Photoacoustic mediated multifunctional tumor antigen trapping nanoparticles inhibit the recurrence and metastasis of ovarian cancer by enhancing tumor immunogenicity.

The hypoimmunogenicity of tumors is one of the main bottlenecks of cancer immunotherapy. Enhancing tumor immunogenicity can improve the efficacy of tumor immunotherapy by increasing antigen exposure and presentation, and establishing an inflammatory microenvironment. Here, a multifunctional antigen trapping nanoparticle with indocyanine green (ICG), aluminum hydroxide (Al(OH)3) and oxaliplatin (OXA) (PPIAO) has been developed for tumor photoacoustic/ultrasound dual-modality imaging and therapy. The combination of photothermal/photodynamic therapy and chemotherapy induced tumor antigen exposure and release through immunogenic death of tumor cells. A timely capture and storage of antigens by aluminum hydroxide enabled dendritic cells to recognize and present those antigens spatiotemporally. In an ovarian tumor model, the photoacoustic-mediated PPIAO NPs combination therapy achieved a transition from "cold tumor" to "hot tumor" that promoted more CD8+ T lymphocytes activation in vivo and intratumoral infiltration, and successfully inhibited the growth of primary and metastatic tumors. An in situ tumor vaccine effect was produced from the treated tumor tissue, assisting mice against the recurrence of tumor cells. This study provided a simple and effective personalized tumor vaccine strategy for better treatment of metastatic and recurrent tumors. The developed multifunctional tumor antigen trapping nanoparticles may be a promising nanoplatform for integrating multimodal imaging monitoring, tumor treatment, and tumor vaccine immunotherapy.

Long-term efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta-analysis including 13,146 patients.

WHAT IS KNOWN AND OBJECTIVE: Previous studies based on small-sample clinical data proved that short-term use of hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors increased haemoglobin levels in anaemic patients with chronic kidney disease (CKD). However, these studies reached conflicting conclusions on iron parameters and adverse event profiles. Our meta-analysis aimed to evaluate the long-term efficacy and safety of HIF-PHD inhibitors in renal anaemia. METHODS: Randomized controlled trials comparing treatment with HIF-PHD inhibitors versus placebo or erythropoiesis-stimulating agents (ESAs) were thoroughly searched in the PubMed, Embase, Cochrane Library and international clinical trial registries. Meta-analysis was performed on main outcomes with random effects models. RESULTS AND DISCUSSION: A total of 30 studies comprising 13,146 patients were included. The HIF-PHD inhibitors used included roxadustat, daprodustat, vadadustat, molidustat, desidustat and enarodustat. HIF-PHD inhibitors significantly increased haemoglobin levels in comparison with placebo [weighted mean difference (WMD) 1.53, 95% confidence interval (CI) 1.39 to 1.67] or ESAs (WMD 0.13, 95% CI 0.03 to 0.22). Hepcidin, ferritin and serum iron levels were decreased, while total iron binding capacity and transferrin levels were increased in the HIF-PHD inhibitor group versus those in placebo or ESAs group. Additionally, HIF-PHD inhibitors medication was associated with cholesterol-lowering effects. As for safety, the risk of serious adverse events in the HIF-PHD inhibitor group was increased in comparison with placebo group [risk ratio (RR) 1.07, 95% CI 1.01 to 1.13], but comparable to the ESAs group (RR 1.02, 95% CI 0.94 to 1.10). Compared with placebo, the agents increased the risk of diarrhoea (1.21, 1.00 to 1.47), nausea (1.46, 1.09 to 1.97), oedema peripheral (1.32, 1.01 to 1.59), hyperkalemia (1.27, 1.05 to 1.54) and hypertension (1.34, 1.02 to 1.76). Compared with ESAs, the drugs increased the risk of vomiting (1.30, 1.02 to 1.65), headache (1.27, 1.05 to 1.53) and thrombosis events (1.31, 1.05 to 1.63). WHAT IS NEW AND CONCLUSION: HIF-PHD inhibitors treatment effectively increased haemoglobin levels and promoted iron utilization in anaemic patients with CKD, and they were well tolerated for long-term use. In order to avoid unfavourable effects of excessive iron consumption, it was appropriate to administer HIF-PHD inhibitors in combination with iron supplements for long-term treatment.

