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Titiania nanotubes have large potential in medical implant applications but their tissue compatibility is still controversial. Considering that the biological behavior of primary osteoblasts is closer to the in vivo situation than other common cell lines, we investigate the response of primary osteoblasts on anodized nanotextured titania surfaces. Two nanotextured surface morphologies, namely the 5 V anodized surface with a pore diameter of 25 nm and the 20 V anodized surface with a tube diameter of 80 nm are chosen for this study. Initial cell adhesion is not obviously affected by the anodized surfaces. With the exception of slightly higher intracellular alkaline phosphatase activity and more extracellular matrix deposition, cell growth, and cell differentiation represented by the expressions of osteogenesis-related genes are impaired on both anodized surfaces. This may be attributed to the compromised focal contact formation on the anodized surfaces. The difference in the phenotypes of the primary osteoblasts and the osteoblastic cell lines may partly account for the controversy in osteoblast cytocompatibility on titania nanotubes. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2010. [ABSTRACT FROM AUTHOR]

Background: Malignant glioma is the most common and deadliest brain cancer due to the obstacle from indistinct tumor margins for surgical excision and blood brain barrier (BBB) for chemotherapy. Here, we designed and prepared multifunctional polyethylenimine-entrapped gold nanoparticles (Au PENPs) for targeted SPECT/CT imaging and radionuclide therapy of glioma. Results: Polyethylenimine was selected as a template for sequential modification with polyethylene glycol (PEG), glioma-specific peptide (chlorotoxin, CTX) and 3-(4-hydroxyphenyl)propionic acid-OSu (HPAO), and were then used to entrap gold nanoparticles (Au NPs). After 131I radiolabeling via HPAO, the 131I-labeded CTX-functionalized Au PENPs as a multifunctional glioma-targeting nanoprobe were generated. Before 131I radiolabeling, the CTX-functionalized Au PENPs exhibited a uniform size distribution, favorable X-ray attenuation property, desired water solubility, and cytocompatibility in the given Au concentration range. The 131I-labeled CTX-functionalized Au PENPs showed high radiochemical purity and stability, and could be used as a nanoprobe for the targeted SPECT/CT imaging and radionuclide therapy of glioma cells in vitro and in vivo in a subcutaneous tumor model. Owing to the unique biological properties of CTX, the developed nanoprobe was able to cross the BBB and specifically target glioma cells in a rat intracranial glioma model. Conclusions: Our results indicated that the formed nanosystem had the significant potential to be applied for glioma targeted diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Oleanolic acid is an active ingredient from natural products with anti-breast cancer activity. However, the poor solubility in water and low bioavailability have limited its effectiveness in clinic. To improve the anticancer activity of oleanolic acid, we synthesized a novel oleanolic quaternary ammonium (QDT), which, driven by electrostatic interactions, was introduced into heparin and coated with chitosan to obtain a QDT/heparin/chitosan nanoaggregate (QDT/HEP/CS NAs). QDT/HEP/CS NAs showed the negative zeta potential (−35.01 ± 4.38 mV), suitable mean particle size (150.45 ± 0.68 nm) with strip shape, and high drug loading (36 %). The coated chitosan had strong anti-leakage characteristics toward QDT under physiological conditions. More importantly, upon sustained release in tumor cells, QDT could significantly decrease the mitochondrial membrane potential and induce apoptosis of breast cancer cells. Further in vivo antitumor study on 4 T1 tumor-bearing mice confirmed the enhanced anticancer efficacy of QDT/HEP/CS NAs via upregulation of caspase-3, caspase-9 and cytochrome C, which was attributed to the high accumulation in tumor via the enhanced permeability and retention effect. Moreover, QDT/HEP/CS NAs significantly enhanced the biosafety and biocompatibility of QDT in vitro and in vivo. Collectively, the development of QDT/HEP/CS NAs with high antitumor activity, favorable biodistribution and good biocompatibility provided a safe, facile and promising strategy to improve the anti-cancer effect of traditional Chinese medicine ingredients. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), α4β2, plays a critical role in various brain functions and pathological states. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer aided drug design (CADD) plays a more and more important role in today''s drug discovery. Methods: Two novel 3-pyridyl ether nicotinic ligands-3-((pyridine-2-yl)methoxy)-5-iodopyridine, and 3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)-methyl)pyridine were designed and synthesized and radiolabeled with I-125 based on our 3D-QSAR models reported previously. Their ability to label high-affinity brain nicotinic acetylcholine receptors (nAChRs) was evaluated. Results: [125I]3-((pyridin-2-yl)methoxy)-5-iodopyridine shows rapid accumulation and elimination with peak (1.86%ID/g) at 5min post injection, but has high blood uptake. [125I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine entered the brain with maximal uptake value 3.01%ID/g at 15min after injection, and showed approximately 27% inhibition of radioactivity uptake in thalamus in mice pretreated with nicotine. Conclusions: The results of this preliminary study show that [125I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine shows relatively high uptake to the brain, however, since the in vivo selectivity for α4β2 nAChRs was not enough, [125I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine does not have the required properties for imaging nAChRs using SPECT. Structure optimization is needed for specific visualization of brain α4β2 nAChRs in vivo. [Copyright &y& Elsevier]

Triptolide (TP) is a potential drug candidate for the treatment of cancer, but its use was hampered by its systemic toxicity and poor water solubility. Hence, a TP-CSO prodrug was synthesized by conjugating TP to chitosan oligosaccharide (CSO), and characterized by 1H NMR, FTIR, DSC and XRD analyses. The TP-CSO containing about 4 wt% of TP exhibited excellent water solubility (15 mg/mL) compared to TP (0.017 mg/mL). Compared with TP, the pharmacokinetics of the conjugate after oral administration showed a three-fold increase in the half-life in the blood circulation and a 3.2-fold increase in AUC (0–∞). The orally administered TP-CSO could more effectively inhibit tumor progression but with much lower systemic toxicity compared with TP, indicating significant potential for further clinical trials. In conclusion, CSO-based conjugate systems may be useful as a platform for the oral delivery of other sparingly soluble drugs. [ABSTRACT FROM AUTHOR]

