ROS-Responsive Injectable Hydrogel Loaded with SLC7A11-modRNA Inhibits Ferroptosis and Mitigates Intervertebral Disc Degeneration in Rats.

Intervertebral disc degeneration (IVDD) is the primary cause of low back pain, with oxidative stress being a recognized factor that causes its development. Presently, low back pain imposes a significant global economic burden. However, the effectiveness of treatments for IVDD remains extremely limited. Therefore, this study aims to explore innovative and effective IVDD treatments by focusing on oxidative stress as a starting point. In this study, an injectable reactive oxygen species-responsive hydrogel (PVA-tsPBA@SLC7A11 modRNA) is developed, designed to achieve rapid loading and selective release of chemically synthesized modified mRNA (modRNA). SLC7A11 modRNA is specifically used to upregulate the expression of the ferroptosis marker SLC7A11. The local injection of PVA-tsPBA@SLC7A11 modRNA into the degenerated intervertebral disc (IVD) results in the cleavage of PVA-tsPBA, leading to the release of enclosed SLC7A11 modRNA. The extent of SLC7A11 modRNA release is directly proportional to the severity of IVDD, ultimately ameliorating IVDD by inhibiting ferroptosis in nucleus pulposus cells (NPCs). This study proposes an innovative system of PVA-tsPBA hydrogel-encapsulated modRNA, representing a potential novel treatment strategy for patients with early-stage IVDD.

Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response.

Osteoarthritis (OA) progression is highly associated with chondrocyte mitochondrial dysfunction and disorders of catabolism and anabolism of the extracellular matrix (ECM) in the articular cartilage. The mitochondrial unfolded protein response (UPRmt), which is an integral component of the mitochondrial quality control (MQC) system, is essential for maintaining chondrocyte homeostasis. We successfully validated the pivotal role of activating transcription factor 5 (ATF5) in upregulating the UPRmt, mitigating IL-1ß-induced inflammation and mitochondrial dysfunction, and promoting balanced metabolism in articular cartilage ECM, proving its potential as a promising therapeutic target for OA. Modified mRNAs (modRNAs) have emerged as novel and efficient gene delivery vectors for nucleic acid therapeutic approaches. In this study, we combined Atf5-modRNA (modAtf5) with engineered exosomes derived from bone mesenchymal stem cells (ExmodAtf5) to exert cytoprotective effects on chondrocytes in articular cartilage via Atf5. However, the rapid localized metabolization of ExmodAtf5 limits its application. PLGA-PEG-PLGA (Gel), an injectable thermosensitive hydrogel, was used as a carrier of ExmodAtf5 (Gel@ExmodAtf5) to achieve a sustained release of ExmodAtf5. In vitro and in vivo, the use of Gel@ExmodAtf5 was shown to be a highly effective strategy for OA treatment. The in vivo therapeutic effect of Gel@ExmodAtf5 was evidenced by the preservation of the intact cartilage surface, low OARSI scores, fewer osteophytes, and mild subchondral bone sclerosis and cystic degeneration. Consequently, the combination of ExmodAtf5 and PLGA-PEG-PLGA could significantly enhance the therapeutic efficacy and prolong the exosome release. In addition, the mitochondrial protease ClpP enhanced chondrocyte autophagy by modulating the mTOR/Ulk1 pathway. As a result of our research, Gel@ExmodAtf5 can be considered to be effective at alleviating the progression of OA.

Exosomes derived from MSC as drug system in osteoarthritis therapy.

Osteoarthritis (OA) is the most common degenerative disease of the joint with irreversible cartilage damage as the main pathological feature. With the development of regenerative medicine, mesenchymal stem cells (MSCs) have been found to have strong therapeutic potential. However, intraarticular MSCs injection therapy is limited by economic costs and ethics. Exosomes derived from MSC (MSC-Exos), as the important intercellular communication mode of MSCs, contain nucleic acid, proteins, lipids, microRNAs, and other biologically active substances. With excellent editability and specificity, MSC-Exos function as a targeted delivery system for OA treatment, modulating immunity, inhibiting apoptosis, and promoting regeneration. This article reviews the mechanism of action of MSC-Exos in the treatment of osteoarthritis, the current research status of the preparation of MSC-Exos and its application of drug delivery in OA therapy.

