Translational Selenium Nanoparticles to Attenuate Allergic Dermatitis through Nrf2-Keap1-Driven Activation of Selenoproteins.

Easy recurrence and strong treatment side effects significantly limit the clinical treatment of allergic dermatitis. The human trace element selenium (Se) plays essential roles in redox regulation through incorporation into selenoproteins in the form of 21st necessary amino acid selenocysteine, to participates in the pathogenesis and intervention of chronic inflammatory diseases. Therefore, based on the safe and elemental properties of Se, we construct a facile-synthesis strategy for antiallergic selenium nanoparticles (LET-SeNPs), and scale up the production by employing a spray drying method with lactose (Lac-LET-SeNPs) or maltodextrin (Mal-LET-SeNPs) as encapsulation agents realizing larger scale production and a longer storage time. As expected, these as-prepared LET-SeNPs could effectively activate the Nrf2-Keap1 signaling pathway to enhance the expression of antioxidative selenoprotein at mRNA and protein levels, then inhibit mast cell activation to achieve efficient antiallergic activity. Interestingly, LET-SeNPs undergo metabolism to seleno-amino acids to promote biosynthesis of selenoproteins, which could suppress ROS-induced cyclooxygenase-2 (COX-2) and MAPKs activation to suppress the release of histamine and inflammatory cytokines. Allergic mouse and Macaca fascicularis models further confirm that LET-SeNPs could increase the Se content and selenoprotein expression in the skin, decrease mast cells activation and inflammatory cells infiltration, and finally exhibit the high therapeutic effects on allergic dermatitis. Taken together, this study not only constructs facile large-scale synthesis of translational Se nanomedicine to break through the bottleneck problem of nanomaterials but also sheds light on its application in the intervention and treatment of allergies.

Metabolic Reprogramming of NK Cells by Black Phosphorus Quantum Dots Potentiates Cancer Immunotherapy.

Low persistence, metabolic dysfunction in microenvironment, and tumor-derived immunosuppression of Natural killer (NK) cells in patients are greatly limited the successful clinical application of NK cell-based cancer immunotherapy. Interestingly, herein that human serum albumin-encapsulated black phosphorus quantum dots (BPQDs@HSA) can effectively augment antitumor efficacy of clinical patients-derived NK cell immunotherapy is found. As the donor of phosphate group, BPQDs@HSA binds with the protein of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1A) and activates the downstream PI3K-Akt and mTOR signaling pathways to reprogram cell metabolism of glycolysis and further promote the oxidative phosphorylation, sequentially maintains the cell viability and immunity of NK cells. And multiomics analysis is therefore conducted to reveal the underlying immunoregulation mechanisms, and that BPQDs@HSA can interact with the Toll-like receptor (TLR) on the NK cell surface and increase the expression level of mTOR, and thus activate downstream NF-κB signalling pathways to regulate cytokine secretion and enhance immune tumoricidal is found. BPQDs@HSA can also enhance immune surveillance, relieve immune suppression, and inhibit tumor immune escape. Collectively, this study not only demonstrates a successful strategy for nanomedicine-potentiated immune-cancer therapy, but also sheds light on the understanding of interface between nanomedicine and immune cells activation.

Reversing breast cancer bone metastasis by metal organic framework-capped nanotherapeutics via suppressing osteoclastogenesis.

Bone metastasis is the major cause of cancer-related morbidity and mortality. To avoid further osteolysis, current treatment ideas focus on tumor cell and the inhibition of osteoclast. Herein, zeolitic imidazolate framework-8-capped Cu2-XSe composite nanoplatform (ICG@Cu2-XSe-ZIF-8) is developed for chemodynamic therapy (CDT) and photothermal therapy (PTT) treatment of malignant breast cancer bone tumors. The rational design of ZIF-8 encapsulation greatly reduces the accumulation of Cu2-XSe to damage the normal cells. Under acidic microenvironment in tumor, ZIF-8 is cleaved to release Cu2-XSe, which can subsequently degrade into Cu (+) and Cu (2+) ions to initiate a Fenton-like reaction inducing CDT. Meanwhile, Cu2-XSe is used to be an effective photothermal transduction agent for exerting the PTT effect. What's more, the selenium element in Cu2-XSe can regulates selenoprotein to inhibit tumor cells and osteoclasts. Of note, the hyperthermia induced by PTT can further enhance the CDT effect in tumor, achieving a synergistic PTT/CDT effect. Based on these advantages, ICG@Cu2-XSe-ZIF-8 effectively suppresses the tumor cells in bone tissue, and reduces the erosion of bone tissue via suppressing osteoclastogenesis. In conclusion, this study demonstrates the potential action mechanism of ZIF-8-capped nanomedicine against osteolysis in bone metastasis.