Background: The biofunctionalization of titanium implants for high osteogenic ability is a promising approach for the development of advanced implants to promote osseointegration, especially in compromised bone conditions. In this study, polyelectrolyte multilayers (PEMs) were fabricated using the layer-by-layer approach with a chitosan-miRNA (CS-miRNA) complex and sodium hyaluronate (HA) as the positively and negatively charged polyelectrolytes on microarc-oxidized (MAO) Ti surfaces via silane-glutaraldehyde coupling. Methods: Dynamic contact angle and scanning electron microscopy measurements were conducted to monitor the layer accumulation. RiboGreen was used to quantify the miRNA loading and release profile in phosphate-buffered saline. The in vitro transfection efficiency and the cytotoxicity were investigated after seeding mesenchymal stem cells (MSCs) on the CS-antimiR-138/HA PEM-functionalized microporous Ti surface. The in vitro osteogenic differentiation of the MSCs and the in vivo osseointegration were also evaluated. Results: The surface wettability alternately changed during the formation of PEMs. The CS-miRNA nanoparticles were distributed evenly across the MAO surface. The miRNA loading increased with increasing bilayer number. More importantly, a sustained miRNA release was obtained over a timeframe of approximately 2 weeks. In vitro transfection revealed that the CS-antimiR-138 nanoparticles were taken up efficiently by the cells and caused significant knockdown of miR-138 without showing significant cytotoxicity. The CS-antimiR-138/HA PEM surface enhanced the osteogenic differentiation of MSCs in terms of enhanced alkaline phosphatase, collagen production and extracellular matrix mineralization. Substantially enhanced in vivo osseointegration was observed in the rat model. Conclusions: The findings demonstrated that the novel CS-antimiR-138/HA PEM-functionalized microporous Ti implant exhibited sustained release of CS-antimiR-138, and notably enhanced the in vitro osteogenic differentiation of MSCs and in vivo osseointegration. This novel miRNA-functionalized Ti implant may be used in the clinical setting to allow for more effective and robust osseointegration. [ABSTRACT FROM AUTHOR]

Titanium implants are often combined with microporous titania coatings simultaneously doped with various elements to enhance their antibacterial, angiogenic and osteogenic activities. To evaluate how Sr doping levels affect properties of titania coatings simultaneously doped with Ca, P, Co and F (TiCPCF coatings), we prepared coatings with Sr contents equal to 6, 11 and 18 wt% (TiCPCF-S6, TiCPCF-S11 and TiCPCF-S18, respectively) using micro-arc oxidation of titanium. Sr presence in TiCPCF coatings did not affect their phase compositions, microstructure, surface wettability, roughness, and adhesion to titanium. Antibacterial, angio- and osteo-genic activities of all the coatings were evaluated. Sr incorporation improved mesenchymal stem cell proliferation, osteogenic differentiation and implant osseointegration. TiCPCF-S11 showed the most optimum Sr content judging by its enhanced osteogenic activity. While Sr incorporation did not weaken angiogenic and antibacterial abilities of TiCPCF. Thus TiCPCF-S11 coating is a very strong candidate to be used as a next-generation bone implant material. [ABSTRACT FROM AUTHOR]

Patients with compromised bone conditions still suffer the problem of deficient osseointegration during dental implant treatment. Developing mesenchymal stem cell (MSC) sheet functionalized titanium implant with proper inductive cue to promote osteogenesis and angiogenesis coupling shall be a good solution. In the present study, the antimiR-138 delivered MSC sheet is used to functionalize the Ti implant. The cell sheet can well integrate with the Ti implant to form the MSC sheet-implant complex (MSIC). The antimiR-138 delivered MSIC shows greatly improved osteogenesis and angiogenesis coupling both in vitro and in vivo . In vitro , the antimiR-138 delivered MSIC significantly promotes the expression of endogenous osteogenesis and angiogenesis related genes and proteins, alkaline phosphatase activity, extracellular matrix mineralization and collagen secretion compared to the antimiR-control and the nothing delivered control. The in vivo ectopic implantation assay uncovers the robust vascularized bone formation of the antimiR-138 delivered MSIC. The antimiR-138 delivered MSIC with promoted osteogenesis and angiogenesis coupling is anticipated to lead to rigid osseointegration in the compromised bone conditions. [ABSTRACT FROM AUTHOR]