Treatment of old femoral neck fractures in young adults with a medial buttress plate combined with three cannulated screws and iliac autograft: Surgical technique and preliminary results.

OBJECTIVES: Whether the application of MBP plus cannulated screws works for old femoral neck fractures (OFNF) is unknown. The purpose of this study is to present a case series of OFNF in young adults using calcar buttress plate and three cannulated screws with autologous iliac bone grafts. METHODS: We conducted a retrospective study of eleven young patients (6 males and 5 females) with femoral neck fractures who were treated with open reduction and internal fixation at a single center between 2013 and 2021. The subjects had trauma-to-surgery intervals longer than 3weeks and all were fixed with a calcar buttress plate combined with three cannulated screws, which were supplemented by autologous iliac bone grafts. RESULTS: All eleven cases achieved radiological union under the surgery technique, which occurred on average at 4.46±1.29months after surgery. Complications included femoral neck shortening in all cases, heterotopic ossification in three cases, and osteonecrosis of the femoral head in two cases. One patient with osteonecrosis of the femoral head received total hip arthroplasty. In follow-ups of 24-52months, the median Harris hip score was 81.64±15.39. CONCLUSIONS: The medial buttress plate in combination with three cannulated screws and iliac autograft may be a good choice for treating old femoral neck fractures in young adults. LEVEL OF EVIDENCE: IV, case series.

Differential Toxicity of Electronic Cigarette Aerosols Generated from Different Generations of Devices In Vitro and In Vivo.

Electronic cigarettes (e-cigs) have become increasingly popular, especially among youth, raising concerns about their potential health risks. JUUL and Tank devices are two common types of e-cigs that deliver aerosols with varying nicotine levels and flavors. However, the differences in the aerosols generated from different devices and their corresponding cytotoxicity and pulmonary injury effects remain poorly understood. This study addresses these knowledge gaps by characterizing the aerosols of JUUL and Tank e-cig devices and testing their toxic effects on THP-1 and BEAS-2B human cell lines as well as the C57BL/6J mouse model. In our study, the lower-voltage device, the 3.7 V JUUL generates 2.72 mg/puff aerosols by using e-liquid containing 3% nicotine salt (i.e., nicotine benzoate), which is less than the 11.06 mg/puff aerosols generated by the 7.5 V Tank using e-liquid containing 2.4% freebase nicotine. Yet, the cytotoxicity results reveal that JUUL aerosols induced higher toxicity and increased production of pro-inflammation cytokines compared to Tank aerosols per puff. Additionally, we observed that JUUL induced more severe pulmonary inflammation and DNA damage compared to Tank after normalizing for cotinine, a nicotine metabolite, in vivo. Our findings suggest that the device design plays a more important role in e-cig aerosol-induced toxicity than the composition of the e-liquid or voltage. These results provide valuable insights into the health risks associated with various electronic-cig devices and offer an approach for evaluating them.

The dependence of particle size on cell toxicity for modern mining dust.

Progressive massive pulmonary fibrosis among coal miners has unexpectedly increased. It would likely due to the greater generation of smaller rock and coal particles produced by powerful equipment used in modern mines. There is limited understanding of the relationship between micro- or nanoparticles with pulmonary toxicity. This study aims to determine whether the size and chemical characteristics of typical coal-mining dust contribute to cellular toxicity. Size range, surface features, morphology, and elemental composition of coal and rock dust from modern mines were characterized. Human macrophages and bronchial tracheal epithelial cells were exposed to mining dust of three sub- micrometer and micrometer size ranges at varying concentrations, then assessed for cell viability and inflammatory cytokine expression. Coal had smaller hydrodynamic size (180-3000 nm) compared to rock (495-2160 nm) in their separated size fractions, more hydrophobicity, less surface charge, and consisted of more known toxic trace elements (Si, Pt, Fe, Al, Co). Larger particle size had a negative association with in-vitro toxicity in macrophages (p < 0.05). Fine particle fraction, approximately 200 nm for coal and 500 nm for rock particles, explicitly induced stronger inflammatory reactions than their coarser counterparts. Future work will study additional toxicity endpoints to further elucidate the molecular mechanism causing pulmonary toxicity and determine a dose-response curve.

