Hydrogen-releasing magnesium hydrogel mitigates post laminectomy epidural fibrosis through inhibition of neutrophil extracellular traps.

Epidural fibrosis is a primary contributor to the failure of laminectomy surgeries, leading to the development of failed back surgery syndrome (FBSS). Post-laminectomy, neutrophils infiltrate the surgical site, generating neutrophil extracellular traps (NETs) that contribute to epidural fibrosis. Reactive oxygen species (ROS) play a pivotal role in mediating NETs formation. Molecular hydrogen, recognized for its selective antioxidant properties and biosafety, emerges as a potential therapeutic gas in suppressing epidural fibrosis. In this study, we developed an in-situ hydrogen release hydrogel that inhibits the formation of NETs and mitigates epidural scarring. Biodegradable magnesium (Mg) microspheres served as a hydrogen source, coated with PLGA to regulate hydrogen release. These microspheres (Mg@PLGA) were then incorporated into a PLGA-PEG-PLGA thermosensitive hydrogel (Mg@PLGA@Gel), providing a surgical implant for sustained, long-term hydrogen release. In vitro experiments confirmed the biocompatibility of the system, demonstrating that hydrogen produced by Mg@PLGA effectively neutralizes neutrophil intracellular ROS and inhibits NETs formation. Histological analyses, including H&E staining, MRI, Masson staining, and immunohistochemistry, collectively indicate that Mg@PLGA@Gel is biocompatible and effectively inhibits epidural fibrosis post-laminectomy. Furthermore, Mg@PLGA@Gel inhibits ROS accumulation and NETs formation at the surgical site. These findings suggest that Mg@PLGA@Gel ensures continuous, therapeutic hydrogen concentration, providing relief from epidural fibrosis in a laminectomy mouse model. STATEMENT OF SIGNIFICANCE: •The hydrogen-releasing hydrogel combines the therapeutic effects of a physical barrier with immunomodulation. •In situ-generated molecular hydrogen scavenges ROS caused by surgical stress and suppresses NETs formation. •The hydrogen-releasing hydrogel is demonstrated to exhibit high biocompatibility and inhibit epidural scar formation in vivo.

PDL1/HER2-Targeted Lipid-Encapsulated Oxygen Nanobubbles Combined with Photodynamic Therapy for HER2+ Breast Cancer Immunotherapy.

Programmed death (PD) 1/PD ligand 1 (PDL1) inhibitors are immune checkpoint inhibitors (ICIs) that may facilitate HER2-positive breast cancer treatment; however, their clinical efficacy remains elusive. Oxygen-enhanced photodynamic therapy (PDT) increases immunogenic cell death (ICD), providing a promising strategy to render the tumor microenvironment more sensitive to the ICIs. Lipid-encapsulated oxygen nanobubbles (Lipo-NBs-O2) obtained using nanobubbles (NBs) water for oxygen delivery in vivo can facilitate enhanced PDT. Here, dual-receptor targeted Lipo-NBs-O2 (DRT@Lipo-NBs-O2) is prepared by modifying Lipo-NBs-O2 with anti-PDL1 scFv and the fusion protein anti-HER2 scFv-tandem-repeat cytochrome c (anti-HER2-nCytc). Copper phthalocyanine is the photosensitizer (PS). DRT@Lipo-PS-NBs-O2 plus near-infrared irradiation leads to robust ICD induction, increasing DC activation and CD8+ T-cell numbers. Modification with anti-PDL1 scFv improves tumor distribution of DRT@Lipo-PS-NBs-O2 and plays the ICI role, invigorating CD8+ T cells and boosting the effects of immunotherapy. Oxygen supplied through DRT@Lipo-PS-NBs-O2 reduces P-glycoprotein expression. Enhanced PDT and Cytc can cause tumor cell death, thereby reducing the immune burden. Under dual receptor targeting and laser local irradiation, tumor cells become subject to the combination effects of PDT, ICD, ICIs, and apoptosis; this effectively suppresses tumor growth and metastasis. Lipo-NBs-O2 affords a combination of oxygen delivery and multidrug therapy to alleviate HER2-positive breast cancer.