Stachydrine is a hydrophilic quaternary amine salt with good antitumor effect, but its application is limited due to its rapid metabolism and low bioavailability. We synthesized and evaluated nine prodrugs of stachydrine, which showed suitable hydrophobicity (CLogP: −2.58–4.78, vs SS-0 : −3.32) and better in vitro anticancer activity (IC 50 : 0.34 μM–14.03 mM, vs SS-0 : 38.97 mM–147.19 mM) in comparison with stachydrine. Among them, SS-12, SS-16 and SS-18 are the most effective compounds against 4T1 cells, and the IC 50 is 2.15–24.14 μM. Especially, compared with stachydrine, SS-12 significantly blocked the cell cycle in the G0/G1 phase, reduced the mitochondrial membrane potential, and induced the apoptosis of 4T1 cells through mitochondria pathway, which increased the expressions of Bax and cleaved caspase-3 protein, decrease the expression of Bcl-2. The pharmacokinetics of SS-12 showed a rational bioavailability (79.6%), and a longer retention time (T 1/2 = 7.62 h) than that of stachydrine (T 1/2 ≈ 1.16 h) in rats. Compared with stachydrine, SS-12 significantly enhanced the anticancer efficacy (56.32% of tumor-inhibition rates, vs SS-0 : 3.89%), meanwhile, ameliorated the tumor-induced organ damage in mice. Therefore, SS-12 may be a promising prodrug of stachydrine against breast cancer. [Display omitted] • A series of novel prodrug of stachydrine was synthesized and characterized. • The stachydrine derivatives can increase the hydrophobicity and in vitro anticancer activity. • mi SS-12 might induce apoptosis of 4T1 cells via mitochondria pathway, and cause cell cycle arrest in the G0/G1 phase. • SS-12 showed long retention time and high bioavailability in rats after oral administration. • The stronger antitumor activity of stachydrine derivatives after oral administration were observed. [ABSTRACT FROM AUTHOR]

Bacterial infection and loosing are serious complications for biomedical implants in the orthopedic, dental, and other biomedical fields and the ideal implants should combine good antibacterial ability and bioactivity. In this study, nanostructured titanium–silver (Ti–Ag) coatings with different Ag contents (1.2 to 21.6 at%) are prepared on Ti substrates by magnetron sputtering. As the Ag concentration is increased, the coatings change from having dense columnar crystals to sparse ones and eventually no columnar structure. The Ti–Ag coatings can effectively kill Staphylococcus aureus during the first few days and remain moderately antibacterial after immersion for 75 days. Compared to pure Ti, the Ti–Ag coatings show good cytocompatibility as indicated by good osteoblast adhesion, proliferation, intracellular total protein synthesis, and alkaline phosphatase (ALP) activity. In addition, cell spreading, collagen secretion, and extracellular matrix mineralization are promoted on the coatings with the proper Ag contents due to the nanostructured morphological features. Our results indicate that favorable antibacterial activity and osseointegration ability can be simultaneously achieved by regulating the Ag contents in Ti–Ag coatings. [ABSTRACT FROM AUTHOR]

Abstract: Cell-sheet technology has already constituted an important part in the regenerative medicine. Nonetheless, oligonucleotide delivery that has been widely performed on isolated stem cells to foster specific function is rarely conducted on the cell sheets. This study is designed with the two-fold aims of verifying the feasibility of non-viral oligonucleotide delivery for the cell sheets and confirming the osteogenesis enhancing effect of antimiR-138 on the cell sheets composed of bone marrow mesenchymal stem cells (BMSCs). The BMSC sheets are fabricated by a vitamin C inducing method, which can be successfully delivered with the oligonucleotides with a high delivery efficiency of nearly 100% by the properly adapted and optimized Lipofactamine2000 based formulation. The antimiR-138 delivery significantly enhances the in vitro osteogenic differentiation of BMSC sheets, indicated by the higher alkaline phosphatase (ALP) production, denser extracellular matrix mineralization and up-regulated osteogenesis related genes including runt-related transcription factor-2 (RUNX2), osterix, ALP, osteocalcin and bone morphogenetic protein-2 at both mRNA and protein levels, compared to controls. Regarding the underlying mechanism, the antimiR-138 delivery down-regulates the endogenous miR-138 levels in the BMSC sheets, consequently activates the extracellular signal regulated kinases 1/2 pathway and enhances the RUNX2 expression. The in vivo results indicate a robust enhancing effect of the antimiR-138 delivery on the bone regeneration ability of BMSC sheets. Massive bone with good vascularization is regenerated by the antimiR-138 delivered BMSC sheets, showing immense clinical significance for bone defect repair/regeneration applications. More importantly, the feasibility of non-viral oligonucleotide delivery system for the cell sheets as verified by our study shall hold a general significance for the cell sheets of various cell type and therapeutic purposes. [Copyright &y& Elsevier]

Abstract: Topographical modification at micro- and nanoscale is widely applied to enhance the tissue integration properties of biomaterials, but the underlying molecular mechanism is poorly understood. The biomaterial topography modulates cell functions via mechanotransduction of direct and indirect. We propose that N-cadherin may play a role in the topographically induced indirect mechanotransduction by regulating the β-catenin signaling. For confirmation, the cell functions, N-cadherin expression and β-catenin signaling activation of osteoblasts on titanium (Ti) surfaces with micro- or/and nanotopography are systemically compared with naive and N-cadherin down-regulating MC3T3-E1 cells. We find that the N-cadherin expression is reversely related to the intracellular β-catenin signaling and the N-cadherin/β-catenin signaling is modulated differentially by the micro- and nanotopography. The nanotopography significantly up-regulates the N-cadherin expression leading to lower β-catenin signaling activity and consequently depressed differentiation, whereas the microtopography down-regulates the N-cadherin expression resulting in enhanced β-catenin signaling and thus osteoblast differentiation. Artificial down-regulation of the N-cadherin expression can significantly up-regulate the β-catenin signaling and consequently enhance the osteoblast differentiation on all the Ti surfaces. The study for the first time clarifies the involvement of the N-cadherin/β-catenin interaction in the micro/nanotopography induced indirect mechanotransduction and provides a potentially new approach for biomaterial modification and biofunctionalization by down-regulating the cell N-cadherin expression to achieve improved clinical performance. [Copyright &y& Elsevier]

