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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.
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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.
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Therapeutic resistance is an essential challenge for nanotherapeutics. Herein, a narrow bandgap RuI3 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 RuI3 can ablate tumor cells while inducing TEDT. Noteworthy, the thermoelectric effect is found firstly in RuI3, 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, RuI3 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, RuI3 possesses both catalase-like and glutathione peroxidase-like properties, which alleviate tumor hypoxia and reduce antioxidant resistance, further exacerbating 1O2 production during RT and TEDT. This integrated therapy platform combining PTT, TEDT, and RT significantly inhibits tumor growth. STATEMENT OF SIGNIFICANCE: RuI3 nanoparticles were synthesized for the first time. RuI3 exhibited the highest photothermal properties among iodides, and the photothermal conversion efficiency was 53.38 %. RuI3 was found to have a thermoelectric effect, and the power factor could be comparable to that of most conventional thermoelectric materials. RuI3 possessed both catalase-like and glutathione peroxidase-like properties, which contributed to enhancing the effect of radiotherapy.
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Terapia Fototérmica , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/terapia , Neoplasias/patologia , Camundongos Nus , Terapia Combinada , Hipertermia Induzida , Radioterapia/métodos , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: 99mTc radiolabeled nanobody NM-02 (99mTc-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 99mTc-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 99mTc-NM-02 SPECT/computed tomography (CT) and 18F-fluorodeoxyglucose (18F-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 (SUVmax) of 18F-FDG and SUVmax and mean SUV (SUVmean) of 99mTc-NM-02 in the lesions were determined to analyze the relationship with HER2 expression. RESULTS: No meaningful relationship was observed between 18F-FDG uptake and HER2 expression in 30 patients with breast cancer. 99mTc-NM-02 uptake was positively correlated with HER2 expression in the newly diagnosed group, but no correlation was observed in the treated group. 99mTc-NM-02 uptake in HER2-positive lesions was lower in those with effective HER2-targeted therapy compared with the newly diagnosed group. 99mTc-NM-02 SPECT/CT detected brain and bone metastases of breast cancer with a different imaging pattern from 18F-FDG PET/CT. 99mTc-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: 99mTc-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.
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Neoplasias Ósseas , Neoplasias da Mama , Receptor ErbB-2 , Feminino , Humanos , Neoplasias Ósseas/secundário , Neoplasias da Mama/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Anticorpos de Domínio ÚnicoRESUMO
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.
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Degeneração Hepatolenticular , Humanos , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/genética , Degeneração Hepatolenticular/patologia , Quelantes/farmacologia , Quelantes/uso terapêutico , Espécies Reativas de Oxigênio , CobreRESUMO
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.
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Nanopartículas , Neoplasias , Humanos , Meios de Contraste/química , Reprodutibilidade dos Testes , Neoplasias/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Nanopartículas/químicaRESUMO
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 ß-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/ß-catenin pathway, where PCAT-1 overexpression intensified PKM2 activity while inhibiting ß-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.
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Doenças Mitocondriais , beta Catenina , Humanos , beta Catenina/metabolismo , beta Catenina/farmacologia , Osteogênese/fisiologia , Cicatrização , Células da Medula Óssea/metabolismo , Trifosfato de Adenosina/farmacologia , Diferenciação Celular/fisiologia , Células CultivadasRESUMO
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 (MnO2) 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 Ca2+ in tumor microenvironment, in which MnO2 nanoparticles mediate CDT via Fenton-like reaction and the organic polymers enable SDT under ultrasound (US) irradiation by generating singlet oxygen (1O2), 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.
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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 99mTc. 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 99mTc) 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.
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Dendrímeros , Neoplasias , Humanos , Tomografia Computadorizada de Emissão de Fóton Único , Linhagem Celular TumoralRESUMO
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.
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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 (Fe3O4) nanoparticles as CDT agents, and glucose oxidase (GOx), all of which are loaded into a singlet oxygen (1O2)-responsive nanocarrier. Under NIR laser irradiation, PGFe produces 1O2 through a photosensitizer-mediated PDT effect, and the produced 1O2 destroys the 1O2-responsive nanocarriers, leading to controlled releases of Fe3O4 nanoparticles and GOx. In a tumor microenvironment, GOx catalyzes glucose degradation to form hydrogen peroxide (H2O2), and thus the CDT effect of Fe3O4 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.