First Report of Nigrospora oryzae Causing Leaf Spot Disease on Amorphophallus albus in Shaanxi Province of China.

Amorphophallus albus P. Y. Liu & J. F. Chen is a typical cash crop widely planted in southwest China (Gao et al., 2022). In early August of 2021, a peculiar leaf spot disease was first detected on A. albus in Ankang Academy of Agricultural Sciences manufacturing base (32°69'N, 109°02'E), Shaanxi, China. Small irregular yellow-brown spots (1 to 2 mm) were observed on the surface of A. albus leaf. Following infection of the leaf, it expanded (3 to 5 mm) and became necrotic. Nine planting bases were investigated, and approximately 75% of plants were symptomatic during the rapid expansion period of bulb growth in Hanyin, Langao and Hanbin counties, Ankang City, Shaanxi, China. Higher disease incidence was observed at temperatures above 30℃ and humidity above 80%. Twenty-seven symptomatic tissues of infected leaves were first surface sterilized by immersion in 75% ethanol for 1 minute, followed by rinsing three times in sterile distilled water. The tissues were then cut into 4-5 mm pieces, plated on 1.5% potato dextrose agar (PDA), and incubated at 28±2°C. The hyphal tip from the growing edge of colonies cultured for three days at 28±2℃ was transferred to PDA to obtain pure cultures. Fungal colonies were white, then grey to black with an unevenly distributed, fast-growing aerial mycelium covering the petri dish within five days at 28±2℃. The colony turned dark brown when maintained in the dark at 28±2℃ after seven days, then grayish brown upon sporulation after 15 days (Fig.1f-g). Conidia were brown or black, smooth, spherical to sub-spherical, single-celled (8-12 µm × 10-13µm, average 9-11.5 µm in diameter, n=5µm). The nutritional hyphae exhibited septa, and a portion of the aerial hyphae formed a long, rough conidium, giving rise to a nearly spherical apical sac (Fig.1h). The surface gave rise to several small peduncles bearing clusters of surfaced spherical conidia (Fig.1i). Surfaced spherical conidia were generated on the surface of the small peduncle (Fig.1j). These morphological features were consistent with Nigrospora oryzae (Li et al., 2017). Genomic DNA was extracted from mycelia of the pathogen using an Ezup column fungal genomic DNA extraction kit (Sangon Biotech, Shanghai, China). To confirm the identity of the pathogen, the genomic fragments for the internal transcribed spacer (ITS), LSU (28S) and BenA gene of the isolate were amplified by PCR (Wang et al., 2017) and sent for sequencing. The resultant sequence (GeneBank ID of gene ITS, LSU, BenA are OR723825, OR775345, OR277316, respectively) were compared with the voucher specimens. BLAST results showed >99% identity with those of N.oryzae (GeneBank ID of N.oryzae strain LC2707 ITS, LSU, BenA are KX985954, KY806242, KY019481, respectively). A neighbor joining phylogenetic tree with the concatenated sequences of these genes showed that A-pb169 had the closest match with N. oryzae (Fig. 2). For pathogenicity testing, fifty plants in a period of rapid expansion of bulb growth were selected. Four leaves per plant were inoculated by sprayed till runoff with a conidial suspension of the pathogen (50 µL, 1×106 conidia/ml sterile water), and incubated at 30±2℃ and 80 ± 5% humidity. Control plants received sterile water. On the third day after inoculation, a yellow-brown spot appeared on leave surfaces, the spot gradually expanded; the infection rate was 90 to 95%. Fifteen days after inoculation, infected leaves showed symptoms like those observed in the field, whereas 100 control leaves sprayed with sterile water remained symptomless (Fig.1 a-e). The pathogen was reisolated from infected leaves and confirmed as N. oryzae by morphology and molecular identification. To our knowledge, this is the first report of leaf spot disease of A. albus caused by N. oryzae in China. Since its one of the major cash crops of the southeastern China, further work is necessary to determine its spread and economic impact as well as developing sustainable disease management options.

