A PD-L1 targeting nanotheranostic for effective photoacoustic imaging guided photothermal-immunotherapy of tumor.

Tumor immunotherapy has been partly effective for specific cancers. However, problems such as low immune response, limited antitumor effectiveness, and high antibody costs still persist. Synergistic therapeutic approaches, such as immune checkpoint inhibition in conjunction with photothermal therapy and photoacoustic imaging, are expected to provide approaches for more precise and efficient immunotherapy of tumors. Furthermore, developing alternatives for antibodies, such as PD-L1 aptamers and nanocarriers, would reduce the cost of tumor immunotherapy. Herein, we develop a PD-L1-targeting nanotheranostic to block immune checkpoints for synergistic photothermal-immunotherapy against tumors, along with effective photoacoustic (PA) imaging. The nanotheranostic is synthesized by the modification of gold nanorods (GNRs) with the PD-L1 aptamer (APDL1), which can sensitively and specifically recognize PD-L1 on the tumor cell surface, and mediate nanoparticle accumulation and strong PA signals in tumors. The aptamer is released from GNR through a competition of glutathione (GSH) and is then functionalized as a PD-L1 blockade. In collaboration with the concurrent photothermal therapy, antitumor immunity is significantly augmented by enhancing the filtration of matured dendritic cells and suppressing regulatory T cells, followed by the activation of cytotoxic T cells and inhibition of T cell exhaustion. Such a nanotheranostic modality effectively suppresses tumor growth in mice, representing an appealing platform for both biological imaging and photoimmunotherapy of tumors.

Anti-BCMA surface engineered biomimetic photothermal nanomissile enhances multiple myeloma cell apoptosis and overcomes the disturbance of NF-κB signaling in vivo.

Conventional chemotherapy for multiple myeloma (MM) faces the challenges of a low complete remission rate and transformation to recurrence/refractory. The current MM first-line clinical drug Bortezomib (BTZ) faces the problem of enhanced tolerance and nonnegligible side effects. B cell maturation antigen (BCMA), for its important engagement in tumor signaling pathways and novel therapy technologies such as Chimeric antigen receptor T-Cell immunotherapy (CAR-T) and Antibody Drug Conjugate (ADC), has been identified as an ideal target and attracted attention in anti-MM therapy. Emerging nanotechnology provided feasible methods for drug delivery and new therapeutic strategies such as photothermal therapy (PTT). Herein, we developed a BCMA-Targeting biomimetic photothermal nanomissile BTZ@BPQDs@EM @anti-BCMA (BBE@anti-BCMA) by integration of BTZ, black phosphorus quantum dots (BPQDs), Erythrocyte membrane (EM) and BCMA antibody (anti-BCMA). We hypothesized that this engineered nanomissile could attack tumor cells in triple ways and achieve effective treatment of MM. Consequently, the intrinsic biomimetic nature of EM and the active targeting property of anti-BCMA enhanced the accumulation of therapeutic agents in the tumor site. Besides, owing to the decrease in BCMA abundance, the potential apoptosis-inducing ability was revealed. With the support of BPQDs' photothermal effect, Cleaved-Caspase-3 and Bax signal increased significantly, and the expression of Bcl-2 was inhibited. Furthermore, the synergistic photothermal/chemo therapy can effectively inhibit tumor growth and reverse the disorder of NF-κB in vivo. Importantly, this biomimetic nanodrug delivery system and antibody induced synergistic therapeutic strategy efficiently killed MM cells with ignorable systemic toxicity, which is a promising method for the future anticancer treatment of hematological malignancies in clinics.

Bisphosphonates Alleviate Bone Loss in People with Acute Spinal Cord Injury：A Systematic Review and Meta-Analysis.

OBJECTIVE: Bone loss is not to be underestimated in people with acute spinal cord injury (SCI). Bisphosphonates can inhibit the bone resorption of osteoclast. To study whether the early application of bisphosphonates can alleviate bone loss after acute SCI, we included 7 randomized controlled trials for meta-analysis. METHODS: Seven randomized controlled trials were found in literature databases. The percentage change in bone mineral density (BMD) at different sites were primary outcomes and serum bone turnover markers were secondary outcomes. A random-effects model was selected for meta-analysis. RESULTS: There were significant differences in the percentage change in BMD of the lumbar spine, total hip, and femoral neck between the bisphosphonates and control groups, but not in the percentage change in distal femur BMD. Besides, there were no statistically significant differences between the groups in the bone formation marker Procollagen type 1 N propeptide; bisphosphonates were effective in reducing the C-terminal telopeptide at the 6-month follow-up, but not at the 12-month follow-up. Subgroup analysis of the effects of zoledronate showed positive effects on BMD of the lumbar spine, total hip, and femoral neck at the 6-month follow-up and showed positive effects on BMD of the total hip and femoral neck at the 12-month follow-up. CONCLUSIONS: Bisphosphonates can effectively alleviate the bone loss of the lumbar spine, total hip, and femoral neck in patients with acute SCI, and early application is advocated.

Efficacy of vitamin K2 in the prevention and treatment of postmenopausal osteoporosis: A systematic review and meta-analysis of randomized controlled trials.

Introduction: Vitamin K (VK) as a nutrient, is a cofactor in the carboxylation of osteocalcin (OC), which can bind with hydroxyapatite to promote bone mineralization and increase bone strength. However, some studies have been inconsistent on whether vitamin K2 (VK2) can maintain or improve bone mineral density (BMD) and reduce the incidence of fractures in postmenopausal women. Therefore, the main objective of this meta-analysis was to determine the effect of VK2 as a nutritional supplement on BMD and fracture incidence in postmenopausal women. Methods: We searched PubMed, EMBASE, and Cochrane Library databases (published before March 17, 2022) and then extracted and pooled data from all randomized controlled trials (RCTs) that met the inclusion criteria. Results: Sixteen RCTs with a total of 6,425 subjects were included in this meta-analysis. The overall effect test of 10 studies showed a significant improvement in lumbar spine BMD (BMD LS) (P = 0.006) with VK2. The subgroup analysis of VK2 combination therapy showed that BMD LS was significantly maintained and improved with the administration of VK2 (P = 0.03). The overall effect test of the six RCTs showed no significant difference in fracture incidence between the two groups (RR=0.96, P=0.65). However, after excluding one heterogeneous study, the overall effect test showed a significant reduction in fracture incidence with VK2 (RR = 0.43, P = 0.01). In addition, this meta-analysis showed that VK2 reduced serum undercarboxylated osteocalcin (uc-OC) levels and the ratio of uc-OC to cOC in both subgroups of VK2 combined intervention and alone. However, for carboxylated osteocalcin (cOC), both subgroup analysis and overall effect test showed no significant effect of VK2 on it. And the pooled analysis of adverse reactions showed no significant difference between the VK2 and control groups (RR = 1.03, 95%CI 0.87 to 1.21, P = 0.76). Conclusions: The results of this meta-analysis seem to indicate that VK2 supplementation has a positive effect on the maintenance and improvement of BMD LS in postmenopausal women, and it can also reduce the fracture incidence, serum uc-OC levels and the ratio of uc-OC to cOC. In conclusion, VK2 can indirectly promote bone mineralization and increase bone strength.