) was developed for photodynamic therapy and diagnostic imaging. The HTAMNs were formed through the self-assembly of chlorin e6 (Ce6)-functionalized polypeptide ligand, methoxy poly (ethyleneglycol)-block-poly (dopamine-ethylenediamine-2,3-dimethylmaleic anhydride)-L-glutamate-Ce6 [mPEG-b-P (Dopa-Ethy-DMMA)LG-Ce6] and superparamagnetic iron oxide nanoparticles (SPIONs). Negatively charged HTAMNs circulate in the blood for prolonged periods and promote tumor retention by passive targeting to the tumor. Once the HTAMNs arrive at the tumor location, the acidic extracellular tumor environment reverses the surface charge of the HTAMNs, resulting in tumor accumulation and cellular uptake. Moreover, in response to the more acidic environment inside cells, the photosensitizers are activated resulted in enhanced diagnostic imaging and cancer treatment. The in vitro and in vivo results indicate the effective tumor accumulation, internalization, diagnostic sensitivity and superior photodynamic therapy effect of the HTAMNs. Therefore, designing smart HTAMNs can promote the rapid development of cancer theranostics for clinical implementation.

Versatile PEG-derivatized phosphine oxide ligands for water-dispersible metal oxide nanocrystals.

We report the simple synthesis of poly(ethylene glycol)(PEG)-derivatized phosphine oxide ligands for water-dispersible metal oxide nanocrystals.

CdSe@ZnS/ZnS quantum dots loaded in polymeric micelles as a pH-triggerable targeting fluorescence imaging probe for detecting cerebral ischemic area.

High photoluminescence (PL) quantum yield (QY), photostability CdSe@ZnS/ZnS core/multishell quantum dots (CM-QDs) were first applied for bioimaging. The solubility, stability and biocompatible of the fluorescence imaging probes were constructed by self-assembly of CM-QDs and pH-responsive methoxy poly(ethylene glycol)-poly(ß-amino ester/amidoamine)-dodecylamine (mPEG-PAEA-DDA) multiblock copolymers. The resulting CM-QDs-loaded mPEG-PAEA-DDA micelles (CM-QDs-PEG-PAEA-DDA) exhibited lower cell cytotoxicity and higher fluorescence intensity than the core/shell CdSe@ZnS QDs-encapsulated mPEG-PAEA-DDA micelles (CS-QDs-PEG-PAEA-DDA). Moreover, the in vivo fluorescence imaging ability confirmed that the CM-QDs-PEG-PAEA-DDA can be employed as a pH-triggerable targeting imaging probe for detection of a rat bearing cerebral ischemia disease. Therefore, we believed that the CM-QDs-PEG-PAEA-DDA may be the next generation of fluorescence imaging probes for targeted diagnosis acidic pathological areas, using pH as a stimulus.

pH-Responsive biodegradable polymeric micelles with anchors to interface magnetic nanoparticles for MR imaging in detection of cerebral ischemic area.

A novel type of pH-responsive biodegradable copolymer was developed based on methyloxy-poly(ethylene glycol)-block-poly[dopamine-2-(dibutylamino) ethylamine-l-glutamate] (mPEG-b-P(DPA-DE)LG) and applied to act as an intelligent nanocarrier system for magnetic resonance imaging (MRI). The mPEG-b-P(DPA-DE)LG copolymer was synthesized by a typical ring opening polymerization of N-carboxyanhydrides (NCAs-ROP) using mPEG-NH2 as a macroinitiator, and two types of amine-terminated dopamine groups and pH-sensitive ligands were grafted onto a side chain by a sequential aminolysis reaction. This design greatly benefits from the addition of the dopamine groups to facilitate self-assembly, as these groups can act as high-affinity anchors for iron oxide nanoparticles, thereby increasing long-term stability at physiological pH. The mPEG moiety in the copolymers helped the nanoparticles to remain well-dispersed in an aqueous solution, and pH-responsive groups could control the release of hydrophobic Fe3O4 nanoparticles in an acidic environment. The particle size of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles was measured by dynamic light scattering (DLS) and cryo-TEM. The superparamagnetic properties of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles were confirmed by a superconducting quantum interference device (SQUID). T2-weighted magnetic resonance imaging (MRI) of Fe3O4-loaded mPEG-b-P(DPA-DE)LG phantoms exhibited enhanced negative contrast with an r2 relaxivity of approximately 106.7 mM(-1) s(-1). To assess the ability of the Fe3O4-loaded mPEG-P(DE-DPA)LG micelles to act as MRI probes, we utilized a cerebral ischemia disease rat model with acidic tissue. We found that a gradual change in contrast in the cerebral ischemic area could be visualized by MRI after 1 h, and maximal signal loss was detected after 24 h post-injection. These results demonstrated that the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles can act as pH-triggered MRI probes for diagnostic imaging of acidic pathological tissues.

Development of a New Hybrid Biodegradable Drug-Eluting Stent for the Treatment of Peripheral Artery Disease.

This study aimed to develop a new biodegradable stent for peripheral artery disease (PAD) that could provide sufficient radial force to maintain long-term patency and flexibility. All self-expandable hybrid biodegradable stents were designed by using a knitting structure composed of poly-L-lactic acid (PLLA) and nitinol. Four different types of stents were implanted in 20 iliac arteries in 10 mini pigs as follows: a bare-metal stent (BMS) (group 1, n = 5), a drug-free hybrid stent (group 2, n = 5), a 50% (50 : 100, w/w) paclitaxel (PTX)/poly-lactide-co-glycolic acid (PLGA; fast PTX-releasing form) hybrid stent (group 3, n = 5), and a 30% (30 : 100, w/w) PTX/PLGA (slow PTX-releasing form) hybrid stent (group 4, n = 5). We performed follow-up angiography and intravascular ultrasonography (IVUS) at 4 and 8 weeks. In a comparison of groups 1, 2, 3, and 4, less diameter stenosis was observed in the angiographic analysis for group 4 at the 4-week follow-up (19.0% ± 12.7% versus 39.3% ± 18.1% versus 46.8% ± 38.0% versus 4.8% ± 4.2%, resp.; p = 0.032). IVUS findings further suggested that the neointima of the patients in group 4 tended to be lesser than those of the others. Our new biodegradable 30% PTX/PLGA (slow-releasing form) stent showed more favorable results for patency than the other stent types.