A Self-Homing and Traceable Cardiac Patch Leveraging Ferumoxytol for Spatiotemporal Therapeutic Delivery.

Mesenchymal stem cell (MSC)-based cardiac patches are envisioned to be a promising treatment option for patients with myocardial infarction. However, their therapeutic efficacy and duration are hampered due to their limited retention on the epicardium. We engineered a scaffold-free MSC sheet with an inherent ability to migrate into the infarcted myocardium, a strategy enabled by actively establishing a sustained intracellular hypoxic environment through the endocytosis of our FDA-approved ferumoxytol. This iron oxide nanoparticle stabilized hypoxia-induced factor-1α, triggering upregulation of the CXC chemokine receptor and subsequent MSC chemotaxis. Thus, MSCs integrated into 2/3 depth of the left ventricular anterior wall in a rat model of acute myocardial infarction and persisted for at least 28 days. This led to spatiotemporal delivery of paracrine factors by MSCs, enhancing cardiac regeneration and function. Ferumoxytol also facilitated the noninvasive MRI tracking of implanted MSCs. Our approach introduces a strategy for mobilizing MSC migration, holding promise for rapid clinical translation in myocardial infarction treatment.

Mixed-valence gold-porphyrin two-dimensional coordination networks for repurposing of chrysotherapy.

Catalytic gold nanomaterials typically exhibit antibacterial properties, albeit significantly weaker than ionic gold in chrysotherapy. The inherent stability of gold nanoparticles prevents the release of gold ions, limiting their ability to achieve efficient antibacterial therapy. To address this limitation, we propose a novel sustained ionic gold release strategy through the construction of a mixed-valence gold-porphyrin coordination network (Au-Por). By adjusting the ratio of Au to porphyrin molecule, an ultrathin two-dimensional Au-Por nanosheet was successfully synthesized, which contains 85.9 % of Au (III). In addition, the remaining gold existed in the form of uniformly distributed ultrasmall nanoclusters on the Au-Por nanosheet. Notably, the Au-Por nanosheet exhibited a sustained release of gold ions. Thus, a multimodal antibacterial therapy was achieved by integrating the direct bactericidal action of ionic gold and lethal reactive oxygen species (ROS) generated through the peroxidase (POD)-like activity of gold nanoclusters and photodynamic therapy (PDT) using porphyrins. The innovative Au-Por exerted broad-spectrum bactericidal activity against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus bacteria mediated by bacterial membrane disruption and DNA damage. Moreover, in vivo studies demonstrated the synergistic effect of Au-Por on combating skin wound infections and facilitating wound healing. Comprehensive safety evaluations proved that Au-Por exhibited no hematotoxicity or hepatorenal toxicity, and it also displayed rapid renal clearance after treatment, indicating favorable biocompatibility. The repurposing of chrysotherapy has revolutionized the antibacterial strategy of nanoscale gold, resulting in a dramatic boost in antibacterial activity and valuable insights for designing highly efficient nanoscale antibacterial agents.

Deep-learning and conventional radiomics to predict IDH genotyping status based on magnetic resonance imaging data in adult diffuse glioma.