Folate-Targeted and Oxygen/Indocyanine Green-Loaded Lipid Nanoparticles for Dual-Mode Imaging and Photo-sonodynamic/Photothermal Therapy of Ovarian Cancer in Vitro and in Vivo.

We have successfully fabricated versatile folate-targeted and oxygen/indocyanine green-loaded lipid nanoparticles (FA-OINPs) for dual-mode imaging-guided therapy in ovarian cancer cells and subcutaneous xenograft models. FA-OINPs were demonstrated to have great potential as superb contrast agents to enhance ultrasound and photoacoustic (US/PA) imaging We have successfully fabricated versatile folate-targeted and oxygen/indocyanine green-loaded lipid nanoparticles (FA-OINPs) for dual-mode imaging-guided therapy in ovarian cancer cells and subcutaneous xenograft models. FA-OINPs were demonstrated to have great potential as superb contrast agents to enhance ultrasound and photoacoustic (US/PA) imaging in vitro and in vivo. Confocal laser scanning microscopy and flow cytometry analysis verified that FA-OINPs could specifically target SKOV3 ovarian cancer cells and be endocytosed with a remarkable efficiency. Compared with other therapeutic options, FA-OINPs exhibited an excellent therapeutic outcome after exposure to laser and ultrasound. The MTT assay and flow cytometry analysis confirmed that cytotoxicity effects and apoptosis/necrosis rates were significantly increased. The fluorescence microscopy and fluorescence microplate reader detection validated that the generation of intracellular reactive oxygen species (ROS) was dramatically improved. Immunohistochemical analyses of tumor tissues demonstrated the enhanced tumor apoptosis, the decreased vascular endothelial growth factor (VEGF) and microvascular density (MVD) expression, and the decreased expression of CD68 after treatment. The presented results suggest that photo-sonodynamic/photothermal mediated FA-OINPs could provide a promising strategy for synergistic therapy in ovarian cancer with the guidance of US/PA dual-mode imaging.

A multifunctional-targeted nanoagent for dual-mode image-guided therapeutic effects on ovarian cancer cells.

PURPOSE: Nanomedicine has emerged as a novel therapeutic modality for cancer treatment and diagnosis. Lipid-polymer hybrid nanoparticles (LPHNPs) are core-shell nanoparticle (NP) structures comprising polymer cores and lipid shells, which exhibit complementary characteristics of both polymeric NPs and liposomes. However, it is difficult to wrap perfluoropentane (PFP) into core-shell NPs in the existing preparation process, which limits its application in the integration of diagnosis and treatment. METHODS: The folate-targeted LPHNPs-loaded indocyanine green/PFP-carrying oxygen (TOI_HNPs) using a combination of two-step method and solution evaporation technique for the first time. The essential properties and dual-mode imaging characteristics of developed NPs were determined. The cellular uptake of TOI_HNPs was detected by confocal microscopy and flow cytometry. The SKOV3 cell viability and apoptosis rate were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry. The ROS was demonstrated by fluorescence microplate reader and the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and IL-6 was detected by Western blot. RESULTS: TOI_HNPs showed spherical morphology with particle size about (166.83±5.54) nm and zeta potential at -(30.57±1.36) mV. It exhibited better stability than lipid NPs and higher encapsulation efficiency as well as active targeting ability than poly (lactic-co-glycolic acid) (PLGA) NPs. In addition, the novel NPs could also act as the contrast agents for ultrasound and photoacoustic imaging, providing precision guidance and monitoring. Furthermore, TOI_HNPs-mediated photo-sonodynamic therapy (PSDT) caused more serious cell damage and more obvious cell apoptosis, compared with other groups. The PSDT mediated by TOI_HNPs induced generation of intracellular ROS and downregulated the expression of HIF-1α and IL-6 in SKOV3 cells. CONCLUSION: This kind of multifunctional-targeted nanoagent may provide an ideal strategy for combination of high therapeutic efficacy and dual-mode imaging guidance.

