Prospects For Clinical Translation Research Articles

USP9X-mediated REV1 deubiquitination promotes lung cancer radioresistance via the action of REV1 as a Rad18 molecular scaffold for cystathionine γ-lyase.

Radioresistance is a key clinical constraint on the efficacy of radiotherapy in lung cancer patients. REV1 DNA directed polymerase (REV1) plays an important role in repairing DNA damage and maintaining genomic stability. However, its role in the resistance to radiotherapy in lung cancer is not clear. This study aims to clarify the role of REV1 in lung cancer radioresistance, identify the intrinsic mechanisms involved, and provide a theoretical basis for the clinical translation of this new target for lung cancer treatment. The effect of targeting REV1 on the radiosensitivity was verified by in vivo and in vitro experiments. RNA sequencing (RNA-seq) combined with nontargeted metabolomics analysis was used to explore the downstream targets of REV1. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify the content of specific amino acids. The coimmunoprecipitation (co-IP) and GST pull-down assays were used to validate the interaction between proteins. A ubiquitination library screening system was constructed to investigate the regulatory proteins upstream of REV1. Targeting REV1 could enhance the radiosensitivity in vivo, while this effect was not obvious in vitro. RNA sequencing combined with nontargeted metabolomics revealed that the difference result was related to metabolism, and that the expression of glycine, serine, and threonine (Gly/Ser/Thr) metabolism signaling pathways was downregulated following REV1 knockdown. LC-MS/MS demonstrated that REV1 knockdown results in reduced levels of these three amino acids and that cystathionine γ-lyase (CTH) was the key to its function. REV1 enhances the interaction of CTH with the E3 ubiquitin ligase Rad18 and promotes ubiquitination degradation of CTH by Rad18. Screening of the ubiquitination compound library revealed that the ubiquitin-specific peptidase 9 X-linked (USP9X) is the upstream regulatory protein of REV1 by the ubiquitin-proteasome system, which remodels the intracellular Gly/Ser/Thr metabolism. USP9X mediates the deubiquitination of REV1, and aberrantly expressed REV1 acts as a scaffolding protein to assist Rad18 in interacting with CTH, promoting the ubiquitination and degradation of CTH and inducing remodeling of the Gly/Ser/Thr metabolism, which leads to radioresistance. A novel inhibitor of REV1, JH-RE-06, was shown to enhance lung cancer cell radiosensitivity, with good prospects for clinical translation.

Macrophage hitchhiking for systematic suppression in postablative multifocal HCC.

HCC, particularly the multifocal HCC, features aggressive invasion and dismal prognosis. Locoregional treatments were often refractory to eliminate tumor tissue, resulting in residual tumor cells persisting and subsequent progression. Owing to problematic delivery to the tumor tissue, systemic therapies, such as lenvatinib (LEN) therapy, show limited clinical benefit in preventing residual tumor progression. Therefore, more advanced strategies for postablative multifocal HCC are urgently needed. Motivated by the chemotaxis in tumor penetration of macrophages, we report a strategy named microinvasive ablation-guided macrophage hitchhiking for the targeted therapy toward HCC. In this study, the strategy leverages the natural inflammatory gradient induced by ablation to guide LEN-loaded macrophages toward tumor targeting, which increased by ~10-fold the delivery efficiency of LEN in postablative HCC in vivo. Microinvasive ablation-guided macrophage hitchhiking has demonstrated significant antitumor activity in various HCC models, including the hydrodynamic tail vein injection multifocal HCC mouse model and the orthotopic xenograft HCC rabbit model, systematically inhibiting residual tumor progression after ablation and prolonging the median survival of tumor-bearing mice. The potential antitumor mechanism was explored using techniques such as flow cytometry, ELISA, and immunohistochemistry. We found that the strategy significantly suppressed tumor cell proliferation and neovascularization, and such enhanced delivery of LEN stimulated systemic immune responses and induced durable immune memory. The macrophage hitchhiking strategy demonstrates exceptional therapeutic efficacy and biosafety across various species, offering promising prospects for clinical translation in controlling residual tumor progression and improving outcomes following HCC ablation.