Objectives: In adult diffuse glioma, preoperative detection of isocitrate dehydrogenase (IDH) status helps clinicians develop surgical strategies and evaluate patient prognosis. Here, we aim to identify an optimal machine-learning model for prediction of IDH genotyping by combining deep-learning (DL) signatures and conventional radiomics (CR) features as model predictors. Methods: In this study, a total of 486 patients with adult diffuse gliomas were retrospectively collected from our medical center (n=268) and the public database (TCGA, n=218). All included patients were randomly divided into the training and validation sets by using nested 10-fold cross-validation. A total of 6,736 CR features were extracted from four MRI modalities in each patient, namely T1WI, T1CE, T2WI, and FLAIR. The LASSO algorithm was performed for CR feature selection. In each MRI modality, we applied a CNN+LSTM-based neural network to extract DL features and integrate these features into a DL signature after the fully connected layer with sigmoid activation. Eight classic machine-learning models were analyzed and compared in terms of their prediction performance and stability in IDH genotyping by combining the LASSO-selected CR features and integrated DL signatures as model predictors. In the validation sets, the prediction performance was evaluated by using accuracy and the area under the curve (AUC) of the receiver operating characteristics, while the model stability was analyzed by using the relative standard deviation of the AUC (RSDAUC). Subgroup analyses of DL signatures and CR features were also individually conducted to explore their independent prediction values. Results: Logistic regression (LR) achieved favorable prediction performance (AUC: 0.920 ± 0.043, accuracy: 0.843 ± 0.044), whereas support vector machine with the linear kernel (l-SVM) displayed low prediction performance (AUC: 0.812 ± 0.052, accuracy: 0.821 ± 0.050). With regard to stability, LR also showed high robustness against data perturbation (RSDAUC: 4.7%). Subgroup analyses showed that DL signatures outperformed CR features (DL, AUC: 0.915 ± 0.054, accuracy: 0.835 ± 0.061, RSDAUC: 5.9%; CR, AUC: 0.830 ± 0.066, accuracy: 0.771 ± 0.051, RSDAUC: 8.0%), while DL and DL+CR achieved similar prediction results. Conclusion: In IDH genotyping, LR is a promising machine-learning classification model. Compared with CR features, DL signatures exhibit markedly superior prediction values and discriminative capability.

Renal Clearable Catalytic 2D Au-Porphyrin Coordination Polymer Augmented Photothermal-Gas Synergistic Cancer Therapy.

As a gasotransmitter, carbon monoxide (CO) possesses antitumor activity by reversing the Warburg effect at higher concentrations. The targeted delivery of carbon monoxide-releasing molecules (CORMs) using nanomaterials is an appealing option for CO administration, but how to maintain CO above the threshold concentration in tumor tissue remains a challenge. Herein, a nanozyme-catalyzed cascade reaction is proposed to promote CO release for high-efficacy photothermal therapy (PTT)-combined CO therapy of cancer. A gold-based porphyrinic coordination polymer nanosheet (Au0 -Por) is synthesized to serve as a carrier for CORM. It also possesses excellent glucose oxygenase-like activity owing to ultrasmall zero-valent gold atoms on the nanosheet. The catalytically generated H2 O2 can efficiently catalyze CORM decomposition, which enables in situ generation of sufficient CO for gas therapy. In vivo, the Au0 -Por nanosheets-enhanced photoacoustic imaging (PAI) and fluorescence imaging collectively demonstrate high tumor-targeting efficiency and nanomaterial retention. Proven to have augmented therapeutic efficacy, the nanoplatform can also be easily degraded and excreted through the kidney, indicating good biocompatibility. Thus, the application of rational designed Au0 -Por nanosheet with facile approach and biodegradable property to PAI-guided synergistic gas therapy can provide a strategy for the development of biocompatible and highly effective gaseous nanomedicine.

Design, synthesis and application of near-infrared fluorescence probe IR-780-Crizotinib in detection of ALK positive tumors.

At present, the early diagnosis and treatment of NSCLC has become an international research hotspot. However, how to realize the organic combination of highly sensitive and high-resolution tumor imaging diagnosis and effective treatment, and to provide effective information for the diagnosis and treatment of cancer is still a major problem in the integration of cancer diagnosis and treatment. In this study, based on the Crizotinib has a good targeted inhibitory effect on ALK positive tumor cells, the near-infrared targeted fluorescent dye IR-780 was covalently bound with the drug molecule Crizotinib, thus the near-infrared fluorescent probe IR-780-Crizotinib targeting ALK positive tumor cells was synthesized. The probe structure is confirmed by NMR and MS. The optical properties of the fluorescent probe and the imaging process in ALK positive tumor-bearing mice were analyzed using ultraviolet spectrophotometer, near-infrared fluorescence spectrometer, and near-infrared fluorescence imaging system. The results show that the probe had better photoactivity. In vivo imaging shows that the probe maintained the biological activity of Crizotinib, effectively targeting the tumor site involved with clear imaging, and ultimately excreted from the body. It was confirmed that the probe could be used for the tracking, positioning and targeted therapy of nude mice with ALK positive tumors in vivo, thus exploring a new approach for the clinical application of near-infrared fluorescent probe to detect ALK positive tumors in the future.