Selenium-driven enhancement of synergistic cancer chemo-/radiotherapy by targeting nanotherapeutics.

To overcome drug resistance in hypoxic tumors and the limitations of radiation impedance and radiation dose, we developed a nano-radiosensitizer to improve the efficacy of cancer radiotherapy. We used multifunctional mesoporous silica nanoparticles (MSNs) as the carriers for a novel anticancer selenadiazole derivative (SeD) and modified its surface with folic acid (FA) to enhance its cervical cancer-targeting effects, forming the nanosystem named SeD@MSNs-FA. Upon radiation, SeD@MSNs-FA inhibits the growth of cervical cancer cells by inducing apoptosis through the death receptor-mediated apoptosis pathway and S phase arrest, significantly improving the sensitivity of cervical cancer cells to X-ray radiation. The combined activity of SeD@MSN-FA and radiation can promote excessive production of intracellular reactive oxygen species (ROS) and induce cell apoptosis by affecting p53, protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) pathways. Furthermore, SeD@MSNs-FA can effectively inhibit tumor growth of xenografted HeLa tumors in nude mice. The toxicity analysis of SeD@MSNs-FA nanoparticles in vivo and the histological analysis performed in the mouse model showed that under the current experimental conditions, the nanoparticles induced no significant damage to the heart, liver, spleen, lungs, kidneys, or other major organs. Taken together, this study provides a translational nanomedicine-based strategy for the simultaneous chemo- and radiotherapy of cervical cancer and sheds light on potential mechanisms that can be used to overcome radiotherapeutic resistance.

Rapid visualizing and pathological grading of bladder tumor tissues by simple nanodiagnostics.

Developing a tissue diagnosis technology to avoid the complicated processes and the usage of expensive reagents while achieving rapid pathological grading diagnosis to provide a better strategy for clinical treatment is an important strategy of tumor diagnose. Herein, we selected the integrin αvß3 as target based on the analysis of clinical data, and then designed a stable and cancer-targeted selenium nanosystem (RGD@SeNPs) by using RGD polypeptide as the targeting modifier. In vitro experiments showed that RGD@SeNPs could specifically recognized tumor cells, especially in co-culture cells model. The RGD@SeNPs can be used for clinical samples staining without the use of primary and secondary antibody. Fluorescence difference of the tissue specimens staining with RGD@SeNPs could be used to distinguish normal tissues and tumor tissues or estimate different pathological grades of cancer at tissue level. 132 clinical tumor specimens with three types of tumor and 76 non-tumor specimens were examined which verified that the nanoparticles could specific and sensitive distinguish tumor tissue from normal tissue with a specificity of 92% and sensitivity of 96%. These results demonstrate the potential of cancer-targeted RGD@SeNPs as translational nanodiagnostics for rapid visualizing and pathological grading of bladder tumor tissues in clinical specimens.

Radiosensitive core/satellite ternary heteronanostructure for multimodal imaging-guided synergistic cancer radiotherapy.