Ruxolitinib-loaded cytokine nanosponge alleviated the cytokine storm and dampened macrophage overactivation for the treatment of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by a positive feedback loop between cytokine storm and macrophages and lymphocytes overactivation, which could serve as a valid therapeutic target for HLH treatment. In this study, the clinically extensively used JAK1/2 inhibitor ruxolitinib was encapsulated into macrophage membrane-coated nanoparticles (M@NP-R) with high drug-loading efficiency for targeted HLH treatment. In vitro and in vivo studies demonstrated that M@NP-R not only efficiently adsorbed extracellular proinflammation cytokines, like IFN-γ and IL-6 to alleviate the cytokine storm, but also effectively dampened macrophage activation and proliferation by intracellular JAK/STAT signaling pathway inhibition. M@NP-R treatment significantly ameliorated the clinical and laboratory manifestations of HLH in mouse models, including trilineage cytopenia, hypercytokinemia, organomegaly, hepatorenal dysfunction, and tissue inflammation. Importantly, M@NP-R significantly enhanced the survival of the lethal HLH mice. Altogether, M@NP-R successfully blocked the positive feedback loop between the cytokine storm and macrophage overactivation by depleting extracellular inflammatory cytokines and inhibiting the intracellular JAK/STAT signaling pathway, both of which worked synergistically in HLH treatment. As ruxolitinib has already been extensively used in clinics with favorable safety, and M@NP is biodegradable and highly biocompatible, M@NP-R has good prospects for clinical translation.

Electrochemiluminescence biosensor for specific detection of pancreatic ductal carcinoma through dual targeting of MUC1 and miRNA-196a

Pancreatic ductal adenocarcinoma (PDAC) poses significant diagnostic challenges due to its asymptomatic nature in its early stages, low specificity of conventional in vitro assays, and limited efficacy of surgical interventions. However, clinical specificity of the current serum biomarkers is suboptimal, leading to diagnostic inaccuracies and oversights. Therefore, this study introduced a novel dual-target electrochemiluminescence (ECL) biosensor to address these critical issues. The ECL biosensor synergistically employs the serum biomarker MUC1 and microRNA-196a to detect early-stage PDAC precisely. While MUC1 is a differential marker between normal and cancerous pancreatic cells, its standalone diagnostic performance is limited. However, integrating miRNA-196a as a complementary marker substantially enhances the specificity of the assay. This biosensor exhibits distinct ECL signal modulation—"on-off” in the presence of MUC1 and “off-on” upon concurrent detection of MUC1 and miRNA-196a. The biosensor achieves remarkably low limits of detection (LODs) at 0.63 fg mL−1 and 4.57 aM for MUC1 and miRNA-196a, respectively. Thus, it facilitates the real-time differentiation between human normal pancreatic (hTERT-HPNE) and pancreatic cancer (PANC-1) cells in authentic biological matrices. This innovative approach heralds a significant advancement in the early and specific detection of PDAC, offering promising prospects for clinical translation and the broader landscape of cancer diagnostics.

Noninvasive Evaluation of Tumoral PD-L1 Using a Novel 99mTc-Labeled Nanobody Tracer with Rapid Renal Clearance.

The expression level of PD-L1 in tumor tissue is considered one of the effective biomarkers to guide PD-1/PD-L1 therapy. Quantifying whole-body PD-L1 expression by SPECT imaging may help in selecting patients that potentially respond to PD-1/PD-L1 therapy. Nanobody is the smallest antibody fragment with antigen-binding ability that is well suited for radionuclide imaging. Nevertheless, high retention of radioactivity in the kidney may limit its clinical translation. The present study aimed to screen, design, and prepare a nanobody-based SPECT probe with rapid renal clearance to evaluate the PD-L1 expression level in vivo noninvasively. A phage library was constructed by immunizing alpaca with recombinant human PD-L1 protein, and 17 anti-PD-L1 nanobodies were screened by the phage display technique. After sequence alignment and flow cytometry analysis, APN09 was selected as the candidate nanobody, and a GGGC chelator was attached to its C-terminus for 99mTc labeling to prepare a SPECT imaging probe. The affinity and specificity of 99mTc-APN09 were evaluated by protein and cell-binding experiments, and SPECT imaging and biodistribution were performed in a mouse model with bilateral transplantation of A549 and A549PD-L1 tumors. The ability of 99mTc-APN09 to quantify the PD-L1 expression level in vivo was validated in tumor models with different PD-L1 expression levels. 99mTc-APN09 had a radiochemical purity higher than 99% and a binding equilibrium dissociation constant of 21.44 ± 1.65 nM with hPD-L1, showing high affinity. SPECT imaging results showed that 99mTc-APN09 could efficiently detect PD-L1-positive tumors within 0.5 h, and the quantitative results of SPECT were well correlated with the expression level of PD-L1 in cell lines. SPECT imaging and biodistribution results also showed that 99mTc-APN09 was rapidly cleared from the kidney in 2 h postinjection. 99mTc-APN09 was a simple and stable tool for visualizing PD-L1 expression in the whole body. In addition, due to its significant reduction in renal retention, it has better prospects for clinical translation.