Rational design of an oxygen-enriching nanoemulsion for enhanced near-infrared laser activatable photodynamic therapy against hypoxic tumors.

Photodynamic therapy (PDT) has emerged as one of the most promising modalities to treat cancers. However, the hypoxic microenvironment in tumors severely limits the efficiency of PDT. IR780 is a near-infrared light activatable photosensitizer for PDT. It has attracted intensive attention owing to its intriguing properties such as mitochondria-targeting ability and fluorescence imaging capability. Nevertheless, its application in tumor treatment is hampered by its low aqueous solubility and poor stability. To address these obstacles, here we designed a novel hierarchical nanoplatform containing a uniquely stable high loading capacity oxygen carrier (perfluoropolyether, in short, PFPE) and IR780. This nanoplatform (IR780-P/W NE, in abbreviation for IR780-PFPE-in-water nanoemulsion) has no detectable dark cytotoxicity. It not only improves the aqueous solubility and stability of IR780, but also transports oxygen to relieve hypoxia and boosts the efficiency of near-infrared light triggered PDT via augmentation of reactive oxygen species generation. Particularly, the innovative nanosized oxygen carrier developed in this research, P/W NE, is a potential universal platform for loading hydrophobic photosensitizers (including but not limited to IR780), sonosensitizers, or radiosensitizers, and simultaneously improving the therapeutic efficacy. Our results highlight the intriguing potential of the developed nanoemulsions for mitigating tumor hypoxia and enhancing the efficiencies of oxygen-dependent therapies including PDT, sonodynamic therapy, radiotherapy, and so on.

Stimuli-responsive poly(ionic liquid) nanoparticles for controlled drug delivery.

A poly(ionic liquid) (PIL) obtained by polymerizing an ionic liquid (IL) monomer exhibits the characteristics of low cost and good biocompatibility, and it retains the excellent properties of the monomer. However, there is still a need to develop PILs for biomedical applications, which has been paid little attention. Herein, an amphiphilic block polymer containing a PIL block is synthesized, which simultaneously includes a targeted ligand, a photo-responsive block, and a pH-responsive block. The resultant amphiphilic block polymer can self-assemble into drug-loaded nanoparticles with a size of ∼80 nm in aqueous solution, and its drug loading capacity is as high as 70%. Moreover, the drug releasing mechanism of these drug-loaded nanoparticles can be triggered by light and pH stimuli. These novel amphiphilic PIL-based drug-loaded nanoparticles show highly effective antitumor effects, providing a promising approach for the delivery and controlled release of chemotherapy drugs in cancer therapy.

Coordination-induced exfoliation to monolayer Bi-anchored MnB2 nanosheets for multimodal imaging-guided photothermal therapy of cancer.

Background: Rapid advance in biomedicine has recently vitalized the development of multifunctional two-dimensional (2D) nanomaterials for cancer theranostics. However, it is still challenging to develop new strategy to produce new types of 2D nanomaterials with flexible structure and function for enhanced disease theranostics. Method: We explore the monolayer Bi-anchored manganese boride nanosheets (MBBN) as a new type of MBene (metal boride), and discover their unique near infrared (NIR)-photothermal and photoacoustic effects, X-ray absorption and MRI imaging properties, and develop them as a new nanotheranostic agent for multimodal imaging-guided photothermal therapy of cancer. A microwave-assisted chemical etching route was utilized to exfoliate the manganese boride bulk into the nanosheets-constructed flower-like manganese boride nanoparticle (MBN), and a coordination-induced exfoliation strategy was further developed to separate the MBN into the dispersive monolayer MBBN by the coordination between Bi and B on the surface, and the B-OH group on the surface of MBBN enabled facile surface modification with hyaluronic acid (HA) by the borate esterification reaction in favor of enhanced monodispersion and active tumor targeting. Result: The constructed MBBN displays superior NIR-photothermal conversion efficiency (η=59.4%) as well as high photothermal stability, and possesses versatile imaging functionality including photoacoustic, photothermal, CT and T1 -wighted MRI imagings. In vitro and in vivo evaluations indicate that MBBN had high photothermal ablation and multimodal imaging performances, realizing high efficacy of imaging-guided cancer therapy. Conclusion: We have proposed new MBene concept and exfloliation strategy to impart the integration of structural modification and functional enhancement for cancer theranostics, which would open an avenue to facile fabrication and extended application of multifunctional 2D nanomaterials.