Developing safe, effective and targeting radiosensitizers with clear action mechanisms to achieve synergistic localized cancer treatment is an important strategy for radiotherapy. Herein, we design and synthesize a ternary heteronanostructure radiosensitizer (SeAuFe-EpC) with core/satellite morphology by a simple method to realize multimodal imaging-guided cancer radiotherapy. The mechanistic studies reveal that Se incorporation could drastically improve the electrical conductivity and lower the energy barrier between the three components, resulting in more electrons transfer between Se-Au interface and migration over the heterogeneous junction of Au-Fe3O4 NPs interface. This synergistic interaction enhanced the energy transfer and facilitated more excited excitons generated by SeAuFe-EpC NPs, thus promoting the transformation of 3O2 to 1O2via resonance energy transfer, finally resulting in irreversible cancer cell apoptosis. Additionally, based on the X-ray attenuation ability and high NIR absorption of AuNPs and the superparamagnetism of Fe3O4, in vivo computer tomography, photoacoustic and magnetic resonance tri-modal imaging have been employed to visualize the tracking and targeting ability of the NPs. As expected, the NPs specifically accumulated in orthotopic breast tumor area and achieved synergistic anticancer efficacy, but showed no toxic side effects on main organs. Collectively, this study sheds light on the potential roles of core/satellite heteronanostructure in imaging-guided cancer radiotherapy.

Construction of Urokinase-Type Plasminogen Activator Receptor-Targeted Heterostructures for Efficient Photothermal Chemotherapy against Cervical Cancer To Achieve Simultaneous Anticancer and Antiangiogenesis.

Rational design and construction of theranostic nanomedicines based on clinical characteristics of cervical cancer is an important strategy to achieve precise cancer therapy. Herein, we fabricate a cervical cancer-targeting gold nanorod-mesoporous silica heterostructure for codelivery of synergistic cisplatin and antiangiogenic drug Avastin (cisplatin-AuNRs@SiO2-Avastin@PEI/AE105) to achieve synergistic chemophotothermal therapy. Based on database analysis and clinical sample staining, conjugation of the AE105-targeting peptide obviously improves the intracellular uptake of the nanosystem and enhances the cancer-killing ability and selectivity between cervical cancer and normal cells. It could also be used to specifically monitor the urokinase-type plasminogen activator receptor (uPAR) expression level in clinical cervical specimens, which would be an early indicator of prognosis in cancer treatment. Under 808 nm laser irradiation, the nanosystem demonstrates smart NIR-light-triggered drug release and prominent photodynamic activity via induction of reactive oxygen species overproduction-mediated cell apoptosis. The nanosystem also simultaneously suppresses HeLa tumor growth and angiogenesis in vivo, with no evident histological damage observed in the major organs. In short, this study not only provides a clinical data-based rational design strategy of smart nanomedicine for precise treatment and rapid clinical diagnosis of cervical cancer but also contributes to the development of the clinical translation of nanomedicines.

Facile Nanolization Strategy for Therapeutic Ganoderma Lucidum Spore Oil to Achieve Enhanced Protection against Radiation-Induced Heart Disease.

Radiotherapy (RT) has been extensively utilized for clinical cancer therapy, however, excessive generation of reactive oxygen species (ROS) is becoming a main cause for radiation-induced heart disease (RIHD). Ganoderma lucidum spore oil (GLSO) is a popular functional food composite with potent antioxidant activity, but it is compromised by poor solubility and stability for further application. Therefore, a strategy for rational fabrication of GLSO@P188/PEG400 nanosystem (NS) is demonstrated in this study to realize good water solubility and achieve enhanced protection against RIHD. As expected, GLSO@P188/PEG400 NS can attenuate X-ray-induced excessive ROS levels thanks to its enhanced free radical scavenging capability, simultaneously protecting on mitochondria from X-ray irradiation (IR). Moreover, GLSO@P188/PEG400 NS alleviates DNA damage and promotes self-repair processes against IR, thus recovering G0/G1 proportion back to normal levels. Furthermore, pre- and post-treated GLSO@P188/PEG400 NS demonstrates potential protection on heart from X-rays in vivo, as evidenced by attenuating cardiac dysfunction and myocardial fibrosis. Meanwhile, the cell antioxidant capacity (including T-SOD, MDA, and GSH-x) stays in balance during this process. This study not only provides a promising strategy for facile nanolization of functional food composites with hydrophobic defects but also sheds light on their cardiac protection and action mechanisms against IR-induced disease.

Development and Characterization of a Preclinical Model for the Evaluation of CD205-Mediated Antigen Delivery Therapeutics in Type 1 Diabetes.