A Biodegradable "One-For-All" Nanoparticle for Multimodality Imaging and Enhanced Photothermal Treatment of Breast Cancer.

Silver sulfide nanoparticles (Ag2S-NP) hold promise for various optical-based biomedical applications, such as near-infrared fluorescence (NIRF) imaging, photoacoustics (PA), and photothermal therapy (PTT). However, their NIR absorbance is relatively low, and previous formulations are synthesized using toxic precursors under harsh conditions and are not effectively cleared due to their large size. Herein, sub-5nm Ag2S-NP are synthesized and encapsulated in biodegradable, polymeric nanoparticles (AgPCPP). All syntheses are conducted using biocompatible, aqueous reagents under ambient conditions. The encapsulation of Ag2S-NP in polymeric nanospheres greatly increases their NIR absorbance, resulting in enhanced optical imaging and PTT effects. AgPCPP nanoparticles exhibit potent contrast properties suitable for PA and NIRF imaging, as well as for computed tomography (CT). Furthermore, AgPCPP nanoparticles readily improve the conspicuity of breast tumors in vivo. Under NIR laser irradiation, AgPCPP nanoparticles significantly reduce breast tumor growth, leading to prolonged survival compared to free Ag2S-NP. Over time, AgPCPP retention in tissues gradually decreases, without any signs of acute toxicity, providing strong evidence of their safety and biodegradability. Therefore, AgPCPP may serve as a "one-for-all" theranostic agent that degrades into small components for excretion after fulfilling diagnostic and therapeutic tasks, offering good prospects for clinical translation.

In Situ Growth of Functional Hydrogel Coatings by a Reactive Polyurethane for Biomedical Devices.

Surface modification of thermoplastic polyurethane (TPU) could significantly enhance its suitability for biomedical devices and public health products. Nevertheless, customized modification of polyurethane surfaces with robust interfacial bonding and diverse functions via a simple method remains an enormous challenge. Herein, a novel thermoplastic polyurethane with a photoinitiated benzophenone unit (BPTPU) is designed and synthesized, which can directly grow functional hydrogel coating on polyurethane (PU) in situ by initiating polymerization of diverse monomers under ultraviolet irradiation, without the involvement of organic solvent. The resulting coating not only exhibits tissue-like softness, controllable thickness, lubrication, and robust adhesion strength but also provides customized functions (i.e., antifouling, stimuli-responsive, antibacterial, and fluorescence emission) to the original passive polymer substrates. Importantly, BPTPU can be blended with commercial TPU to produce the BPTPU-based tube by an extruder. Only a trace amount of BPTPU can endow the tube with good photoinitiated capacity. As a proof of concept, the hydrophilic hydrogel-coated BPTPU is shown to mitigate foreign body response in vivo and prevent thrombus formation in rat blood circulation without anticoagulants in vitro. This work offers a new strategy to guide the design of functional polyurethane, an elastomer-hydrogel composite, and holds great prospects for clinical translation.

How Advancing is Peripheral Nerve Regeneration Using Nanofiber Scaffolds? A Comprehensive Review of the Literature.

Peripheral nerve injuries present significant challenges in regenerative medicine, primarily due to inherent limitations in the body's natural healing processes. In response to these challenges and with the aim of enhancing peripheral nerve regeneration, nanofiber scaffolds have emerged as a promising and advanced intervention. However, a deeper understanding of the underlying mechanistic foundations that drive the favorable contributions of nanofiber scaffolds to nerve regeneration is essential. In this comprehensive review, we make an exploration of the latent potential of nanofiber scaffolds in augmenting peripheral nerve regeneration. This exploration includes a detailed introduction to the fabrication methods of nanofibers, an analysis of the intricate interactions between these scaffolds and cellular entities, an examination of strategies related to the controlled release of bioactive agents, an assessment of the prospects for clinical translation, an exploration of emerging trends, and thorough considerations regarding biocompatibility and safety. By comprehensively elucidating the intricate structural attributes and multifaceted functional capacities inherent in nanofiber scaffolds, we aim to offer a prospective and effective strategy for the treatment of peripheral nerve injury.