Comparative analysis of pathogen distribution in patients with fracture-related infection and periprosthetic joint infection: a retrospective study.

BACKGROUND: The purpose of this study is to investigate the microbial patterns of periprosthetic joint infection (PJI) and fracture-related infection (FRI), and guide for the formulation of more accurate empirical antimicrobial regimens based on the differences in pathogen distribution. METHODS: A comparative analysis of pathogen distribution was conducted between 153 patients (76 with PJI and 77 with FRI). Predicted analyses against isolated pathogens from two cohorts were conducted to evaluate the best expected efficacy of empirical antimicrobial regimens (imipenem + vancomycin, ciprofloxacin + vancomycin, and piperacillin/tazobactam + vancomycin). RESULTS: Our study found significant differences in pathogen distribution between the PJI and FRI cohorts. Staphylococci (61.3% vs. 31.9%, p = 0.001) and Gram-negative bacilli (GNB, 26.7% vs. 56.4%, p < 0.001) were responsible for the majority of infections both in the PJI and FRI cohorts, and their distribution in the two cohorts showed a significant difference (p < 0.001). Multi-drug resistant organisms (MDRO) were more frequently detected in the FRI cohort (29.3% vs. 44.7%, p = 0.041), while methicillin-resistant coagulase-negative Staphylococci (MRCoNS, 26.7% vs. 8.5%, p = 0.002) and Canidia albicans (8.0% vs. 1.1%, p = 0.045) were more frequently detected in the PJI cohort. Enterobacter spp. and Acinetobacter baumannii were detected only in the FRI cohort (11.7% and 8.5%, respectively). CONCLUSIONS: Staphylococci and GNB were responsible for the majority of infections in both PJI and FRI. Empirical antimicrobial therapy should focus on the coverage of Staphylococci in PJI and GNB in FRI, and infections caused by MDROs should be more vigilant in FRI, while the high incidence of MRCoNS in PJI should be noted, which could guide for the formulation of more accurate empirical antimicrobial regimens. Targeted therapy for FRI caused by A. baumannii and PJI caused by C. albicans needs to be further investigated. Our study reports significant differences in pathogen distribution between the two infections and provides clinical evidence for studies on the mechanism of implant-associated infection.

Development and Preliminary Application of a Droplet Digital PCR Assay for Quantifying the Oncolytic Herpes Simplex Virus Type 1 in the Clinical-Grade Production.

Oncolytic herpes simplex virus (oHSV) is a type of virus that selectively targets and kills cancer cells, leaving normal cells unharmed. Accurate viral titer is of great importance for the production and application of oHSV products. Droplet digital PCR (ddPCR) is known for having good reproducibility, not requiring a standard curve, not being affected by inhibitors, and being precise even in the detection of low copies. In the present study, we developed a droplet digital PCR assay for the quantification of HSV-1 and applied it in the oHSV production. The established ddPCR showed good specificity, linearity, a low limit of quantification, great reproducibility, and accuracy. The quantification result was well-associated with that of plaque assay and CCID50. Amplification of the purified virus without DNA extraction by ddPCR presented similar results to that from the extracted DNA, confirming the good resistance against PCR inhibitors. With the ddPCR, viral titer could be monitored in real time during the production of oHSV; the optimal harvest time was determined for the best virus yield in each batch. The ddPCR can be used as a useful tool for the quantification of oHSV and greatly facilitate the manufacturing process of oHSV products.