Dendritic cells (DCs) are crucial for the production of adaptive immune responses to disease-causing microbes. However, in the steady state (i.e., in the absence of an infection or when Ags are experimentally delivered without a DC-activating adjuvant), DCs present Ags to T cells in a tolerogenic manner and are important for the establishment of peripheral tolerance. Delivery of islet Ags to DCs using Ag-linked Abs to the DC endocytic receptor CD205 has shown promise in the NOD mouse model of type 1 diabetes (T1D). It is important to note, however, that all myeloid DCs express CD205 in humans, whereas in mice, only one of the classical DC subsets does (classical DC1; CD8α+ in spleen). Thus, the evaluation of CD205-targeted treatments in mice will likely not accurately predict the results observed in humans. To overcome this challenge, we have developed and characterized a novel NOD mouse model in which all myeloid DCs transgenically express human CD205 (hCD205). This NOD.hCD205 strain displays a similar T1D incidence profile to standard NOD mice. The presence of the transgene does not alter DC development, phenotype, or function. Importantly, the DCs are able to process and present Ags delivered via hCD205. Because Ags taken up via hCD205 can be presented on both class I and class II MHC, both CD4+ and CD8+ T cells can be modulated. As both T cell subsets are important for T1D pathogenesis, NOD.hCD205 mice represent a unique, patient-relevant tool for the development and optimization of DC-directed T1D therapies.

Designing multifunctionalized selenium nanoparticles to reverse oxidative stress-induced spinal cord injury by attenuating ROS overproduction and mitochondria dysfunction.

Spinal cord injury (SCI) remains a challenging clinical problem worldwide, due to the lack of effective drugs for precise treatment. Among the complex pathophysiological events following SCI, reactive oxygen species (ROS) overproduction plays a particularly significant role. As therapeutic agents for neurological diseases, tetramethylpyrazine (TMP) and monosialotetrahexosylganglioside (GM1) have been widely used in the clinical treatment of SCI. Our previous studies have reported that functionalized selenium nanoparticles (SeNPs) exhibit excellent antioxidant activity against oxidative stress-related diseases. Therefore, in this study, novel multifunctionalized SeNPs decorated with polysaccharide-protein complex (PTW)/PG-6 peptide and loaded with TMP/GM1 were rationally designed and synthesized, which exhibited a satisfactory size distribution and superior stability. Furthermore, the protective effects of SeNPs@GM1/TMP on PC12 cells against tert-butyl hydroperoxide (t-BOOH)-induced cytotoxicity and the underlying mechanisms were also explored. Flow cytometric analysis indicated that SeNPs@GM1/TMP showed strongly protective effects against t-BOOH-induced G2/M phase arrest and apoptosis. Moreover, we found that SeNPs@GM1/TMP could attenuate ROS overproduction to prevent mitochondria dysfunction via inhibiting the activation of p53 and MAPK pathways. Effects of SeNPs@GM1/TMP on functional recovery after SCI were evaluated by the Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test, and footprint analysis. The results of hematoxylin-eosin staining and Nissl staining also showed that SeNPs@GM1/TMP provided a neuroprotective effect in SCI rats. This finding suggests that SeNPs@GM1/TMP could be further developed as a promising nanomedicine for efficient SCI treatment.

Autophagy is an important action mode for functionalized selenium nanoparticles to exhibit anti-colorectal cancer activity.

Selenium nanoparticles (SeNPs) have attracted much interest as potential anticancer nanodrugs. Our previous studies also demonstrated that SeNPs could be developed as carriers of clinically used anticancer drugs to achieve synergistic efficacy. Here, we describe the synthesis of Pleurotus tuber-regium (PTR)-conjugated SeNPs (PTR-SeNPs) and their application in the treatment of colorectal cancer (CRC), which is one of the principal causes of cancer morbidity and mortality in the world. PTR-SeNPs were absorbed by cancer cells via clathrin-mediated endocytosis into lysosomes and caveolae-mediated endocytosis into the Golgi apparatus. Internalized PTR-SeNPs trigger intracellular dose- and time-dependent G2/M phase arrest and apoptosis. Moreover, as shown by using a pEGFP-LC3 plasmid transfection model, PTR-SeNPs activate autophagy to promote the death of cancer cells via upregulation of beclin 1-related signaling pathways. In summary, this study demonstrates the high efficacy of functionalized SeNPs for therapy of colorectal cancer and reveals the important role of autophagy in promoting apoptosis and cell cycle arrest to induce cell death.