Genetically Modified Mesenchymal Stromal Cells in Cartilage Regeneration.

Articular cartilage injury is common in various conditions, including osteoarthritis, rheumatic diseases, and trauma. Current treatments for cartilage injury fail to completely regenerate the damaged cartilage. Mesenchymal stromal cells (MSCs) have emerged as potential candidates for cartilage regeneration. However, MSCs exhibit hypertrophic differentiation, and their chondrogenic ability is reduced in an inflammatory environment. In recent years, genetic modification has been proposed for optimizing MSC-based therapies, some of which are expected to enter clinical trials. This review summarizes recent research findings and developments in genetic engineering strategies to enhance stem cell-based therapy for cartilage regeneration. We also discuss the mechanisms of biofunctions of MSCs in cartilage regeneration and outline the efficacy and safety of the different genetic modification strategies, including viral and nonviral delivery transduction. Finally, we highlight the major challenges and prospects for clinical translation of genetically modified MSCs.

In Vivo Evaluation of a Gallium-68-Labeled Tumor-Tracking Cyanine Dye for Positron Emission Tomography/Near-Infrared Fluorescence Carcinoma Imaging, Image-Guided Surgery, and Photothermal Therapy.

Positron emission tomography (PET)/near-infrared fluorescence (NIRF) dual-modal imaging presents an enticing prospect for tumor diagnosis and surgical navigation. In this study, we developed a novel probe IR808-DOTA for tumor-targeted PET/NIRF imaging, image-guided surgery, and photothermal therapy. This construct had better water solubility and pharmacokinetics than IR808 and had similar photophysical properties, tumor targeting ability, and photothermal anticancer effect to IR808. By a simple labeling process, IR808-DOTA was labeled with gallium-68 and applied as a PET probe for tumor imaging in MCF-7 tumor xenografted mice. IR808-DOTA itself acted as an NIRF imaging agent in the following surgery for intraoperative navigation to aid surgeons in the delineation of tumor margins and visualizing sentinel lymph nodes to facilitate a more thorough tumor resection. Irradiation by laser, IR808-DOTA could prominently inhibit tumor growth in MCF-7 subcutaneous tumor model mice by directly ablating tumor cells, inhibiting tumor proliferation, and promoting tumor cell apoptosis. In summary, 68Ga-DOTA-IR808 could enable a convenient and user-friendly workflow for tumor imaging and guided surgery, and therefore, it may have great prospects for clinical translation as a PET/NIRF dual-modal probe.

Niobium promotes fracture healing in rats by regulating the PI3K-Akt signalling pathway: An in vivo and in vitro study.

BackgroundStable fixation is crucial in fracture treatment. Currently, optimal fracture fixation devices with osteoinductivity, mechanical compatibility, and corrosion resistance are urgently needed for clinical practice. Niobium (Nb), whose mechanical properties are similar to those of bone tissue, has excellent biocompatibility and corrosion resistance, so it has the potential to be the most appropriate fixation material for internal fracture treatment. However, not much attention has been paid to the use of Nb in the area of clinical implants. Yet its role and mechanism of promoting fracture healing remain unclear. Hence, this study aims at elucidating on the effectiveness of Nb by systematically evaluating its osteogenic performance via in vivo and ex vivo tests.MethodsSystematic in vivo and in vitro experiments were conducted to evaluate the osteogenic properties of Nb. In vitro experiments, the biocompatibility and osteopromoting activity of Nb were assessed. And the osteoinductive activity of Nb was assessed by alizarin red, ALP staining and PCR test. In vivo experiments, the effectiveness and biosafety of Nb in promoting fracture healing were evaluated using a rat femoral fracture model. Through the analysis of gene sequencing results of bone scab tissues, the upregulation of PI3K-Akt pathway expression was detected and it was verified by histochemical staining and WB experiments.ResultsExperiments in this study had proved that Nb had excellent in-vitro cell adhesion and proliferation-promoting effects without cytotoxicity. In addition, ALP activity, alizarin red staining and semi-quantitative analysis in the Nb group had indicated its profound impact on enhancing osteogenic differentiation of MC3T3-E1 cells. We also found that the use of Nb implants can accelerate fracture healing compared to that with Ti6Al4V using an animal model of femur fracture in rats, and the biosafety of Nb was confirmed in vivo via histological evaluation. Furthermore, we found that the osteogenic effects of Nb were achieved through activation of the PIK/Akt3 signalling pathway.ConclusionAs is shown in the present research, Nb possessed excellent biosafety in clinical implants and accelerated fracture healing by activating the PI3K-Akt signalling pathway, which had good prospects for clinical translation, and it can replace titanium alloy as a material for new functional implants.