Core decompression with ß-tri-calcium phosphate grafts in combination with platelet-rich plasma for the treatment of avascular necrosis of femoral head.

BACKGROUND: This study was aimed to investigate whether the application of platelet-rich plasma (PRP) combined with ß-tri-calcium phosphate (ß-TCP) grafts after core decompression (CD) could improve the clinical outcomes of early stage of avascular necrosis of femoral head. METHODS: Forty-five (54 hips) patients with Ficat-Arlet classification stage I-II treated by CD with ß-TCP grafts with or without the application of PRP from July 2015 to October 2020 were reviewed. Group A (CD + ß-TCP grafts) included 24 patients (29 hips), while group B (CD + ß-TCP grafts + PRP) included 21 patients (25 hips). Visual analogue scale (VAS) score, Harris hip score (HHS), change in modified Kerboul angle and the hip joint survival were evaluated and compared between the groups. Patients had a mean follow-up period of 62.1 ± 17.2 months and 59.3 ± 14.8 months in group A and group B, respectively. RESULTS: The mean VAS scores in group A was significantly higher than group B at the 6 months (2.9 ± 0.7 vs 1.9 ± 0.6, p < 0.01) and final follow up postoperative (2.8 ± 1.2 vs 2.2 ± 0.7, p = 0.04). The mean HHS in group A was significantly lower than group B at the 6 months (80.5 ± 13.8 vs 89.8 ± 12.8, p = 0.02). However, at the final follow up, there is no significant difference between the groups (77.0 ± 12.4 vs 83.1 ± 9.3, p = 0.07). The mean change in modified Kerboul angle was -7.4 ± 10.6 in group A and -19.9 ± 13.9 in group B which is statistically significant (p < 0.01). Survivorship from total hip arthroplasty were 86.2%/84% (p = 0.86) at the final follow up, which was not statistically significant. No serious complications were found in both groups. CONCLUSIONS: A single dose of PRP combined with CD and ß-TCP grafts provided significant pain relief, better functional outcomes, and delayed progression in the short term compared to CD combined with ß-TCP grafts. However, the prognosis of the femoral head did not improve significantly in the long term. In the future, designing new implants to achieve multiple PRP injections may improve the hip preservation rate.

Cellulose laurate films containing curcumin as photoinduced antibacterial agent for meat preservation.

Hydrophobic cellulose laurate (CL) with high degree of substitution has been successfully synthesized. The mechanical property, water-resistance, antimicrobial activity, barrier properties and food decontamination of cellulose-laurate-curcumin films (CL-Cux, x = 0.1, 0.5, and 1) were investigated. The results showed that the mechanical properties of CL-Cux hardly change after soaking in water for 24 h, probably due to the strong hydrophobicity of cellulose laurate. CL-Cu1 represented a good photoinduced antibacterial effect against S. aureus. After irradiation of white light at 60 mW·cm-2 for 20 min, the inhibition efficiency reached to 95 ± 2.02%, probably owing to the generated active 1O2. In comparison with CL-Cu1 stored in natural light, the bacteriostatic effect of CL-Cu1 in dark storage was better, and the inhibition rate of CL-Cu1 remained 80 ± 1.22 at 60th day. The stabler excited state of curcumin in hydrophobic cellulose laurate was probably assigned to inhibition of tautomerism or conformational transition, which was beneficial to the generation of singlet oxygen. CL-Cu1 can significantly inhibit the growth of TVBN and TVC values of chilled meat upon white light irradiation, indicating the potential application of cellulose-laurate-curcumin films in food decontamination.

Cellulosic films reinforced by chitosan-citric complex for meat preservation: Influence of nonenzymatic browning.