Abstract: Most commercial dental implants are made of titanium (Ti) because Ti possesses excellent properties such as osseointegration. However, many types of Ti products still suffer from insufficient antibacterial capability and bacterial infection after surgery remains one of the most common and intractable complications. In this study, a dual process encompassing anodization and silver plasma immersion ion implantation (Ag PIII) is utilized to produce titania nanotubes (TiO2-NTs) containing Ag at different sites and depths. The concentration and depth of the incorporated Ag can be tailored readily by changing the PIII parameters. The Ag-embedded TiO2-NTs which retain the nanotubular morphology are capable of sterilizing oral pathogens as opposed to pure Ti plates and pristine TiO2-NTs. Biological assays indicate that the in vitro and in vivo biocompatibility of the sample plasma-implanted at a lower voltage of 0.5 kV (NT-Ag-0.5) is significantly compromised due to the large amount of surface Ag. On the other hand, the sample implanted at 1 kV (NT-Ag-1.0) exhibits unimpaired effects due to the smaller surface Ag accumulation. Sample NT-Ag-1.0 is further demonstrated to possess sustained antibacterial properties due to the large embedded depth of Ag and the technique and resulting materials have large potential in dental implants. [Copyright &y& Elsevier]

Abstract: A versatile strategy to endow biomaterials with long-term antibacterial ability without compromising the cytocompatibility is highly desirable to combat biomaterial related infection. TiO2 nanotube (NT) arrays can significantly enhance the functions of many cell types including osteoblasts thus having promising applications in orthopedics, orthodontics, as well as other biomedical fields. In this study, TiO2 NT arrays with Ag2O nanoparticle embedded in the nanotube wall (NT-Ag2O arrays) are prepared on titanium (Ti) by TiAg magnetron sputtering and anodization. Well-defined NT arrays containing Ag concentrations in a wide range from 0 to 15 at % are formed. Ag incorporation has little influence on the NT diameter, but significantly decreases the tube length. Crystallized Ag2O nanoparticles with diameters ranging from 5 nm to 20 nm are embedded in the amorphous TiO2 nanotube wall and this unique structure leads to controlled release of Ag+ that generates adequate antibacterial activity without showing cytotoxicity. The NT-Ag2O arrays can effectively kill Escherichia coli and Staphylococcus aureus even after immersion for 28 days, demonstrating the long lasting antibacterial ability. Furthermore, the NT-Ag2O arrays have no appreciable influence on the osteoblast viability, proliferation, and differentiation compared to the Ag free TiO2 NT arrays. Ag incorporation even shows some favorable effects on promoting cell spreading. The technique reported here is a versatile approach to develop biomedical coatings with different functions. [Copyright &y& Elsevier]

Abstract: Titanium implants having enhanced osteogenic activity and antibacterial property are highly desirable for the prevention of implant associated infection and promotion of osseointegration. In this study, coatings containing titania nanotubes (NTs) incorporated with zinc (NT-Zn) are produced on Ti implants by anodization and hydrothermal treatment in Zn containing solutions. The amount of incorporated Zn can be adjusted by varying the structural parameters such as the nanotube diameter and length as well as hydrothermal treatment time. The suitable NT-Zn coatings with good intrinsic antibacterial properties can prevent post-operation infection. Excellent osteogenesis inducing ability in the absence of extraneous osteogenic supplements is demonstrated and the ERK1/2 signaling is found to be involved. The NT-Zn structure which is simple, stable, and easy to produce and scale up has immense potential in bone implant applications. [Copyright &y& Elsevier]

The resistance of malignant tumors to multiple drugs is a significant obstacle in cancer treatment and prognosis. Accordingly, we synthesized a celastrol (Cel) prodrug (Cel-CSO) by conjugating chitosan oligosaccharides (CSO) to Cel for reversing Taxol resistance in chemotherapy, followed by self-assembly with Taxol into a novel nanoplatform of Cel-CSO/Taxol nanoparticles (termed NPs). NPs showed a suitable size (about 153 nm), excellent stability and prolonged release of Cel and Taxol in a manner that depended on both pH and time. NPs effectively inhibited the overexpression of multidrug resistance-related protein P-gp, hypoxia inducible factor-1α (HIF-1α), and triggered the MCF-7/Taxol cell apoptosis through inhibiting the PI3K/AKT/NF-κB/HIF-1α pathway. In tumor-bearing mice, NPs exhibited significant curative effects in inducing apoptosis of MCF-7/Taxol tumors which showed a low expression level of P-gp, microtubule-related proteins TUBB3 and Tau. The results indicated that NPs may be a promising strategy to overcome drug resistance caused by P-gp, which improve the antitumor effects in drug-resistant breast cancer., Competing Interests: Declarations. Ethics approval and consent to participate: Approval for the experiments were granted by the Animal Ethics Committee for Experiments at Henan University of Chinese Medicine (NO. DWLL202103173). Consent for publication: NA. Competing interests: The authors report no declarations of interest., (© 2024. Controlled Release Society.)