Synergistic in vitro effects of indocyanine green and ethylenediamine tetraacetate-mediated antimicrobial photodynamic therapy combined with antibiotics for resistant bacterial biofilms in diabetic foot infection.

BACKGROUND: Antibiotic resistance has emerged as one of the most important determinants in diabetic foot infections outcomes. Antimicrobial Photodynamic therapy(A-PDT) or Photodynamic antimicrobial chemotherapy (PACT) has been proposed as an alternative approach for inactivating bacteria, especially resistant bacterial biofilms. This research investigated the synergistic effects of PACT mediated by the photosensitizer indocyanine green (ICG) and ethylenediamine tetraacetate (EDTA) combined with antibiotics against common pathogens of diabetic foot ulcer infection, including Staphylococcus aureus and Pseudomonas aeruginosa, in vitro. METHODS: Planktonic bacteria and biofilms of S. aureus and P. aeruginosa were incubated with ICG and EDTA, and then exposed to laser treatment. Quantitative viable counting estimates the phototoxic effects on S. aureus and P. aeruginosa. The susceptibility of methicillin-resistant S. aureus (MRSA) and multidrug-resistant P. aeruginosa (MRPA) to PACT treatment was detected by disk diffusion and micro-broth dilution methods. Confocal microscopy was used to detect the morphology of biofilms treated with PACT and antibiotics. The resazurin assay was used to quantify the metabolic activity of bacteria in biofilms. RESULTS: PACT mediated by ICG and EDTA led to a more pronounced antibacterial effect in S. aureus and P. aeruginosa compared with ICG alone-mediated PACT. P. aeruginosa was more sensitive to ICG and EDTA-mediated PACT than S. aureus. After PACT treatment, the susceptibility of MRSA and MRPA to antibiotics increased. Furthermore, PACT combined with antibiotic treatment significantly contributed to killing bacteria in the biofilm and disrupting biofilm structure. CONCLUSIONS: ICG and EDTA-mediated PACT combined with antibiotics synergistically enhanced the effects of sterilization and biofilm destruction.

Enhanced therapeutic efficacy of LHRHa-targeted brucea javanica oil liposomes for ovarian cancer.

BACKGROUND: Although brucea javanica oil liposomes (BJOLs) have been used clinically to treat ovarian cancer, its clinical efficacy is often limited by systemic side effects due to non-specific distribution. Luteinizing hormone releasing hormone receptor (LHRHR) is overexpressed in most ovarian cancers but negligibly expressed in most of the other visceral organs. In this study, we aimed to develop a novel LHRHa targeted and BJO-loaded liposomes (LHRHa-BJOLs), and investigate its characteristics, targeting ability and anti-ovarian cancer efficiency both in vitro and in vivo. METHODS: The LHRHa-BJOLs were prepared by film-dispersion and biotin-streptavidin linkage methods, and characterized in terms of its morphology, particle size, zeta potential, ligand conjugation, encapsulation efficiency and stability. The targeting nature and antitumor effects of the liposomes were evaluated in vitro using cultured human ovarian cancer A2780/DDP cells, and in vivo using ovarian cancer-bearing nude mice. RESULTS: The LHRHa-BJOLs were successfully synthesized, with a uniformly spherical shape, appropriate particle size and zeta potential, as well as a high encapsulation efficiency. Compared to non-targeted liposomes and BJO emulsion, the LHRHa-BJOLs could significantly increase specific intracellular uptaking rate, enhance cell inhibitory effect and induce cell apoptosis in A2780/DDP cells in vitro. Meanwhile, LHRHa-BJOLs also had a significantly stronger activity of targeting tumor tissue, inhibiting tumor growth, inducing tumor apoptosis and prolonging survival time in ovarian cancer-bearing mice in vivo. CONCLUSIONS: Our experiment suggests that LHRHa-BJOLs may be a useful targeted drug for the treatment of ovarian cancer.