Modelling SHH-Medulloblastoma Using Cerebellar Organoids

Abstract AIMS Medulloblastoma (MB) comprises four main groups (SHH, WNT, group 3 and group 4), with distinct molecular, clinical and demographic features. These differences suggest opportunities for tailored and improved treatment. Despite its promise, translation into targeted therapy has been slow, limited by the lack of laboratory models that recapitulate patient tumours. Sporadic and inherited forms of SHH-MB are frequently due to mutations in the tumour suppressor gene PTCH1. Here, we aim to exploit human induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 gene editing, to target PTCH1 in a clinically relevant context, thereby establishing an innovative model of MB. METHOD CRISPR/Cas9 mutation of PTCH1 in hiPSCs was followed by their differentiation into cerebellar organoids. Mutant organoids were studied for early consequences on cerebellar development and tumorigenesis. RESULTS PTCH1-mutation resulted in enhanced SHH-pathway activity in cerebellar organoids. Homozygous PTCH1-mutation prevented the formation of cerebellar progenitor cells, closely mimicking the effects of high SHH- signalling on neuronal progenitors in early embryonal development. Heterozygous PTCH1-mutant hiPSCs could be differentiated into cerebellar organoids, displayed increased growth rate and expressed oncogenes specific to SHH-MB, resembling preneoplasia and MB stem cells. CONCLUSION These results show that cerebellar organoids are a promising new model to study early oncogenic events in MB. Our model presents opportunities for the discovery of new targets which could benefit patients with a genetic predisposition to MB in particular. Refined knowledge of early drivers will be invaluable to guide drug selection and improve prospects for clinical translation.

Development and Evaluation of a Peptide Heterodimeric Tracer Targeting CXCR4 and Integrin αvβ3 for Pancreatic Cancer Imaging.

Nowadays, pancreatic cancer is still a formidable disease to diagnose. The CXC chemokine receptor 4 (CXCR4) and integrin αvβ3 play important roles in tumor development, progression, invasion, and metastasis, which are overexpressed in many types of human cancers. In this study, we developed a heterodimeric tracer 68Ga-yG5-RGD targeting both CXCR4 and integrin αvβ3, and evaluated its feasibility and utility in PET imaging of pancreatic cancer. The 68Ga-yG5-RGD could accumulate in CXCR4/integrin αvβ3 positive BxPC3 tumors in a high concentration and was much higher than that of 68Ga-yG5 (p < 0.001) and 68Ga-RGD (p < 0.001). No increased uptake of 68Ga-yG5-RGD was found in MX-1 tumors (CXCR4/integrin αvβ3, negative). In addition, the uptake of 68Ga-yG5-RGD in BxPC3 was significantly blocked by excess amounts of AMD3100 (an FDA-approved CXCR4 antagonist) and/or unlabeled RGD (p < 0.001), confirming its dual-receptor targeting properties. The ex vivo biodistribution and immunohistochemical results were consistent with the in vivo imaging results. The dual-receptor targeting strategy achieved improved tumor-targeting efficiency and prolonged tumor retention in BxPC3 tumors, suggesting 68Ga-yG5-RGD is a promising tracer for the noninvasive detection of tumors that express either CXCR4 or integrin αvβ3 or both, and therefore may have good prospects for clinical translation.

Sprayable Antibacterial Hydrogels by Simply Mixing of Aminoglycoside Antibiotics and Cellulose Nanocrystals for the Treatment of Infected Wounds.

