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.

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.

High-Throughput and Efficient Intracellular Delivery Method via a Vibration-Assisted Nanoneedle/Microfluidic Composite System.

Intracellular delivery and genetic modification have brought a significant revolutionary to tumor immunotherapy, yet existing methods are still limited by low delivery efficiency, poor throughput, excessive cell damage, or unsuitability for suspension immune cells, specifically the natural killer cell, which is highly resistant to transfection. Here, we proposed a vibration-assisted nanoneedle/microfluidic composite system that uses large-area nanoneedles to rapidly puncture and detach the fast-moving suspension cells in the microchannel under vibration to achieve continuous high-throughput intracellular delivery. The nanoneedle arrays fabricated based on the large-area self-assembly technique and microchannels can maximize the delivery efficiency. Cas9 ribonucleoprotein complexes (Cas9/RNPs) can be delivered directly into cells due to the sufficient cellular membrane nanoperforation size; for difficult-to-transfect immune cells, the delivery efficiency can be up to 98%, while the cell viability remains at about 80%. Moreover, the throughput is demonstrated to maintain a mL/min level, which is significantly higher than that of conventional delivery techniques. Further, we prepared CD96 knockout NK-92 cells via this platform, and the gene-edited NK-92 cells possessed higher immunity by reversing exhaustion. The high-throughput, high-efficiency, and low-damage performance of our intracellular delivery strategy has great potential for cellular immunotherapy in clinical applications.

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.