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Peróxido de Hidrogênio , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio , Raios Infravermelhos , Glucose Oxidase , PolímerosRESUMO
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 (IC50: 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 IC50 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 (T1/2 = 7.62 h) than that of stachydrine (T1/2 ≈ 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.
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Antineoplásicos , Neoplasias , Ratos , Animais , Camundongos , Linhagem Celular Tumoral , Fase G1 , Ciclo Celular , Prolina/farmacologia , Apoptose , Proliferação de Células , Antineoplásicos/farmacologiaRESUMO
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 99mTc-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 99mTc-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 99mTc-HYNIC-PSMA SPECT/CT. Conclusion: 99mTc-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.
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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 68Ga-labeled WVP peptide (68Ga-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 68Ga 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 68Ga-DOTA-WVP was investigated using Micro-PET/CT in a BAPN-induced TAAD mouse model. The relationship between 68Ga-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: 68Ga-DOTA-WVP was readily prepared with high radiochemical purity and stability in vitro. 68Ga-DOTA-WVP Micro-PET/CT could detect Col-IV exposure of unstable aneurysms and early dissection in BAPN-induced TAAD mice, but little 68Ga-DOTA-WVP uptake was shown in the control group at each imaging time point. The differences of Col-IV expression and distribution of 68Ga-DOTA-WVP both in TAAD and control groups further verified the imaging efficiency of 68Ga-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: 68Ga-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.
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Purpose: The unique structure of nanobodies is advantageous for the development of radiopharmaceuticals for nuclear medicine. Nanobodies targeted to human epidermal growth factor receptor 2 (HER2) can be used as tools for the imaging and therapy of HER2-overexpressing tumors. In this study, we aimed to describe the generation of a 131I-labeled anti-HER2 nanobody as a targeted radionuclide therapy (TRNT) agent for HER2-positive breast cancer. Methods: The anti-HER2 nanobody NM-02 was labeled with 131I using the iodogen method, and its radiochemical purity and stability in vitro were assessed. The pharmacokinetic profile of 131I-NM-02 was investigated in normal mice. Tumor accumulation, biodistribution, and therapeutic potential of 131I-NM-02 were evaluated in HER2-positive SKBR3 xenografts; HER2-negative MB-MDA-231 xenografts were used as the control group. Results: 131I-NM-02 could be readily prepared with satisfactory radiochemical purity and stability in vitro. Apparent tumor uptake was observed in HER2-positive tumor-bearing mice with rapid blood clearance and favorable biodistribution. 131I-NM-02 could significantly inhibit tumor growth and extend the life of these mice with good organ compatibility. Negligible tumor accumulation and inhibitory effects of 131I-NM-02 were observed in the negative control group. Conclusion: 131I-NM-02 has the potential to be explored as a novel tool for TRNT of HER2-positive breast cancer.
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Neoplasias da Mama , Anticorpos de Domínio Único , Camundongos , Humanos , Animais , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Neoplasias da Mama/metabolismo , Anticorpos de Domínio Único/química , Distribuição Tecidual , Receptor ErbB-2/metabolismo , Radioisótopos do Iodo , Compostos Radiofarmacêuticos/farmacocinética , Linhagem Celular TumoralRESUMO
With the aging of population and the rapid improvement of public health and medical level in recent years, people have had an increasing demand for orthopedic implants. However, premature implant failure and postoperative complications frequently occur due to implant-related infections, which not only increase the social and economic burden, but also greatly affect the patient's quality of life, finally restraining the clinical use of orthopedic implants. Antibacterial coatings, as an effective strategy to solve the above problems, have been extensively studied and motivated the development of novel strategies to optimize the implant. In this paper, a variety of antibacterial coatings recently developed for orthopedic implants were briefly reviewed, with the focus on the synergistic multi-mechanism antibacterial coatings, multi-functional antibacterial coatings, and smart antibacterial coatings that are more potential for clinical use, thereby providing theoretical references for further fabrication of novel and high-performance coatings satisfying the complex clinical needs.