Antibiotic hydrogels with sustained release profiles are recognized as promising candidates to treat local bacterial infections with reduced adverse effects. However, it still remains challenging for clinical translation of these antibiotic gels due to safety concern of gel ingredients, complicated synthesis and fabrication procedures, and unsatisfactory rheological properties for practical uses in vivo. Herein, the preparation of a type of sprayable hydrogels by ionic interactions between aminoglycosides and cellulose nanocrystals (CNC) is proposed for the treatment of local infections such as bacteria-infected wounds. The CNC-based hydrogels are applicable for all kinds of aminoglycoside antibiotics and show excellent gel stability and rheological behaviors such as shear thinning and fast self-healing, allowing facile administration by injection or spraying. The hydrogels exhibit efficient antibacterial activity both in vitro and in vivo, and accelerate bacteria-infected wounds by spraying on the infected area. The proposed hydrogels by simply mixing of aminoglycosides and CNC provide great prospects for clinical translation in the treatment of local infections.

Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation.

Survival of pig cardiac xenografts in a non-human primate (NHP) model has improved significantly over the last 4 years with the introduction of costimulation blockade based immunosuppression (IS) and genetically engineered (GE) pig donors. The longest survival of a cardiac xenograft in the heterotopic (HHTx) position was almost 3 years and only rejected when IS was stopped. Recent reports of cardiac xenograft survival in a life-sustaining orthotopic (OHTx) position for 6 months is a significant step forward. Despite these achievements, there are still several barriers to the clinical success of xenotransplantation (XTx). This includes the possible transmission of porcine pathogens with pig donors and continued xenograft growth after XTx. Both these concerns, and issues with additional incompatibilities, have been addressed recently with the genetic modification of pigs. This review discusses the spectrum of issues related to cardiac xenotransplantation, recent progress in preclinical models, and its feasibility for clinical translation.

Mucosa‐Like Conformal Hydrogel Coating for Aqueous Lubrication

Mucosa is a protective and lubricating barrier in biological tissue, which has a great clinical inspiration because of its slippery, soft, and hydrophilic surface. However, mimicking mucosal traits on complex surface remains an enormous challenge. Herein, a novel approach to create mucosa-like conformal hydrogel coating is developed. A thin conformal hydrogel layer mimicking the epithelial layer is obtained by first absorbing micelles, followed by forming covalent interlinks with the polymer substrate via interface-initiated hydrogel polymerization. The resulting coating exhibits uniform thickness (≈15µm), mucosa-matched compliance (Young's modulus = 1.1± 0.1kPa) and lubrication (coefficients of friction = 0.018± 0.003), robust interfacial bonding against peeling (peeling strength = 1218.0± 187.9 J m-2 ), as well as high water absorption capacity. It effectively resists adhesion of proteins and bacteria without compromising biocompatibility. As demonstrated by an in vivo cynomolgus monkey model and clinical trial, applications of the mucosa-like conformal hydrogel coating on the endotracheal tube significantly reduce intubation-related complications, such as invasive stimuli, mucosal lesions, laryngeal edema, inflammation, and postoperative pain. This work offers a promising prototype for surface decoration of biomedical devices and holds great prospects for clinical translation to enable interventional operations with minimally invasive impacts.

Visualizing T-Cell Responses: The T-Cell PET Imaging Toolbox.

T lymphocytes are key mediators of the adaptive immune response. Inappropriate or imbalanced T-cell responses are underlying factors in cancer progression, allergy, and other immune disorders. Monitoring the spatiotemporal dynamics of T cells and their functional status has the potential to provide unique biologic insights into health and disease. Noninvasive PET imaging represents an ideal whole-body modality for achieving this goal. With the appropriate PET imaging probes, T-cell dynamics can be monitored invivo with high specificity and sensitivity. Herein, we provide a comprehensive overview of the applications of this state-of-the-art T-cell PET imaging toolbox and the potential it has to improve the clinical management of cancer immunotherapy and T-cell-driven diseases. We also discuss future directions and prospects for clinical translation.

Gold Nanostars: A Novel Platform for Developing 211At-Labeled Agents for Targeted Alpha-Particle Therapy.