Zwitterionic Polymer Coating of Sulfur Dioxide-Releasing Nanosystem Augments Tumor Accumulation and Treatment Efficacy.

Multiple drug resistance (MDR) exhibited by cancer cells and low intratumor accumulation of chemotherapeutics are the main obstacles in cancer chemotherapy. Herein, the preparation of a redox-responsive sulfur dioxide (SO2 )-releasing nanosystem, with high SO2 -loading capacity, aimed at improving the treatment efficacy of cancers exhibiting MDR is described. The multifunctional nanomedicine (MON-DN@PCBMA-DOX) is designed and constructed by coating mesoporous organosilica nanoparticles with a zwitterionic polymer, poly(carboxybetaine methacrylate) (PCBMA), which can concurrently load SO2 prodrug molecules (DN, 2,4-dinitrobenzenesulfonylchloride) and chemotherapeutics (DOX, doxorubicin). The generated SO2 molecules can sensitize cells to chemotherapy and overcome the MDR by downregulating the expression of P-glycoprotein. Furthermore, the PCBMA coating prolongs the blood circulation time of the inner core, leading to an increased intratumor accumulation of the nanomedicine. Owing to the prolonged blood circulation, enhanced tumor accumulation, and SO2 sensitization of cells to chemotherapy, the nanomedicine exhibits excellent tumor suppression with a tumor inhibition rate of 94.8%, and might provide a new platform for cancer therapy.

Novel lipophilic SN38 prodrug forming stable liposomes for colorectal carcinoma therapy.

Background: SN38 (7-ethyl-10-hydroxy camptothecin), as a potent metabolite of irinotecan, is highly efficacious in cancer treatment. However, the clinical utility of SN38 has been greatly limited due to its undesirable properties, such as poor solubility and low stability. Materials and methods: In order to overcome these weaknesses, moeixitecan, a lipophilic SN38 prodrug containing a SN-38, a trolox, a succinic acid linker, and a hexadecanol chain, was loaded into liposomal nanoparticles by ethanol injection method. Results: Experiments showed that the moeixitecan-loaded liposomal nanoparticles (MLP) with a diameter of 105.10±1.49 nm have a satisfactory drug loading rate (90.54±0.41%), high solubility and stability, and showed sustained release of SN38. Notably, MLP exhibited better antitumor activity against human colon adenocarcinoma cells than irinotecan, a FDA-approved drug for the treatment of advanced colorectal cancer. Furthermore, xenograft model results showed that MLP outperformed irinotecan in terms of pharmacokinetics, in vivo therapeutic efficacy and safety. Finally, we used molecular dynamic simulations to explore the association between the structure of MLP and the physical and functional properties of MLP, moeixitecan molecules in MLP folded themselves inside the hydrocarbon chain of the lipid bilayer, which led an increased acyl chain order of the lipid bilayer, and therefore enhanced the lactone ring stability protecting it from hydrolysis. Conclusion: Our MLP constructing strategy by liposome engineering technology may serve a promising universal approach for the effective and safe delivery of lipophilic prodrug.

Micro/Nanomaterials-Augmented Hydrogen Therapy.