Stable black phosphorus/Bi2O3 heterostructures for synergistic cancer radiotherapy.

X-ray induced photodynamic therapy (X-ray-PDT) is a promising approach for synergistic cancer radiotherapy and development of suitable radiosensitizers is highly desired. In this paper, we propose black phosphorus/Bi2O3 (BP/Bi2O3) heterostructures as efficient and biocompatible radiosensitizers for synergistic cancer radiotherapy. The heterostructures are synthesized by growth of ultrasmall Bi2O3 nanoparticles onto BP nanosheets. The Bi2O3 decoration inhibits the rapid degradation of BP nanosheets by occupation of the defect sites, and the synergistic effects of BP and Bi2O3 enable 1O2 overproduction under X-ray irradiation. This X-ray-PDT effect of the BP/Bi2O3 nanosheets enhances the radiotherapy activity towards cancer cells by inducing cell apoptosis and cycle arrest. In vivo treatment of melanoma conducted on a clinical radiotherapeutic instrument demonstrates that the BP/Bi2O3 sensitized radiotherapy inhibits tumor growth efficiently. Furthermore, the BP/Bi2O3 nanosheets composed of biological friendly P, O, and Bi elements shows good biocompatibility in vitro and in vivo. This radiosensitizer thus has immense clinical potential for cancer therapy, and our findings reveal a general strategy to fabricate stable BP-based heterostructures for different applications.

Cancer-Targeted Selenium Nanoparticles Sensitize Cancer Cells to Continuous γ Radiation to Achieve Synergetic Chemo-Radiotherapy.

Cancer radiotherapy with 125 I seeds demonstrates higher long-term efficacy and fewer side effects than traditional X-ray radiotherapy owing to its low-dose and continuous radiation but is still limited by radioresistance in clinical applications. Therefore, the design and synthesis of sensitizers that could enhance the sensitivity of cancer cells to 125 I seeds is of great importance for future radiotherapy. Selenium nanoparticles (SeNPs) have been found to exhibit high potential in cancer chemotherapy and as drug carriers. In this study, we found that, based on the Auger-electron effect and Compton effect of Se atoms, cancer-targeted SeNPs in combination with 125 I seeds achieve synergetic effects to inhibit cancer-cell growth and colony formation through the induction of cell apoptosis and cell cycle arrest. Detailed studies on the action mechanisms reveal that the combined treatments effectively activate intracellular reactive oxygen species (ROS) overproduction to regulate p53-mediated DNA damage apoptotic signaling pathways and mitogen-activated protein kinase (MAPK) phosphorylation and to prevent the self-repair of cancer cells simultaneously. Taken together, the combination of SeNPs with 125 I seeds could be further exploited as a safe and effective strategy for next-generation cancer chemo-radiotherapy in clinical applications.

Functionalized Selenium Nanosystem as Radiation Sensitizer of 125I Seeds for Precise Cancer Therapy.

Although radiotherapy has been extensively applied in cancer treatment, external beam radiation therapy is still unable to avoid damage to adjacent normal tissues in the process of delivering a sufficient radiation dose to the tumor sites of patients. To overcome this limitation, chemoradiotherapy, as a combination of chemotherapy and radiotherapy of a radioactive seed, has been proposed to decrease the damage to tumor-surrounding tissues and enhance the radiosensitivity of solid tumors. In this study, we designed and synthesized folic acid-conjugated selenium nanoparticles (FA@SeNPs) as a cancer-targeting agent that could be synergistically enhanced by radioactive 125I seeds to realize anticancer efficacy and inhibited colony formation ability. Interestingly, when compared with X-ray irradiation, 125I seeds demonstrate a larger synergistic effect with the FA@SeNPs, drastically increasing reactive oxygen species overproduction to trigger apoptosis and influencing the cell cycle distribution in human breast cancer cells, inducing DNA damage and activating the mitogen-activated protein kinase and p53 signaling pathways. Moreover, this combination treatment demonstrates better in vivo antitumor activity and lower systemic toxicity. Therefore, this study demonstrates a new strategy for using functionalized SeNPs as a radiation sensitizer for 125I seeds for cancer therapy.