The methods to obtain cellulose-chitosan composite films exhibiting excellent water-resisting and antibacterial abilities have been widely explored. Cellulose-chitosan-citric films (C-Chx-F) were successfully obtained by a facile coating of chitosan-citric complex on the surface of cellulose. The occurrence of nonenzymatic browning at 80 °C improved the thermal stability, water-resistance, mechanical property and oxygen-barrier ability of C-Chx-F membranes. C-Ch3-F hydrogel showed excellent breaking stress of 6.03 ± 0.25 MPa, and elastic module of 27.09 ± 1.21 MPa, probably assigned to nonenzymatic browning. Under different test temperatures, the nonenzymatic browning and the content of chitosan-citric complex will significantly improve the oxygen barrier property of membranes (P < 0.05), and C-Ch3-F membrane represented the value of oxygen permeation below the detection level. Excellent antibacterial capability of C-Chx-F hydrogels demonstrated that polycationic chitosan-citric complex immobilized in films still retained excellent antibacterial ability. The excellent decontamination in meat preservation endowed C-Chx-F films with potential application in food packaging.

Nanocellulose Length Determines the Differential Cytotoxic Effects and Inflammatory Responses in Macrophages and Hepatocytes.

Nanocellulose including cellulose nanocrystal (CNC) and cellulose nanofiber (CNF) has attracted much attention due to its exceptional mechanical, chemical, and rheological properties. Although considered biocompatible, recent reports have demonstrated nanocellulose can be hazardous, including serving as drug carriers that accumulate in the liver. However, the nanocellulose effects on liver cells, including Kupffer cells (KCs) and hepatocytes are unclear. Here, the toxicity of nanocellulose with different lengths is compared, including the shorter CNCs (CNC-1, CNC-2, and CNC-3) and longer CNF (CNF-1 and CNF-2), to liver cells. While all CNCs triggered significant cytotoxicity in KCs and only CNC-2 induced toxicity to hepatocytes, CNFs failed to induce significant cytotoxicity due to their minimal cellular uptake. The phagocytosis of CNCs by KCs induced mitochondria ROS generation, caspase-3/7 activation, and apoptotic cell death as well as lysosomal damage, cathepsin B release, NLRP3 inflammasome and caspase-1 activation, and IL-1ß production. The cellular uptake of CNC-2 by hepatocytes is through clathrin-mediated endocytosis, and it induced the caspase-3/7-mediated apoptosis. CNC-2 shows the highest levels of uptake and cytotoxicity among CNCs. These results demonstrate the length-dependent mechanisms of toxicity on liver cells in a cell type-dependent fashion, providing information to safely use nanocellulose for biomedical applications.

Dissolution of 2D Molybdenum Disulfide Generates Differential Toxicity among Liver Cell Types Compared to Non-Toxic 2D Boron Nitride Effects.

2D boron nitride (BN) and molybdenum disulfide (MoS2 ) materials are increasingly being used for applications due to novel chemical, electronic, and optical properties. Although generally considered biocompatible, recent data have shown that BN and MoS2 could potentially be hazardous under some biological conditions, for example, during, biodistribution of drug carriers or imaging agents to the liver. However, the effects of these 2D materials on liver cells such as Kupffer cells (KCs), liver sinusoidal endothelial cells, and hepatocytes, are unknown. Here, the toxicity of BN and MoS2 , dispersed in Pluronic F87 (designated BN-PF and MoS2 -PF) is compared with aggregated forms of these materials (BN-Agg and MoS2 -Agg) in liver cells. MoS2 induces dose-dependent cytotoxicity in KCs, but not other cell types, while the BN derivatives are non-toxic. The effect of MoS2 could be ascribed to nanosheet dissolution and the release of hexavalent Mo, capable of inducing mitochondrial reactive oxygen species generation and caspases 3/7-mediated apoptosis in KUP5 cells. In addition, the phagocytosis of MoS2 -Agg triggers an independent response pathway involving lysosomal damage, NLRP3 inflammasome activation, caspase-1 activation, IL-1ß, and IL-18 production. These findings demonstrate the importance of Mo release and the state of dispersion of MoS2 in impacting KC viability.

