Phase and Defect Engineering of MoSe2 Nanosheets for Enhanced NIR-II Photothermal Immunotherapy.

Inducing immunogenic cell death (ICD) during photothermal therapy (PTT) has the potential to effectively trigger photothermal immunotherapy (PTI). However, ICD induced by PTT alone is often limited by inefficient PTT, low immunogenicity of tumor cells, and a dysregulated redox microenvironment. Herein, we develop MoSe2 nanosheets with high-percentage metallic 1T phase and rich exposed active Mo centers through phase and defect engineering of MoSe2 as an effective nanoagent for PTI. The metallic 1T phase in MoSe2 nanosheets endows them with strong PTT performance, and the abundant exposed active Mo centers endow them with high activity for glutathione (GSH) depletion. The MoSe2-mediated high-performance PTT synergizing with efficient GSH depletion facilitates the release of tumor-associated antigens to induce robust ICD, thus significantly enhancing checkpoint blockade immunotherapy and activating systemic immune response in mouse models of colorectal cancer and triple-negative metastatic breast cancer.

Phase-Change Based Oxygen Carriers Improve Acute Cerebral Hypoxia.

Stroke is the second leading cause of death worldwide, and hypoxia is a major crisis of the brain after stroke. Therefore, providing oxygen to the brain microenvironment can effectively protect neurons from damage caused by cerebral hypoxia. However, there is a lack of timely and effective means of oxygen delivery clinically to the brain for acute cerebral hypoxia. Here, a phase-change based nano oxygen carrier is reported, which can undergo a phase change in response to increasing temperature in the brain, leading to oxygen release. The nano oxygen carrier demonstrate intracerebral oxygen delivery capacity and is able to release oxygen in the hypoxic and inflammatory region of the brain. In the acute ischemic stroke mouse model, the nano oxygen carrier can effectively reduce the area of cerebral infarction and decrease the level of inflammation triggered by cerebral hypoxia. By taking advantage of the increase in temperature during cerebral hypoxia, phase-change oxygen carrier proposes a new intracerebral oxygen delivery strategy for reducing acute cerebral hypoxia.

An In Situ Assembled Trapping Gel Repairs Spinal Cord Injury by Capturing Glutamate and Free Calcium Ions.

Spinal cord injury (SCI) can lead to devastating autonomic dysfunction. One of the most challenging issues for functional repair in SCI is the secondary damage caused by the increased release of glutamate and free Ca2+ from injured cells. Here, an in situ assembled trapping gel (PF-SA-GAD) is developed to sweep glutamate and Ca2+ , promoting SCI repair. The hydrogel solution is a mixture of recombinant glutamate decarboxylase 67 (rGAD67) protein, sodium alginate (SA), and pluronic F-127 (PF-127). After intrathecal administration, temperature-sensitive PF-127 promoted in situ gelation. Glutamate (Glu) is captured and decarboxylated by rGAD67 into γ-aminobutyric acid (GABA). SA reacted with the free Ca2+ to generate gellable calcium alginate. Thereby, this in situ trapping gel retarded secondary neuron injury caused by Glu and free Ca2+ during SCI. In rat models of SCI, PF-SA-GAD reduces the lesion volume and inflammatory response after SCI, restores the motor function of rats with SCI. Together, the in situ assembled trapping gel is a long-term effective and minimally invasive sweeper for the direct elimination of glutamate and Ca2+ from injury lesions and can be a novel strategy for SCI repair by preventing secondary injury.

Symbiotic Algae-Bacteria Dressing for Producing Hydrogen to Accelerate Diabetic Wound Healing.

Oxidative stress induced by hyperglycemia or chronic inflammation can limit diabetic wound healing, resulting in diabetic foot ulcers. Hydrogen has the potential to act as an antioxidant and scavenge reactive oxygen species, thereby attenuating inflammation in these chronic wounds. However, most of the reported H2 delivery systems for wound healing, including hydrogen gas, hydrogen-rich water, and hydrogen-rich saline, are very short-lived for the low solubility of hydrogen gas. Here, we introduce a hydrogen-producing hydrogel made of living Chlorella and bacteria within a cell-impermeable casing that can continuously produce hydrogen for 60 h. This microbe-hydrogel system can selectively reduce highly toxic •OH and ONOO- species and reduce inflammation. Additional experiments indicated that the microbe-hydrogel dressing could promote cell proliferation and diabetic wound healing by almost 50% at day 3. The symbiotic algae-bacteria hydrogel has excellent biocompatibility and reactive oxygen species scavenging features, indicating it has great promise for clinical use.

Recent Advances of Tumor Therapy Based on the CD47-SIRPα Axis.