Designing Core-Shell Gold and Selenium Nanocomposites for Cancer Radiochemotherapy.

Radiotherapy is an important regime for treating malignant tumors. There is interest in the development of radiosensitizers to increase the local treatment efficacy under a relatively low and safe radiation dose. In this study, we designed Au@Se-R/A nanocomposites (Au@Se-R/A NCs) as nano-radiosensitizer to realize synergistic radiochemotherapy based on the radiotherapy sensitization property of Au nanorods (NRs) and antitumor activity of Se NPs. In vitro studies show that the combined treatment of A375 melanoma cells in culture with NCs and X-ray induces cell apoptosis through alteration in expression of p53 and DNA-damaging genes and triggers intracellular ROS overproduction, leading to greatly enhanced anticancer efficacy. Further studies using clinically used radiotherapy equipment demonstrate that the combined treatment of NCs and X-ray significantly inhibits the tumor growth in vivo and shows negligible acute toxicity to the major organs. Taken together, this study provides a strategy for clinical translation application of nanomedicne in cancer radiochemotherapy.

RGD peptide-conjugated selenium nanoparticles: antiangiogenesis by suppressing VEGF-VEGFR2-ERK/AKT pathway.

Angiogenesis is essential for tumorigenesis, progression and metastasis. Herein we described the synthesis of RGD peptide-decorated and doxorubicin-loaded selenium nanoparticles (RGD-NPs) targeting tumor vasculature to enhance the cellular uptake and antiangiogenic activities in vitro and in vivo. After internalization by receptor-mediated endocytosis, this nanosystem disassembled under acidic condition with the presence of lysozymes and cell lysate, leading to bioresponsive triggered drug release. Mechanistic investigation revealed that RGD-NPs inhibited angiogenesis through induction of apoptosis and cell cycle arrest in human umbilical vein endothelial cells (HUVECs) via suppression of VEGF-VEGFR2-ERK/AKT signaling axis by triggering ROS-mediated DNA damage. Additionally, RGD-NPs can inhibit MCF-7 tumor growth and angiogenesis in nude mice via down-regulation of VEGF-VEGFR2, effectively reduce the toxicity and prolong the blood circulation in vivo. Our results suggest that the strategy to use RGD-peptide functionalized SeNPs as carriers of anticancer drugs is an efficient way to achieve cancer-targeted antiangiogenesis synergism.

Selective cellular uptake and induction of apoptosis of cancer-targeted selenium nanoparticles.

Selenium nanoparticles (SeNPs) have garnered a great deal of attention as potential cancer therapeutic payloads. However, the in vivo targeting drug delivery has been challenging. Herein, we describe the synthesis of tansferrin (Tf)-conjugated SeNPs and its use as a cancer-targeted drug delivery system to achieve enhanced cellular uptake and anticancer efficacy. Tf as targeting ligand significantly enhances the cellular uptake of doxorubicin (DOX)-loaded SeNPs through clathrin-mediated and caveolae/lipid raft-mediated endocytosis in cancer cells overexpressing transferrin receptor, and increases their selectivity between cancer and normal cells. DOX-loaded and Tf-conjugated SeNPs (Tf-SeNPs) exhibits unprecedented enhanced cytotoxicity toward cancer cells through induction of apoptosis with the involvement of intrinsic and extrinsic pathways. Internalized Tf-SeNPs triggers intracellular ROS overproduction, thus activates p53 and MAPKs pathways to promote cell apoptosis. In the nude mice xenograft experiment, Tf-SeNPs significantly inhibits the tumor growth via induction of p53-mediated apoptosis. This cancer-targeted design of SeNPs opens a new path for synergistic treating of cancer with higher efficacy and decreased side effects.