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In recent years, porous titanium (Ti) scaffolds with BaTiO3 coatings have been designed to promote bone regeneration. However, the phase transitions of BaTiO3 have been understudied, and their coatings have yielded low effective piezoelectric coefficients (EPCs < 1 pm/V). In addition, piezoelectric nanomaterials bring many advantages in eliciting cell-specific responses. However, no study has attempted to design a nanostructured BaTiO3 coating with high EPCs. Herein, nanoparticulate tetragonal phase BaTiO3 coatings with cube-like nanoparticles but different effective piezoelectric coefficients were fabricated via anodization combining two hydrothermal processes. The effects of nanostructure-mediated piezoelectricity on the spreading, proliferation, and osteogenic differentiation of human jaw bone marrow mesenchymal stem cells (hJBMSCs) were explored. We found that the nanostructured tetragonal BaTiO3 coatings exhibited good biocompatibility and an EPC-dependent inhibitory effect on hJBMSC proliferation. The nanostructured tetragonal BaTiO3 coatings of relatively smaller EPCs (<10 pm/V) exhibited hJBMSC elongation and reorientation, broad lamellipodia extension, strong intercellular connection and osteogenic differentiation enhancement. Overall, the improved hJBMSC characteristics make the nanostructured tetragonal BaTiO3 coatings promising for application on implant surfaces to promote osseointegration.
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Células-Tronco Mesenquimais , Nanoestruturas , Humanos , Osteogênese , Titânio/química , Diferenciação Celular , Nanoestruturas/químicaRESUMO
Liposome is a conventional drug delivery system which has been widely used in the pharmacy field. However, its applications are greatly restricted in clinical practice by the disadvantages of cholesterol and nonselective distribution. Herein, a novel platform for anti-tumor drug delivery was developed by incorporating an amphiphilic stachydrine-octadecane conjugate (SS) as the mitochondria-targeting molecule onto the triptolide-liposome surfaces (SS-TP LPs). The polyethylene glycol (PEG) and the suitable particle size (about 133 nm) of liposomes facilitated their stabilities, the long half-life in blood and the escape from the rapid elimination. The SS-TP LPs were internalized and accumulated into the mitochondria of cancer cells in a time-dependent manner, followed by triggering permeabilization of the mitochondrial outer membrane by inhibiting Bcl-2, and then further caused greater cancer cell death via releasing cytochrome C and initiating a cascade of caspase 3 reactions. In the Pan02 tumor-bearing mice, the SS-TP LPs showed significant efficacy in inhibiting tumor growth and reducing tumor size but synchronously exhibited specific mitochondria-targeting and much lower subacute toxicity compared with the free TP and TP LPs. Our study suggests that SS-TP LPs can be a promising anticancer drug delivery system for mitochondria-targeted therapy in pancreatic cancer.
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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with a high mortality rate. One of the main reasons for this poor prognosis is the failure of a specific diagnosis. As a tumor-homing and penetrating peptide, iRGD has not only the properties of binding to neuropilin-1 and integrin αvß3 but also internalizing into TNBC cells. In this study, we designed and prepared 99mTc-labeled iRGD (99mTc-HYNIC-iRGD) as a single-positron emission computed tomography (SPECT) imaging probe and investigated its feasibility for the targeted diagnosis of TNBC. The results showed that the iRGD peptide had acceptable biocompatibility within the studied concentration range and could specifically bind to TNBC cells in vitro. The 99mTc-HYNIC-iRGD was readily prepared with high radiochemical purity and stability. SPECT imaging of 99mTc-HYNIC-iRGD in a TNBC tumor-bearing mouse model showed obvious tumor accumulation with rapid blood clearance and favorable biodistribution. Our findings indicate that this active-targeted strategy has great potential to be developed as a novel tool for TNBC imaging.
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Peri-implant epithelial sealing is the first line of defense against external pathogens or stimuli; hence, an essential process to prevent peri-implantitis. Laminin 332 (LN332) is the main component of the internal basal lamina and participates in peri-implant epithelial sealing by forming hemidesmosomes (HDs) with integrin α6ß4. In this work, poly (D, L-lactide) (PDLLA)-LN332 composite coating was successfully constructed by a method similar to layer-by-layer assembly, displaying staged LN332 release for as long as 28 days. The PDLLA-LN332 composite coating can activate the intracellular PI3K-Akt pathway via binding to cellular integrin α6ß4, which can promote adhesion, migration and proliferation of HaCaT cells and further enhance the expression of keratinocyte HD-related molecules, including integrin α6ß4, LN332 and plectin. Furthermore, the PDLLA-LN332 composite coating can promote the adhesion, spreading and proliferation of gingival mesenchymal stem cells and accelerate their epithelial differentiation. Therefore, the PDLLA-LN332 composite coating can enhance implant soft tissue sealing, warranting further in vivo study.