Current research on the relationship between environmental endocrine disrupting chemicals (EDCs) and breast cancer remains insufficient, with limited evidence and inconsistent conclusions. Mendelian randomization (MR) is a robust method for establishing causality, as it reduces biases from confounding factors and reverse causation. This study uses MR to investigate the effects of three types of EDCs, including bisphenols, parabens, and phthalates, on the risk of overall breast cancer and its subtypes-Luminal A, Luminal B, triple negative, human epidermal growth factor receptor 2-enriched, and estrogen receptor-positive/negative. The study also examines the 1400 blood metabolome as potential mediators and explores EDCs-associated DNA methylation changes as potential factors, with a focus on European populations. Our results shows that n-butyl paraben (n-BuP) is positively associated with Luminal A, mono-methyl phthalate is negatively associated with Luminal B, and mono-iso-butyl phthalate (MiBP) is positively associated with triple negative breast cancer (TNBC). Mediation analysis reveals that blood metabolites, such as caffeic acid sulfate and the caffeine-to-paraxanthine ratio, mediate the effect of n-BuP on Luminal A, while methylsuccinate mediate the effect of MiBP on TNBC. Epigenetic analysis shows associations between EDCs exposure-related DNA methylation changes at specific CpG sites (cg26325335, cg08537847, cg27454300) and different breast cancer risks. These findings not only suggest potential biomarkers for early detection and intervention but also underscore the imperative for further research to rigorously validate these associations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Repairing large bone defects remains a significant clinical challenge. Stem cell is of great importance in bone regeneration, and periosteum is rich in periosteal stem cell, which has a great influence on repairing bone defects. Bioengineered periosteum with excellent biocompatibility and stem cell homing capabilities to promote bone regeneration is of great clinical significance. The E7 peptide (EPLQLKM), which exhibits a specific affinity for mesenchymal stem cells (MSCs), is beneficial for modulating cellular functions. In this study, a unique microporous structured carboxymethyl chitosan/sodium alginate membrane with a proper mass ratio is developed by the addition of Poloxam 407 （P407）, which is then functionalized with the E7 affinitive peptide. This membrane, characterized by its microporous structure and E7 peptide functionalization (CSSA/P/E), not only demonstrated favorable mechanical properties, enhanced hydrophilicity, satisfactory biodegradation profile, and excellent biocompatibility, but also synergistically enhanced MSCs recruitment. It is found to promote the proliferation, spreading, and osteogenic differentiation of MSCs in vitro and to accelerate early periosteal regeneration, bone matrix deposition, and vascularization in vivo, leading to effective regeneration of critical-sized bone defects. Overall, this study presents a robust, cell and growth factor-free strategy for bioengineering periosteum, offering a potential solution for the challenging large size bone defects., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Tumor immunotherapy represents a highly promising modality for the treatment of triple-negative breast cancer (TNBC). Nevertheless, its therapeutic efficacy has been profoundly impacted by challenges such as low drug uptake, hypoxia, and immunosuppression. To address these problems, the study develops a strategy combining sonodynamic therapy (SDT) and immunotherapy using biomimetic nanoparticles coated with hybrid membranes. The nanoparticles are loaded with semiconducting polymers (PFODBT), Atovaquone (ATO), and TMP195 to enhance biocompatibility, targeting ability, and drug uptake and retention at the tumor site. In in vitro experiments, the biomimetic nanoparticles alleviate hypoxia, induce immunogenic cell death (ICD), and prompt reprogramming of tumor-associated macrophages (TAMs) from M2 type to M1 type. In in vivo experiments, the synergistic effects of enhanced SDT-mediated ICD and TAMs repolarization significantly inhibit the proliferation of primary and distant tumor in the 4T1 subcutaneous tumor model, and effectively attenuated metastasis of lung and liver. Moreover, the in vivo immune responses are further activated by improving the maturation of dendritic cells, filtration of CD8 + T cells, and depletion of regulatory T cells. This study offers a novel strategy for TNBC therapy by converting the tumor microenvironment from the "cold" into "hot" tumor through multiple synergistic therapies., (© 2024 Wiley‐VCH GmbH.)

Plectin, a scaffolding protein overexpressed in tumor cells, plays a significant role in hepatocellular carcinoma (HCC) proliferation, invasion, and migration. However, the use of L-type peptides for targeting plectin is hindered by their limited stability and retention. We designed a D-type plectin-targeting peptide ( D PTP) and developed a novel single-photon emission computed tomography (SPECT) probe for HCC imaging. The D PTP targeting ability was evaluated in vitro using flow cytometry and ex vivo fluorescence imaging. 99m Tc radiolabeling was performed using tricine and ethylenediamine- N , N '-diacetic acid (EDDA) as coligands after modification with 6-hydrazino nicotinamide (HYNIC) at the N termini of D PTP. The radiochemical purity (RCP), in vitro stability, and binding affinity of the prepared 99m Tc-HYNIC- D PTP were analyzed. Tumor uptake, metabolic stability, biodistribution, and pharmacokinetics of 99m Tc-HYNIC- D PTP were investigated and compared with those of 99m Tc-labeled L-type PTP ( 99m Tc-HYNIC-PTP) in HCC tumor-bearing mice. D PTP could be efficiently radiolabeled with 99m Tc using the HYNIC/tricine/EDDA system with a high RCP and good in vitro stability. Compared with the L-type PTP, D PTP exhibited improved targeting ability, and 99m Tc-HYNIC- D PTP displayed higher tumor uptake, better metabolic stability, longer blood circulation time, and lower kidney retention, resulting in superior imaging performance and biodistribution in vivo . 99m Tc-HYNIC- D PTP has great potential as a novel SPECT probe for diagnosing HCC.

Purpose: Gold nanoparticles (Au NPs) are widely used as versatile templates to develop multifunctional nanosystems for disease diagnosis and treatment. Iodine can bind to gold via chemisorption, making this a simple method for labeling Au NPs with radioactive iodine. However, the evaluation of tumor radionuclide therapy is insufficient. In this study, we investigated the feasibility of 131 I-adsorbed Au NPs as novel nanoprobes for tumor radionuclide therapy., Materials and Methods: Radiolabeling was performed by mixing Au NPs and 131 I, and the radiochemical purity (RCP) and in vitro stability of 131 I-adsorbed Au NPs were analyzed under different conditions, including various temperatures, pH values, and 131 I concentrations. The tumor accumulation and therapeutic potential of 131 I-adsorbed Au NPs were assessed using a subcutaneous tumor model after intratumoral injection., Results: The data showed that the chemisorption of the Au NPs onto 131 I was instant, specific, and quantitative. The 131 I-adsorbed Au NPs exhibited high in vitro stability in different media, distinct inhibitory effects on tumor cells in vitro, good retention ability, and therapeutic effects after intratumoral injection into tumor-bearing mice in vivo., Conclusion: Our work demonstrates that chemisorption of Au NPs and radioiodine has great potential as a strategy for constructing various nanosystems for theranostic applications., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Zhu et al.)