Hydrogen therapy is an emerging and promising therapy strategy of using molecular hydrogen as a new type of safe and effective therapeutic agent, exhibiting remarkable therapeutic effects on many oxidative stress-/inflammation-related diseases owing to its bio-reductivity and homeostatic regulation ability. Different from other gaseous transmitters such as NO, CO, and H2 S, hydrogen gas has no blood poisoning risk at high concentration because it does not affect the oxygen-carrying behavior of blood red cells. Hydrogen molecules also have low aqueous solubility and high but aimless diffusibility, causing limited therapy efficacy in many diseases. To realize the site-specific hydrogen delivery, controlled hydrogen release and combined therapy is significant but still challenging. Here, a concept of hydrogen nanomedicine to address the issues of hydrogen medicine by using functional micro/nanomaterials for augmented hydrogen therapy is proposed. In this review, various strategies of micro/nanomaterials-augmented hydrogen therapy, including micro/nanomaterials-mediated targeted hydrogen delivery, controlled hydrogen release, and nanocatalytic and multimodel enhancement of hydrogen therapy efficacy, are summarized, which can open a new window for treatment of inflammation-related diseases.

Nitric oxide detection methods in vitro and in vivo.

Initially being considered as an environmental pollutant, nitric oxide has gained the momentum of research since its discovery as endothelial derived growth factor in 1987. Extensive researches have revealed the various pathological and physiological roles of nitric oxide such as inflammation, vascular and neurological regulation functions. Hence, the development of methods for quantifying nitric oxide concentration and its metabolites will be beneficial to well know about its biological functions and effects. This review summaries various methods for in vitro and in vivo nitric oxide detection, and introduces their merits and demerits.

Intelligent Metal Carbonyl Metal-Organic Framework Nanocomplex for Fluorescent Traceable H2 O2 -Triggered CO Delivery.

The recognized therapeutic benefits from carbon monoxide (CO) have caused booming attention to develop a CO therapy for various major diseases, such as cancer. However, the controlled release of CO gas and the monitoring of the CO release are vitally important to the on-demand CO administration for a safe and efficient therapy, but greatly challenging. In this work, a new CO-releasing nanocomplex was constructed by the adsorption and coordination of manganese carbonyl ([MnBr(CO)5 ], abbreviated as MnCO) with a Ti-based metal-organic framework (Ti-MOF) to realize an intratumoral H2 O2 -triggered CO release and real-time CO release monitoring by fluorescence imaging. A high CO prodrug loading capacity (0.532 g MnCO per gram Ti-MOF) is achieved due to the high surface area of Ti-MOF, and the intracellular H2 O2 -triggered CO release from the MnCO@Ti-MOF is realized to enable the nanocomplex selectively release CO in tumor cells and kill tumor cells rather than normal cells. Particularly significant is that the real-time fluorescence imaging monitoring of the CO release is realized based on an annihilation effect of the fluorescence after MnCO loading into Ti-MOF and an activation effect of the fluorescence after CO release from Ti-MOF. The quantitative relationship between the fluorescence intensity and the released CO amount is established in great favor of guiding on-demand CO administration. The results demonstrate the advantage of versatile MOFs for high efficient CO delivery and monitoring, which is critical for the improvement of the effectiveness of future therapeutic application.

Liposomally formulated phospholipid-conjugated novel near-infrared fluorescence probe for particle size effect on cellular uptake and biodistribution in vivo.

Lipid based nanoparticles (LBNs) with excellent biocompatibility and versatility have received much attention from the drug delivery community recently. A detailed understanding of in vitro and vivo fate of LBNs is important for developing different types of LBNs with improved selectivity and low cytotoxicity. We developed a novel near-infrared (NIR) probe with high fluorescence, designated as DSPE-ir623 (iDSPE). Then, we prepared iDSPE-embeded liposomes (iLPs) with two different hydrodynamic sizes (∼100nm and ∼400nm) to evaluate the effect of particle size on cellular uptake and biodistribution of nanoliposomes in vivo. These iLPs were proved to exhibit good monodispersity, excellent fluorescence and stability. In vitro cell uptake tests demonstrated that iLPs-1 (∼100nm) were taken up more by HT-29 cells than iLPs-2 (∼400nm). Notably, the fluorescence of iLPs can be employed for real-time monitoring of the subcellular locating and its metabolic distribution in vivo. Near-infrared imaging in vivo illustrated that iLPs-1 was mainly accumulated in the tumor tissues, while iLPs-2 was accumulated in liver and spleen. The results indicated that the size of iLPs play an important role in the regulation of intracellular trafficking and biodistribution of liposomes, which also provide a new insight into the development of more effective LBNs. Hence, iDSPE might be a promising tool for the reliable tracing of different types of LBNs.