Cancer is still a major disease that is currently difficult for humans to overcome. When the expression of the cluster of differentiation 47 (CD47) is upregulated, tumor cells interact with the macrophage inhibitory receptor signal regulatory protein α (SIRPα) to transmit the "Don't eat me" signal, thereby avoiding phagocytosis by the macrophages. Therefore, when the CD47-SIRPα axis is inhibited, the macrophages' phagocytic function can be restored and can also exert antitumor effects. This Review mainly introduces recent advances in tumor therapy targeted on the CD47-SIRPα axis, including the antibody and fusion protein, small molecule, gene therapy, cell therapy, and drug delivery system, to inhibit the function of CD47 expressed on tumor cells and promote tumor phagocytosis by macrophages. In addition, this Review also summarizes the current approaches to avoid anemia, a common side effect of CD47-SIRPα inhibitions, and provides ideas for clinical transformation.

Perfluorocarbon nanoparticle-mediated platelet inhibition promotes intratumoral infiltration of T cells and boosts immunotherapy.

Cancer immunotherapy can stimulate and enhance the ability of the immune system to recognize, arrest, and eliminate tumor cells. Immune checkpoint therapies (e.g., PD-1/PD-L1) have shown an unprecedented and durable clinical response rate in patients among various cancer types. However, a large fraction of patients still does not respond to these checkpoint inhibitors. The main cause of this phenomenon is the limited T-cell infiltration in tumors. Therefore, additional strategies to enhance T-cell trafficking into tumors are urgently needed to improve patients' immune responses. In this study, we screened an array of perfluorocarbon compounds, reporting that albumin-based perfluorotributylamine nanoparticles (PFTBA@Alb) can effectively increase the permeability of tumor blood vessels, and no distinct side effects were found on normal blood vessels. After i.v. administration of PFTBA@Alb, the number of tumor-infiltrating CD8+ and CD4+ T cells showed an obvious rising trend. More important, a striking tumor inhibition rate, reaching nearly 90%, was observed when combining PFTBA@Alb with anti-PD-L1 antibody. These findings suggest that PFTBA@Alb can be regarded as an enhancer for anti-PD-L1 immunotherapy.

Copper-Based Nanoscale Coordination Polymers Augmented Tumor Radioimmunotherapy for Immunogenic Cell Death Induction and T-Cell Infiltration.

Insufficient T-cell infiltration seriously hinders the efficacy of tumor immunotherapy. Induction of immunogenic cell death (ICD) is a potentially feasible approach to increase T-cell infiltration. Since ionizing radiation can only induce low-level ICD, this study constructs Cu-based nanoscale coordination polymers (Cu-NCPs) with mixed-valence (Cu+ /Cu2+ ), which can simultaneously and independently induce the generation of Cu+ -triggered hydroxyl radicals and Cu2+ -triggered GSH elimination, to synergize with radiation therapy for potent ICD induction. Markedly, this synergetic therapy remarkably enhances dendritic cell maturation and promotes antitumor CD8+ T-cell infiltration, thereby potentiating the development of checkpoint blockade immunotherapies against primary and metastatic tumors.

Photosynthetic Microorganisms-Based Biophotothermal Therapy with Enhanced Immune Response.

The production of oxygen by photosynthetic microorganisms (PSMs) has recently attracted interest concerning the in vivo treatment of multiple diseases for their photosynthetic oxygen production in vivo, since PSMs have good biological safety. Here, the first evidence that PSMs can be used as a photothermal source to perform biophotothermal therapy (bio-PTT) is provided. In vitro and in vivo experiments proved that PSMs can generate heat for the direct elimination of tumors and release a series of pathogen-associated molecular patterns and adjuvants for immune stimulation under light irradiation. Bio-PTT enabled a local tumor inhibition rate exceeding 90% and an abscopal tumor inhibition rate exceeding 75%. This strategy also produced a stronger antitumor immune memory effect to prevent tumor recurrence. The bio-PTT strategy provides a novel direction for photothermal therapy as it simultaneously produces local and abscopal antitumor effects.

Hydrogel-Based Controlled Drug Delivery for Cancer Treatment: A Review.

As an emerging drug carrier, hydrogels have been widely used for tumor drug delivery. A hydrogel drug carrier can cause less severe side effects than systemic chemotherapy and can achieve sustained delivery of a drug at tumor sites. In addition, hydrogels have excellent biocompatibility and biodegradability and lower toxicity than nanoparticle carriers. Smart hydrogels can respond to stimuli in the environment (e.g., heat, pH, light, and ultrasound), enabling in situ gelation and controlled drug release, which greatly enhance the convenience and efficiency of drug delivery. Here, we summarize the different sizes of hydrogels used for cancer treatment and their related delivery routes, discuss the design strategies for stimuli-responsive hydrogels, and review the research concerning smart hydrogels reported in the past few years.

Clinical evaluation of plasma coagulation parameters in patients with advanced-stage non-small cell lung cancer treated with palliative chemotherapy in China.