Therapeutic resistance is an essential challenge for nanotherapeutics. Herein, a narrow bandgap RuI 3 nanoplatform has been constructed firstly to synergize radiotherapy (RT), photothermal therapy (PTT), and thermoelectric dynamic therapy (TEDT) for tumor eradication. Specifically, the photothermal performance of RuI 3 can ablate tumor cells while inducing TEDT. Noteworthy, the thermoelectric effect is found firstly in RuI 3 , which can spontaneously generate an electric field under the temperature gradient, prompting carrier separation and triggering massive ROS generation, thus aggravating oxidative stress level and effectively inhibiting HSP-90 expression. Moreover, RuI 3 greatly enhances X-ray deposition owing to its high X-ray attenuation capacity, resulting in a pronounced computed tomography imaging contrast and DNA damage. In addition, RuI 3 possesses both catalase-like and glutathione peroxidase-like properties, which alleviate tumor hypoxia and reduce antioxidant resistance, further exacerbating 1 O 2 production during RT and TEDT. This integrated therapy platform combining PTT, TEDT, and RT significantly inhibits tumor growth. STATEMENT OF SIGNIFICANCE: RuI 3 nanoparticles were synthesized for the first time. RuI 3 exhibited the highest photothermal properties among iodides, and the photothermal conversion efficiency was 53.38 %. RuI 3 was found to have a thermoelectric effect, and the power factor could be comparable to that of most conventional thermoelectric materials. RuI 3 possessed both catalase-like and glutathione peroxidase-like properties, which contributed to enhancing the effect of radiotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Wilson's disease (WD) is a genetic disorder that primarily leads to the pathological accumulation of copper (Cu) in the liver, causing an abnormal increase in reactive oxygen species (ROS). The prevailing clinical therapy for WD involves lifelong use of Cu chelation drugs to facilitate Cu excretion in patients. However, most available drugs exert severely side-effects due to their non-specific excretion of Cu, unsuitable for long-term use. In this study, we construct a prochelator that enables precise and controlled delivery of Cu chelator drugs to the liver in WD model, circumventing toxic side effects on other organs and normal tissues. This innovative prochelator rapidly releases the chelator and the fluorescent molecule methylene blue (MB) upon activation by ROS highly expressed in the liver of WD. The released chelator coordinates with Cu, efficiently aiding in Cu removal from the body and effectively inhibiting the pathological progression of WD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

This study focused on unravelling the role of PCAT-1 in wound-healing process, particularly its impact on regenerative and osteogenic abilities of mesenchymal stem cells (MSCs). We delved into how PCAT-1 regulates mitochondrial oxidative phosphorylation (OXPHOS) and interacts with pivotal molecular pathways, especially β-catenin and PKM2, using human bone marrow-derived MSCs. MSCs were cultured under specific conditions and PCAT-1 expression was modified through transfection. We thoroughly assessed several critical parameters: MSC proliferation, mitochondrial functionality, ATP production and expression of wound healing and osteogenic differentiation markers. Further, we evaluated alkaline phosphatase (ALP) activity and mineral deposition, essential for bone healing. Our findings revealed that overexpressing PCAT-1 significantly reduced MSC proliferation, hampered mitochondrial performance and lowered ATP levels, suggesting the clear inhibitory effect of PCAT-1 on these vital wound-healing processes. Additionally, PCAT-1 overexpression notably decreased ALP activity and calcium accumulation in MSCs, crucial for effective bone regeneration. This overexpression also led to the reduction in osteogenic marker expression, indicating suppression of osteogenic differentiation, essential in wound-healing scenarios. Moreover, our study uncovered a direct interaction between PCAT-1 and the PKM2/β-catenin pathway, where PCAT-1 overexpression intensified PKM2 activity while inhibiting β-catenin, thereby adversely affecting osteogenesis. This research thus highlights PCAT-1's significant role in impairing wound healing, offering insights into the molecular mechanisms that may guide future therapeutic strategies for enhancing wound repair and bone regeneration., (© 2023 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: 99m Tc radiolabeled nanobody NM-02 ( 99m Tc-NM-02) is a novel single photon emission computed tomography (SPECT) probe with a high affinity and specificity for human epidermal growth factor receptor 2 (HER2). In this study, a clinical imaging trial was conducted to investigate the relationship between 99m Tc-NM-02 uptake and HER2 expression in patients with breast cancer., Methods: Thirty patients with pathologically confirmed breast cancer were recruited and imaged with both 99m Tc-NM-02 SPECT/computed tomography (CT) and 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/CT. According to the treatment conditions before recruitment, patients were divided into two groups, the newly diagnosed group (n = 24) and the treated group (n = 6). The maximal standard uptake value (SUV max ) of 18 F-FDG and SUV max and mean SUV (SUV mean ) of 99m Tc-NM-02 in the lesions were determined to analyze the relationship with HER2 expression., Results: No meaningful relationship was observed between 18 F-FDG uptake and HER2 expression in 30 patients with breast cancer. 99m Tc-NM-02 uptake was positively correlated with HER2 expression in the newly diagnosed group, but no correlation was observed in the treated group. 99m Tc-NM-02 uptake in HER2-positive lesions was lower in those with effective HER2-targeted therapy compared with the newly diagnosed group. 99m Tc-NM-02 SPECT/CT detected brain and bone metastases of breast cancer with a different imaging pattern from 18 F-FDG PET/CT. 99m Tc-NM-02 showed no non-specific uptake in inflamed tissues and revealed intra- and intertumoral HER2 heterogeneity by SPECT/CT imaging in 9 of the 30 patients with breast cancer., Conclusions: 99m Tc-NM-02 SPECT/CT has the potential for visualizing whole-body HER2 overexpression in untreated patients, making it a promising method for HER2 assessment in patients with breast cancer., Trial Registration: NCT04674722, Date of registration: December 19, 2020., (© 2024. The Author(s).)