A Cyclodextrin-Hosted Ir(III) Complex for Ratiometric Mapping of Tumor Hypoxia In Vivo.

Hypoxia is considered as a key microenvironmental feature of solid tumors. Luminescent transition metal complexes particularly those based on iridium and ruthenium have shown remarkable potentials for constructing sensitive oxygen-sensing probes due to their unique oxygen quenching pathway. However, the low aqueous solubility of these complexes largely retards their sensing applications in biological media. Moreover, it remains difficult so far to use the existing complexes typically possessing only one luminescent domain to quantitatively detect the intratumoral hypoxia degree. Herein, an Ir(III) complex showing red emissions is designed and synthesized, and innovatively encapsulated within a hydrophobic pocket of Cyanine7-modified cyclodextrin. The Ir(III) complex enables the oxygen detection, while the cyclodextrin is used not only for improving the water solubility and suppressing the luminescence quenching effect of the surrounding aqueous media, but also for carrying Cyanine7 to establish a ratiometric oxygen fluorescence probe. 2D nuclear magnetic resonance is carried out to confirm the host-guest structure. The oxygen-responsive ability of the resulting ratiometric probe is evaluated through in vitro cell and multicellular experiments. Further animal studies about tumor oxygen level mapping demonstrate that the probe can be successfully used for quantitatively visualizing tumor hypoxia in vivo.

Nanoparticle-Based Activatable Probes for Bioimaging.

Molecular imaging can provide functional and molecular information at the cellular or subcellular level in vivo in a noninvasive manner. Activatable nanoprobes that can react to the surrounding physiological environment or biomarkers are appealing agents to improve the efficacy, specificity, and sensitivity of molecular imaging. The physiological parameters, including redox status, pH, presence of enzymes, and hypoxia, can be designed as the stimuli of the activatable probes. However, the success rate of imaging nanoprobes for clinical translation is low. Herein, the recent advances in nanoparticle-based activatable imaging probes are critically reviewed. In addition, the challenges for clinical translation of these nanoprobes are also discussed in this review.

Electronic cigarette aerosols induce oxidative stress-dependent cell death and NF-κB mediated acute lung inflammation in mice.

Electronic cigarette (e-cigarette) use has been linked to recent acute lung injury case clusters in over 2000 patients and dozens of deaths in the United States, however, the mechanism leading to lung injury is not certain although ultrafine particles, heavy metals, volatile organic compounds, and other harmful ingredients have been implicated. To systematically evaluate e-cigarette toxicity, we generated e-cigarette aerosols by varying the puff numbers (20-480), nicotine contents (0-24 mg/mL), and collected e-cigarette samples through an impinger system for biological assays. The calculated samples' concentration ranged from 1.96 to 47.06 mg/mL. THP-1 monocyte-differentiated macrophages, BEAS-2B bronchial epithelial cells, wild-type C57BL/6 mice, and NF-κB-luc transgenic mice were used to test the effects of these samples. E-cigarette samples showed cytotoxicity to THP-1 cells and BEAS-2B in vitro, leading to increased oxidative stress, inflammatory cytokine production with or without nicotine, and cell death. Furthermore, aerosol generated from PG is more toxic than VG. The toxicity of e-cigarette samples is at least partially due to the reactive oxygen species and aldehydes, which are generated during the aerosolization processes by the e-cigarette device. After NF-κB-luc mice exposed with e-cigarette samples by oropharyngeal aspiration, NF-κB expressions were observed in a dose-response fashion with or without nicotine. In addition, the e-cigarette samples induced neutrophil infiltration, IL-1ß production, oxidative stress marker heme oxygenase-1 expression in wild-type C57BL/6 mice. These results suggested that oxidative stress, pro-inflammatory NF-κB pathway activation, and cell death are involved in e-cigarette aerosol-induced acute lung inflammation.

Photoredox/Cobalt-Catalyzed Phosphinyloxy Radical Addition/Cyclization Cascade: Synthesis of Phosphaisocoumarins.