Liposomally formulated phospholipid-conjugated novel near-infrared fluorescence probe for particle size effect on cellular uptake and biodistribution in vivo.

Lipid based nanoparticles (LBNs) with excellent biocompatibility and versatility have received much attention from the drug delivery community recently. A detailed understanding of in vitro and vivo fate of LBNs is important for developing different types of LBNs with improved selectivity and low cytotoxicity. We developed a novel near-infrared (NIR) probe with high fluorescence, designated as DSPE-ir623 (iDSPE). Then, we prepared iDSPE-embeded liposomes (iLPs) with two different hydrodynamic sizes (∼100nm and ∼400nm) to evaluate the effect of particle size on cellular uptake and biodistribution of nanoliposomes in vivo. These iLPs were proved to exhibit good monodispersity, excellent fluorescence and stability. In vitro cell uptake tests demonstrated that iLPs-1 (∼100nm) were taken up more by HT-29 cells than iLPs-2 (∼400nm). Notably, the fluorescence of iLPs can be employed for real-time monitoring of the subcellular locating and its metabolic distribution in vivo. Near-infrared imaging in vivo illustrated that iLPs-1 was mainly accumulated in the tumor tissues, while iLPs-2 was accumulated in liver and spleen. The results indicated that the size of iLPs play an important role in the regulation of intracellular trafficking and biodistribution of liposomes, which also provide a new insight into the development of more effective LBNs. Hence, iDSPE might be a promising tool for the reliable tracing of different types of LBNs.

Redox responsive liposomal nanohybrid cerasomes for intracellular drug delivery.

Cerasome is a freshly developped bilayer vehicle that resemble traditional liposome but has higher mophorlogical stability. In this study, a novel redox-responsive cerasome (RRC) was developed for tumor-targeting drug delivery. The cerasome-forming lipid (CFL) that comprise a cleavable disulfide bond as connector unit of the triethoxysilyl head and the hydrophobic alkyl double chain was synthesized and subsequently used to prepare cerasome through ethanol injection method. RRC that has liposome-resembling lipid bilayer structure was proved being outstanding at drug loading capacity as well as morphological stability as compared to conventional liposomes. In addition, in vitro drug release tests of DOX/RRCs showed a redox-responsive drug release profile: accelerated DOX releasing compared to reduction-insensitive cerasomes (RICs) in the presence of 10mM of GSH. Under the same condition, the reduction sensibility of RRC was further proved by increased hydrodynamic diameter and destroying of integrity from DLS and SEM results. RRC showed non-toxic to human embryonic kidney 293 cells, indicating that this material has good biocompatibility. On the other hand, DOX/RRCs showed a resemble IC50 (half inhibitory concentration) value to that of free DOX to human hepatoma SMMC-7721 cells and breast cancer MCF-7 cells. IC50 values at 48h were found to decrease in the following order: DOX/RIC>DOX/RRC>DOX. Taken together, the RRC developped in this study is of great potential to be utilized as a promising platform for intracellular anticancer drug delivery.

Synthesis and characterization of a novel near-infrared fluorescent probe for applications in imaging A549 cells.

OBJECTIVE: To design and synthesize a novel near-infrared (NIR) fluorescent probe based on indocyanine Green (ICG), that can be applied in imaging living cells. RESULTS: A highly fluorescent novel NIR fluorescent probe (IR-793) was synthesized in two steps. IR-793 had better fluorescence and optical stability than ICG. In addition, no obvious cytotoxicity effect of IR-793 was observed and cell viability was above 75% at the maximum concentration (120 nM). IR-793 also exhibited good performance in imaging living A549 cells. CONCLUSION: IR-793, a novel NIR fluorescent probe that is stable, low-cost, highly fluorescent and low cytotoxicity, has been designed and synthesized for imaging living cells.