Computed tomography (CT) is a widely utilized noninvasive diagnostic tool in clinical practice. However, the commonly employed small molecular iodinated contrast agents (ICAs) in clinical CT imaging have limitations such as nonspecific distribution in body, rapid clearance through kidneys, etc., leading to a narrow imaging time window. In contrast, existing nano-sized ICAs face challenges like structural uncertainty, poor reproducibility, low iodine content, and uniformity issues. In this study, a novel approach is presented utilizing the aggregation-induced emission luminogen (AIEgen) to design and fabricate a kind of monocomponent nano-sized ICA (namely, BioDHU-CT NPs) that exhibits a unique aggregation effect upon activation. The small sized BioDHU-CT nanoparticles exhibit excellent tumor targeting capabilities and can release ICA modified with AIEgen with a high release efficiency up to 88.45%, under the activation of reactive oxygen species highly expressed in tumor regions. The released ICA performs in situ aggregation capability in the tumor region, which can enhance the retention efficiency of CT contrast agents, extending the imaging time window and improving the imaging quality in tumor regions., (© 2023 Wiley-VCH GmbH.)

Nanoplatforms with amplified passive tumor targeting and enhanced protein resistance can evade unnecessary uptake by the reticuloendothelial system and achieve high tumor retention for accurate tumor theranostics. To achieve this goal, we here constructed phosphorus core-shell tecto dendrimers (CSTDs) with a rigid aromatic backbone core as a nanoplatform for enhanced fluorescence and single-photon emission computed tomography (SPECT) dual-mode imaging of tumors. In this study, the phosphorus P-G2.5/G3 CSTDs (G denotes generation) were partially conjugated with tetraazacyclododecane tetraacetic acid (DOTA), cyanine5.5 (Cy5.5) and 1,3-propane sulfonate (1,3-PS) and then labeled with 99m Tc. The formed P-G2.5/G3-DOTA-Cy5.5-PS CSTDs possess good monodispersity with a particle size of 10.1 nm and desired protein resistance and cytocompatibility. Strikingly, compared to the counterpart material G3/G3-DOTA-Cy5.5-PS with both the core and shell components being soft poly(amidoamine) dendrimers, the developed P-G2.5/G3-DOTA-Cy5.5-PS complexes allow for more efficient cellular uptake and more significant penetration in 3-dimensional tumor spheroids in vitro , as well as more significant tumor retention and accumulation for enhanced dual-mode fluorescence and SPECT (after labelling with 99m Tc) tumor imaging in vivo . Our studies suggest that the rigidity of the core for the constructed CSTDs matters in the amplification of the tumor enhanced permeability retention (EPR) effect for improved cancer nanomedicine development.

Objective: To describe the use of a large size deepithelized gingival graft (DGG) associated with full-split tunnel technique in a clinical case of advanced gingival recession secondary to surgical failure (GRSF). Clinical Considerations . The presented case report helped to achieve satisfactory root coverage, ideal keratinized tissue gain, improvement in soft tissue quality and esthetics, scar deformity correction, and vestibular depth deepening with a one-step procedure of large size DGG associated with full-split tunnel technique for a condition of deep gingival recessions of 7-11 mm caused by a failed bone implantation surgery., Conclusions: The large size DGG associated with full-split tunnel technique provided a versatile one-step procedure to obtain ideal results for advanced GRSF. Clinical Significance . GRSF that is generally associated with inadequate keratinized tissue and scar formation could be rather difficult to deal with. The large size DGG associated with full-split tunnel technique, as a one-step procedure, provided a predictable and practical treatment modality., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Lingzhou Zhao et al.)

Introduction: Although various therapies have been adopted to treat cancer, metastasis of tumor cells still is a big challenge that compromises therapeutic benefits. Methods: We herein report an injectable drug-loaded hybrid hydrogel that can achieve sonodynamic therapy (SDT) and chemodyanmic therapy (CDT) combined action and suppression of tumor metastasis. This alginate (ALG)-based hydrogel (termed as AMPS) contains manganese dioxide (MnO 2 ) nanoparticles as the CDT agents, an organic polymer as the sonosensitizer, and a SIS3 drug as metastasis inhibitor. Results: AMPS is formed via the chelation of ALG by Ca 2+ in tumor microenvironment, in which MnO 2 nanoparticles mediate CDT via Fenton-like reaction and the organic polymers enable SDT under ultrasound (US) irradiation by generating singlet oxygen ( 1 O 2 ), allowing for combinational action of CDT and SDT. In addition, SIS3 is released from AMPS hydrogels to inhibit the metastasis of tumor cells. As such, the AMPS enables a combinational action of SDT and CDT to greatly inhibit the growths of subcutaneous tumors in living mice and also completely suppress the tumor metastasis in lungs and livers. Conclusion: This study thus offers a hybrid hydrogel platform for combinational therapy and metastasis suppression simultaneously., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2023 Wang, Zhu, Zhou, Zhao, Li and Liu.)

