A novel shockwave-driven nano-motor composite microneedle transdermal delivery system for the localized treatment of osteoporosis: a basic science study.

BACKGROUND: Clinical protocols in osteoporosis treatment could not meet the requirement of increasing local bone mineral density. A local delivery system was brought in to fix this dilemma. The high-energy extracorporeal shock wave (ESW) can travel into the deep tissues with little heat loss. Hence, ESW-driven nanoparticles could be used for local treatment of osteoporosis. MATERIALS AND METHODS: An extracorporeal shock wave (ESW)--actuated nanomotor (NM) sealed into microneedles (MN) (ESW-NM-MN) was constructed for localized osteoporosis protection. The NM was made of calcium phosphate nanoparticles with a high Young's modulus, which allows it to absorb ESW energy efficiently and convert it into kinetic energy for solid tissue penetration. Zoledronic (ZOL), as an alternative phosphorus source, forms the backbone of the NM (ZOL-NM), leading to bone targeting and ESW-mediated drug release. RESULTS: After the ZOL-NM is sealed into hyaluronic acid (HA)--made microneedles, the soluble MN tips could break through the stratum corneum, injecting the ZOL-NM into the skin. As soon as the ESW was applied, the ZOL-NM would absorb the ESW energy to move from the outer layer of skin into the deep tissue and be fragmented to release ZOL and Ca2+ for anti-osteoclastogenesis and pro-osteogenesis. In vivo, the ZOL-NM increases localized bone parameters and reduces fracture risk, indicating its potential value in osteoporotic healing and other biomedical fields. CONCLUSION: The ESW-mediated transdermal delivery platform (ESW-NM-MN) could be used as a new strategy to improve local BMD and protect local prone-fracture areas.

Boron Neutron Capture Therapy-Derived Extracellular Vesicles via DNA Accumulation Boost Antitumor Dendritic Cell Vaccine Efficacy.

Radiated tumor cell-derived extracellular vesicles (RT-EVs) encapsulate abundant DNA fragments from irradiated tumor cells, in addition to acting as integrators of multiple tumor antigens. Accumulating evidence indicates these DNA fragments from damaged cells are involved in downstream immune responses, but most of them are degraded in cells before incorporation into derived RT-EVs, thus the low abundance of DNA fragments limits immune responses of RT-EVs. Here, this study found that different radiations affected fates of DNA fragments in RT-EVs. Boron neutron capture therapy (BNCT) induced DNA accumulation in RT-EVs (BEVs) by causing more DNA breaks and DNA oxidation resisting nuclease degradation. This is attributed to the high-linear energy transfer (LET) properties of alpha particles from the neutron capture reaction of 10B. When being internalized by dendritic cells (DCs), BEVs activated the DNA sensing pathway, resulting in functional enhancements including antigen presentation, migration capacity, and cytokine secretion. After vaccination of the BEVs-educated DCs (BEV@BMDCs), the effector T cells significantly expanded and infiltrated into tumors, suggesting robust anti-tumor immune activation. BEV@BMDCs not only effectively inhibited the primary tumor growth and metastasis formation but also elicited long-term immune memory. In conclusion, a successful DC vaccine is provided as a promising candidate for tumor vaccine.

Boron-Containing Mesoporous Silica Nanoparticles with Effective Delivery and Targeting of Liver Cancer Cells for Boron Neutron Capture Therapy.

Nanocarriers have been researched comprehensively for the development of novel boron-containing agents in boron neutron capture therapy (BNCT). We designed and synthesized a multifunctional mesoporous silica nanoparticle (MSN)-based boron-containing agent. The latter was coated with a lipid bilayer (LB) and decorated with SP94 peptide (SFSIIHTPILPL) on the surface as SP94-LB@BA-MSN. The latter incorporated boric acid (BA) into hydrophobic mesopores, coated with an LB, and modified with SP94 peptide on the LB. SP94-LB@BA-MSN enhanced nano interface tumor-targeting ability but also prevented the premature release of drugs, which is crucial for BNCT because adequate boron content in tumor sites is required. SP94-LB@BA-MSN showed excellent efficacy in the BNCT treatment of HepG-2 cells. In animal studies with tumor-bearing mice, SP94-LB@BA-MSN exhibited a satisfactory accumulation at the tumor site. The boron content reached 40.18 ± 5.41 ppm in the tumor site 4 h after injection, which was 8.12 and 15.51 times higher than those in mice treated with boronated phenylalanine and those treated with BA. For boron, the tumor-to-normal tissue ratio was 4.41 ± 1.13 and the tumor-to-blood ratio was 5.92 ± 0.45. These results indicated that nanoparticles delivered boron to the tumor site effectively while minimizing accumulation in normal tissues. In conclusion, this composite (SP94-LB@BA-MSN) shows great promise as a boron-containing delivery agent for the treatment of hepatocellular carcinoma using BNCT. These findings highlight the potential of MSNs in the field of BNCT.