A novel visible-light photoredox-catalyzed phosphinyloxy radical addition/cyclization cascade of arylphosphinic acids or arylphosphonic acid monoesters with alkynes has been developed, which provides an efficient and practical access to various phosphaisocoumarins by using a dual catalytic system containing an acridinium photosensitizer and a cobaloxime proton-reducing catalyst [Co(dmgH)2]PyCl at ambient temperature. This method has advantages of a broad substrate scope, mild condition, as well as no sacrificial oxidant.

Coordinatively Unsaturated Fe3+ Based Activatable Probes for Enhanced MRI and Therapy of Tumors.

Exogenous FeIII can be used for cancer magnetic resonance (MR) imaging and potentially for cancer treatment by a ferroptosis pathway or photothermal ablation. To achieve this, effective and accurate delivery of FeIII to cancerous sites is critical, requiring a balance of release kinetics of Fe3+ in tumorous and normal tissues. A nanoprobe is described consisting of upconversion luminescence (UCL) nanoparticles as a core and a coordinatively unsaturated FeIII -containing Fe3+ /gallic acid complex as a shell. Owing to the introduction of an unsaturated coordination structure, FeIII in the nanoprobe can be released only in the tumor microenvironment in response to the lightly acidic pH. The multiple UCLs are used for quantitatively visualizing the release of Fe3+ in vivo, whilst the release resultant serves as a photothermal agent. This nanoprobe exhibited ligand-free tumor targeting ability, activatable MR imaging performance, and efficacious therapeutic effects against tumors in vivo.

"Smart" Nanoprobes for Visualization of Tumor Microenvironments.

Physiological parameters in tumor microenvironments, including hypoxia, low extracellular pH, enzymes, reducing conditions, and so on, are closely associated with the proliferation, angiogenesis, invasion, and metastasis of cancer, and impact the therapeutic administrations. Therefore, monitoring the tumor microenvironment is significant for diagnosing tumors, predicting the invasion potential, evaluating therapeutic efficacy, planning the treatment, and cancer prognostics. Noninvasive molecular imaging technologies combined with novel "smart" nanoparticle-based activatable probes provide a feasible approach to visualize tumor-associated microenvironment factors. This review summarizes recent achievements in the designs of "smart" molecular imaging nanoprobes responding to the tumor microenvironment-related features, and highlights the state of the art in tumor heterogeneity imaging.

Timely Visualization of the Collaterals Formed during Acute Ischemic Stroke with Fe3 O4 Nanoparticle-based MR Imaging Probe.

Ischemic stroke is one of the major leading causes for long-term disability and mortality. Collateral vessels provide an alternative pathway to protect the brain against ischemic injury after arterial occlusion. Aiming at visualizing the collaterals occurring during acute ischemic stroke, an integrin αv ß3 -specific Fe3 O4 -Arg-Gly-Asp (RGD) nanoprobe is prepared for magnetic resonance imaging (MRI) of the collaterals. Rat models are constructed by occluding the middle cerebral artery for imaging studies of cerebral ischemia and ischemia-reperfusion on 7.0 Tesla MRI using susceptibility-weighted imaging sequence. To show the binding specificity to the collaterals, the imaging results acquired with the Fe3 O4 -RGD nanoprobe and the Fe3 O4 mother nanoparticles, respectively, are carefully compared. In addition, an RGD blocking experiment is also carried out to support the excellent binding specificity of the Fe3 O4 -RGD nanoprobe. Following the above experiments, cerebral ischemia-reperfusion studies show the collateral dynamics upon reperfusion, which is very important for the prognosis of various revascularization therapies in the clinic. The current study has, for the first time, enabled the direct observation of collaterals in a quasi-real time fashion and further disclosed that the antegrade flow upon reperfusion dominates the blood supply of primary ischemic tissue during the early stage of infarction, which is significantly meaningful for clinical treatment of stroke.