Chemodynamic therapy (CDT) is an emerging treatment strategy for cancer, but the low therapeutic efficacy and potential side effects still limit its applications. In this study, we report a semiconducting polymer nanocatalyst (PGFe) that can generate reactive oxygen species (ROS) only upon near-infrared (NIR) light-activation for photodynamic therapy (PDT)-synergized CDT. Such PGFe consists of a semiconducting polymer as a photosensitizer, iron oxide (Fe 3 O 4 ) nanoparticles as CDT agents, and glucose oxidase (GOx), all of which are loaded into a singlet oxygen ( 1 O 2 )-responsive nanocarrier. Under NIR laser irradiation, PGFe produces 1 O 2 through a photosensitizer-mediated PDT effect, and the produced 1 O 2 destroys the 1 O 2 -responsive nanocarriers, leading to controlled releases of Fe 3 O 4 nanoparticles and GOx. In a tumor microenvironment, GOx catalyzes glucose degradation to form hydrogen peroxide (H 2 O 2 ), and thus the CDT effect of Fe 3 O 4 nanoparticles is greatly improved. As such, an amplified ROS level in tumor cells is obtained by PGFe to induce cell death. PGFe can be utilized to treat subcutaneous 4T1 tumors, observably inhibiting the tumor growth and suppressing lung and liver metastasis. This study thus provides a NIR light-activated ROS generation strategy for precise and effective treatments of tumors.

Objective: Type IV collagen (Col-IV) is a prospective biomarker for diagnosing and treating of unstable thoracic aortic aneurysm and dissection (TAAD). This study aims to evaluate the feasibility of 68 Ga-labeled WVP peptide ( 68 Ga-DOTA-WVP) as a novel Col-IV-targeted probe for TAAD biological diagnosis using PET/CT., Methods: WVP peptide was modified with bifunctional chelator DOTA for 68 Ga radiolabeling. Immunohistochemical staining was used to evaluate the expression and location of Col-IV and elastin in aortas treated with 3-aminopropionitrile fumarate (BAPN) at different time points (0, 2, and 4 weeks). The imaging performance of 68 Ga-DOTA-WVP was investigated using Micro-PET/CT in a BAPN-induced TAAD mouse model. The relationship between 68 Ga-DOTA-WVP uptake in aortic lesions and the serum levels of TAAD-related biomarkers including D-dimer, C-reactive protein (CRP), and serum soluble suppression of tumorigenicity-2 (sST2) was also analyzed., Results: 68 Ga-DOTA-WVP was readily prepared with high radiochemical purity and stability in vitro . 68 Ga-DOTA-WVP Micro-PET/CT could detect Col-IV exposure of unstable aneurysms and early dissection in BAPN-induced TAAD mice, but little 68 Ga-DOTA-WVP uptake was shown in the control group at each imaging time point. The differences of Col-IV expression and distribution of 68 Ga-DOTA-WVP both in TAAD and control groups further verified the imaging efficiency of 68 Ga-DOTA-WVP PET/CT. Additionally, a higher sST2 level was found in the imaging positive ( n  = 14) than the negative ( n  = 8) group (9.60 ± 1.14 vs. 8.44 ± 0.52, P  = 0.014)., Conclusion: 68 Ga-DOTA-WVP could trace the exposure and abnormal deposition of Col-IV in enlarged and early injured aortas, showing a potential for biological diagnosis, whole-body screening, and progression monitoring of TAAD., Competing Interests: Author HZ is employed by Cellomics (Shenzhen) Co., Ltd and PH is employed by Xiangpeng Youkang (Beijing) Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Lu, Zhu, Zhao, Qi, Zou, He, Zhou, Shi and Du.)

Purpose: Compared with PET/CT or PET/MRI, SPECT/CT is cheaper and more readily accessible. This study was designed to investigate the efficacy of 99m Tc-HYNIC-PSMA SPECT/CT in detecting primary tumors and metastases in patients with newly diagnosed prostate cancer (PCa)., Methods: A retrospective analysis of 31 patients with pathologically proven PCa was performed at Shanghai General Hospital from November 2020 to November 2021. Planar whole-body imaging was performed on all patients with a SPECT/CT scan of PSMA-positive regions 3-4 h after intravenous injection of 740 MBq 99m Tc-HYNIC-PSMA. Positive PSMA uptake lesions were evaluated, and SUVmean and SUVmax were measured in each lesion. Associations between SPECT/CT parameters and clinicopathologic factors (tPSA and Gleason Score) were analyzed. The diagnostic capability of SPECT/CT parameters, tPSA, and GS in distant metastatic detection was evaluated by logistic regression., Results: The SUVmean and SUVmax of the high-risk stratification subgroups (tPSA>20 ng/ml, GS ≥8, and tPSA >20 ng/ml and GS≥8) were higher than those of the low-moderate risk stratification subgroups, with sensitivities of 92% and 92%, respectively. Neither SPECT/CT parameters (SUVmean, SUVmax) nor clinicopathologic factors (tPSA, GS) had high sensitivity (80%, 90%, 80%, and 90%, respectively, P <0.05) in distant metastatic prediction. For both the guideline tPSA level (20 ng/ml) and the cut-off level (84.3 ng/ml), the difference in the distant metastasis detection rate between the low predicted tPSA group and the high predicted tPSA group was statistically significant (0% vs . 47.62%, P = 0.005; 9.09% vs . 88.89%, P = 0.000, respectively). Twenty patients with pathological 99mTc-PSMA avid only in the prostate beds underwent radical prostatectomy. Seven of them underwent lymph node dissection, a total of 35 lymph nodes were removed, and no lymph nodes were detected with metastasis, which was consistent with 99m Tc-HYNIC-PSMA SPECT/CT., Conclusion: 99m Tc-HYNIC-PSMA SPECT/CT is effective in the risk stratification and distant metastasis detection of primary PCa patients. It is of great value in guiding treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Zhao, Qiao, Sun, Zhao and Xing.)