Boron-Containing MOF Nanoparticles with Stable Metabolism in U87-MG Cells Combining Microdosimetry To Evaluate Relative Biological Effectiveness of Boron Neutron Capture Therapy.

Accurate prediction of the relative biological effectiveness (RBE) of boron neutron capture therapy (BNCT) is challenging. The therapy is different from other radiotherapy; the dynamic distribution of boron-containing compounds in tumor cells affects the therapeutic outcome considerably and hampers accurate measurement of the neutron-absorbed dose. Herein, we used boron-containing metal-organic framework nanoparticles (BMOFs) with high boron content to target U87-MG cells and maintain the concentration of the 10B isotope in cells. The content of boron in the cells could maintain 90% (60 ppm) within 20 min compared with that at the beginning; therefore, the accurate RBE of BNCT can be acquired. The effects of BNCT upon cells after neutron irradiation were observed, and the neutron-absorbed dose was obtained by Monte Carlo simulations. The RBE of BMOFs was 6.78, which was 4.1-fold higher than that of a small-molecule boron-containing agent (boric acid). The energy spectrum of various particles was analyzed by Monte Carlo simulations, and the RBE was verified theoretically. Our results suggested that the use of nanoparticle-based boron carriers in BNCT may have many advantages and that maintaining a stable boron distribution within cells may significantly improve the efficiency of BNCT.

Stability evaluation of rock pillar between twin tunnels using the YAI.

The stability of rock pillar is crucial for ensuring the construction safety of twin tunnels with small clearance, especially when transitioning from the traditional left-right tunnel layouts to the up-down configurations due to complex and variable site constraints. However, there are limited researches on the evaluation and comparative study of the stability of these two types of rock pillars in twin tunnels. This paper introduces the yield approach index (YAI) as a measure to assess the stability of rock pillar in twin tunnels with small clearance, and various influencing factors including side pressure coefficient (SPC), stress release rate (SRR), and the thickness of rock pillar (characterised by the ratio of rock pillar thickness to tunnel diameter, RPT/TD) are considered in the analysis. The study compares and analyzes the stability differences of the rock pillar in different situations. It is observed that the two sides of up-down tunnels pose a higher risk while the rock pillar in the left-right configuration being the most vulnerable. The stability of the rock pillar between the up-down tunnels is significantly higher than that of the left-right tunnels under similar conditions. Moreover, the up-down tunnels exhibit greater sensitivity to SPC, whereas the left-right tunnels are more sensitive to SRR. Additionally, the study reveals that increasing the RPT/TD can effectively improve the stability of the rock pillar within a specific range (1/4 to 2/3). The research method and obtained results of this paper can provide some important references for the stability evaluation and design of twin tunnels with small clearance.

A Bone-Penetrating Precise Controllable Drug Release System Enables Localized Treatment of Osteoporotic Fracture Prevention via Modulating Osteoblast-Osteoclast Communication.

Improving local bone mineral density (BMD) at fracture-prone sites of bone is a clinical concern for osteoporotic fracture prevention. In this study, a featured radial extracorporeal shock wave (rESW) responsive nano-drug delivery system (NDDS) is developed for local treatment. Based on a mechanic simulation, a sequence of hollow zoledronic acid (ZOL)-contained nanoparticles (HZNs) with controllable shell thickness that predicts various mechanical responsive properties is constructed by controlling the deposition time of ZOL and Ca2+ on liposome templates. Attributed to the controllable shell thickness, the fragmentation of HZNs and the release of ZOL and Ca2+ can be precisely controlled with the intervention of rESW. Furthermore, the distinct effect of HZNs with different shell thicknesses on bone metabolism after fragmentation is verified. In vitro co-culture experiments demonstrate that although HZN2 does not have the strongest osteoclasts inhibitory effect, the best pro-osteoblasts mineralization results are achieved via maintaining osteoblast-osteoclast (OB-OC) communication. In vivo, the HZN2 group also shows the strongest local BMD enhancement after rESW intervention and significantly improves bone-related parameters and mechanical properties in the ovariectomy (OVX)-induced osteoporosis (OP) rats. These findings suggest that an adjustable and precise rESW-responsive NDDS can effectively improve local BMD in OP therapy.

3D culture boosting fullerenol nanoparticles to induce calreticulin exposure on MCF-7 cells for enhanced macrophage-mediated cell removal.