AimTo develop an innovative 211At nanoplatform with high radiolabeling efficiency and low in vivo deastatination for future targeted alpha-particle therapy (TAT) to treat cancer.MethodsStar-shaped gold nanoparticles, gold nanostars (GNS), were used as the platform for 211At radiolabeling. Radiolabeling efficiency under different reaction conditions was tested. Uptake in the thyroid and stomach after systemic administration was used to evaluate the in vivo stability of 211At-labeled GNS. A subcutaneous U87MG human glioma xenograft murine model was used to preliminarily evaluate the therapeutic efficacy of 211At-labeled GNS after intratumoral administration.ResultsThe efficiency of labeling GNS with 211At was almost 100% using a simple and rapid synthesis process that was completed in only 1 min. In vitro stability test in serum showed that more than 99% of the 211At activity remained on the GNS after 24 h incubation at 37°C. In vivo biodistribution results showed low uptake in the thyroid (0.44–0.64%ID) and stomach (0.21–0.49%ID) between 0.5 and 21 h after intravenous injection, thus indicating excellent in vivo stability of 211At-labeled GNS. The preliminary therapeutic efficacy study demonstrated that 211At labeled GNS substantially reduced tumor growth (P < 0.001; two-way ANOVA) after intratumoral administration.ConclusionThe new 211At radiolabeling strategy based on GNS has the advantages of a simple process, high labeling efficiency, and minimal in vivo dissociation, making it an attractive potential platform for developing TAT agents that warrants further evaluation in future preclinical studies directed to evaluating prospects for clinical translation.

Dual-functional hybrid quaternized chitosan/Mg/alginate dressing with antibacterial and angiogenic potential for diabetic wound healing.

BackgroundClinic treatment of diabetic foot ulcers (DFUs) is considerably challenging. Impaired wound healing may be caused by poor vascularization and dysfunction of the extracellular matrix, which leads to poor re-epithelialization and increased risk of infection. In this study, we evaluated the treatment potential of a functional dressing comprising quaternized chitosan (hydroxypropyltrimethyl ammonium chloride chitosan) and magnesium (Mg) on DFUs.MethodsDressings were prepared by vacuum freeze-drying. The cellular proliferation, migration, and angiogenesis potential of the functional dressings were determined in vitro. Methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300) and methicillin-resistant Staphylococcus epidermidis 287 (MRSE287) were used to evaluate the antibacterial efficiency of the dressings. Finally, a diabetic rat model with infected wounds was used to further evaluate the effects of functional dressings on the healing of DFUs.ResultsFunctional dressings facilitated the migration of human dermal fibroblasts and human umbilical vein endothelial cells (HUVECs), while also stimulating angiogenesis in HUVECs. Additionally, the functional dressing could effectively eradicate MRSA and MRSE, exhibiting excellent antibacterial ability against drug-resistant bacteria. The results of in vivo microbiological and histological tests demonstrated effective anti-infection ability and wound-healing potential of this functional dressing.ConclusionsThe dual-functional dressing exhibited wound-healing ability and anti-infection efficiency, demonstrating potential application prospects in DFU treatment.Translational potential of this articleAs one of the common and serious complications of diabetes, DFUs do not heal easily, causing great suffering to patients. Therefore, improvement in the prognosis of DFUs is a crucial clinical need. The dual-functional dressing prepared in this study was proven to improve the treatment of DFUs, both in vitro and in vivo. Considering its urgent clinical necessity and good biocompatibility of its raw materials, such as alginate, Mg, and chitosan derivatives, this dual-functional dressing presents good prospects for clinical translation.

MiR-21: A Key Small Molecule with Great Effects in Combination Cancer Therapy.

The increasing incidence of various cancers indicates the urgent need for finding accurate early diagnostic markers and more effective treatments for these malignancies. MicroRNAs (miRNAs) are small noncoding RNAs with great potentials to enter into cancer clinics as both diagnostic markers and therapeutic targets. miR-21 is elevated in many cancers, and promotes cell proliferation, metastasis, and drug resistance. In recent years, many studies have shown that targeting miR-21 combined with conventional chemotherapeutic agents could enhance their therapeutic efficacy, and overcome drug resistance and cancer recurrence both in vitro and in animal models. In this review, we first summarize the effects and importance of miR-21 in various cancers, and explore its function in drug resistance of cancer cells. Next, the challenges and prospects for clinical translation of anti-miR-21, as a therapeutic agent, will be discussed in combination cancer therapy.