Calreticulin (CRT) on the cell surface that acts as an "eat me" signal is vital for macrophage-mediated programmed cell removal. The polyhydroxylated fullerenol nanoparticle (FNP) has appeared as an effective inducer to cause CRT exposure on cancer cell surface, but it failed in treating some cancer cells such as MCF-7 cells based on previous findings. Here, we carried out the 3D culture of MCF-7 cells, and interestingly found that the FNP induced CRT exposure on cells in 3D spheres via re-distributing CRT from endoplasmic reticulum (ER) to cell surface. Phagocytosis experiments in vitro and in vivo illustrated the combination of FNP and anti-CD47 monoclonal antibody (mAb) further enhanced macrophage-mediated phagocytosis to cancer cells. The maximal phagocytic index in vivo was about three times higher than that of the control group. Moreover, in vivo tumorigenesis experiments in mice proved that FNP could regulate the progress of MCF-7 cancer stem-like cells (CSCs). These findings expand the application of FNP in tumor therapy of anti-CD47 mAb and 3D culture can be used as a screening tool for nanomedicine.

Oral Administration of Omega-3 Fatty Acids Attenuates Lung Injury Caused by PM2.5 Respiratory Inhalation Simply and Feasibly In Vivo.

For developing an effective interventional approach and treatment modality for PM2.5, the effects of omega-3 fatty acids on alleviating inflammation and attenuating lung injury induced by inhalation exposure of PM2.5 were assessed in murine models. We found that daily oral administration of the active components of omega-3 fatty acids, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) effectively alleviated lung parenchymal lesions, restored normal inflammatory cytokine levels and oxidative stress levels in treating mice exposed to PM2.5 (20 mg/kg) every 3 days for 5 times over a 14-day period. Especially, CT images and the pathological analysis suggested protective effects of DHA and EPA on lung injury. The key molecular mechanism is that DHA and EPA can inhibit the entry and deposition of PM2.5, and block the PM2.5-mediated cytotoxicity, oxidative stress, and inflammation.

Multi-View Representation Learning With Deep Gaussian Processes.

Multi-view representation learning is a promising and challenging research topic, which aims to integrate multiple data information from different views to improve the learning performance. The recent deep Gaussian processes (DGPs) have the advantages of good uncertainty estimates, powerful non-linear mapping ability and great generalization capability, which can be used as an excellent data representation learning method. However, DGPs only focus on single view data and are rarely applied to the multi-view scenario. In this paper, we propose a multi-view representation learning algorithm with deep Gaussian processes (named MvDGPs), which inherits the advantages of deep Gaussian processes and multi-view representation learning, and can learn more effective representation of multi-view data. The MvDGPs consist of two stages. The first stage is multi-view data representation learning, which is mainly used to learn more comprehensive representations of multi-view data. The second stage is classifier design, which aims to select an appropriate classifier to better employ the representations obtained in the first stage. In contrast with DGPs, MvDGPs support asymmetrical modeling depths for different views of data, resulting in better characterizations of the discrepancies among different views. Experimental results on real-world multi-view data sets verify the effectiveness of the proposed algorithm, which indicates that MvDGPs can integrate the complementary information in multiple views to discover a good representation of the data.

Rapamycin suppresses TLR4-triggered IL-6 and PGE(2) production of colon cancer cells by inhibiting TLR4 expression and NF-kappaB activation.

Toll-like receptor 4 (TLR4) signaling in tumor cells can mediate tumor cell immune escape and tumor progression, being regarded as one of the mechanisms for chronic inflammation in tumorigenesis and progression. So, intervention of TLR4-mediated immune escape and metastasis has been proposed as one of the approaches to cancer prevention and treatment. Rapamycin, an immunosuppressant agent widely used for treatment of autoimmune diseases and transplantation rejection, is recently used for cancer therapy. However, the underlying mechanisms remain to be fully understood. In the present study, we demonstrate that rapamycin can significantly inhibit TLR4-triggered IL-6 and PGE(2) production and invasion of colon cancer cells. Suppression of TLR4-induced IL-6 and PGE(2) production is responsible for the rapamycin-mediated decrease of TLR4-evoked invasion of colon cancer cells. Furthermore, disruption of NF-kappaB pathway contributes to the inhibition of TLR4-induced IL-6, PGE(2) production and invasion by rapamycin in colon cancer cells. Rapamycin can also downregulate TLR4 expression. Therefore, we demonstrate that rapamycin may abrogate TLR4-triggered tumor cell immune escape and invasion by downregulating TLR4 expression and inhibiting TLR4-activated NF-kappaB pathway, thus providing new mechanistic explanation for the antitumor effect of rapamycin.