AIMS OF THE STUDY: Blood coagulation parameters are colossally important for clinical evaluation of palliative chemotherapy; however, this niche was not explored earlier for advanced-stage non-small cell lung cancer (NSCLC). Study focuses to explore the clinical relevancy of Coagulation parameters; prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), D-dimer and international normalised ratio (INR) and their response to palliative chemotherapy in advanced-stage NSCLC. METHODS: A retrospective study was conducted between 2013 and 2019 in Jiangsu Cancer hospital, Nanjing, PR. China. Medical records of 5445 patients were succinctly reviewed and classified accordingly to the inclusion and exclusion criteria. A total of 216 advanced NSCLC patients who used a first-line chemotherapy and antiangiogenic therapy regimen were enrolled in this study under ethical approval (JSCH-2020C-009). Blood samples were collected from these patients to measure the response levels of these coagulation parameters at time of admission to hospital and at the beginning of 4 cycles of Palliative therapy. We find the clinical value of all these coagulation parameters by using SPSS 24. Univariate Cox regression and Multivariate Cox regression models were used to identify the factors that were associated with progression-free survival (PFS) and the response to palliative chemotherapy. RESULTS: In the Kaplan-Meier survival analysis for overall median (95% CI) survival of high pre-treatment coagulation parameters showed shorter PFS compared with normal pre-treatment except TT and their overall median (95% CI) follow-up was 3.3 (3.12-3.47). Coagulation parameters have showed clinical relevance as a potential independent prognostic factor of PFS in the Univariate Cox regression. In multivariable model, Age (≥60 years vs < 60 years), cancer differentiation (Unknown vs Poor), PT (High vs Normal) range, FIB (High vs Normal) range and D-dimer (High vs Normal) range, (P = .025, P = .045, P = .029, P = .049 and P = .011, respectively) were associated as a prognostic factor of PFS in NSCLC. Patients on 3-drugs regimen found to have better PFS compared with the ones taking the 2-drugs treatment regimen (P = .043). CONCLUSION: The high range of PT, FIB and D-dimers was associated with poor prognosis of advanced-stage NSCLC. Our findings also confirmed that patients on 3-drugs regimen showed longer PFS compared with 2-drugs regimen.

Perfluorocarbon Nanoparticles Mediated Platelet Blocking Disrupt Vascular Barriers to Improve the Efficacy of Oxygen-Sensitive Antitumor Drugs.

Currently, limited tumor drug permeation and poor oxygen perfusion are two major bottlenecks that significantly impair the efficacy of existing antitumor drugs, especially oxygen-sensitive antitumor drugs. One vital cause of these major bottlenecks is the abnormal tumor vessel barrier. To the best knowledge of the authors, platelets play a vital role in the maintenance of an abnormal tumor blood barrier through platelet-tumor interaction. Thus, platelet inhibition may present a new way to enhance drug delivery. In this study, it is originally discovered that perfluorotributylamine-based albumin nanoparticles (PFTBA@HSA) possess excellent platelet inhibiting abilities, which then selectively disrupt the tumor vessel barrier, resulting in a remarkably enhanced intratumoral drug accumulation. Interestingly enough, the tumor hypoxia is also obviously relieved by enhanced oxygen carrier red blood cell distribution and PFTBA@HSA infiltration in the tumors. Finally, the efficacy of oxygen-sensitive antitumor drugs is significantly amplified by PFTBA@HSA owing to enhanced drug permeation and relieved tumor hypoxia. Therefore, for the first time, it is demonstrated that PFTBA@HSA could be used as an effective way to improve the efficacy of existing tumor therapies by disrupting tumor vessel barriers through targeted platelet inhibition.

Facile Deposition of Manganese Dioxide to Albumin-Bound Paclitaxel Nanoparticles for Modulation of Hypoxic Tumor Microenvironment To Improve Chemoradiation Therapy.

Tumor microenvironment with hypoxia and excess hydrogen peroxide (H2O2) tremendously limits the effect of chemoradiation therapy of colorectal cancer. For the first time, we developed a facile method to deposit manganese dioxide (MnO2) on the surface of albumin bound paclitaxel nanoparticles (ANPs-PTX) to obtain MnO2-functioned ANPs-PTX (MANPs-PTX). In the tumor microenvironment, MANPs-PTX could consume excess hydrogen peroxide (H2O2) to produce abundant oxygen for tumor oxygenation and improve chemoradiation therapy. Meanwhile, the released Mn2+ from MANPs-PTX had excellent T1 magnetic resonance imaging (MRI) performances for tumor detection. Notably, the obtained MANPs-PTX would be a promising theranostic agent and have potential clinical application prospects.

Enhanced photodynamic therapy by encapsulation of perfluorocarbon into PEGylated near-infared dyes.

Near-Infrared (NIR) dyes, with improved tissue penetration, minimal invasiveness and high specificity, have gained great interests in diagnosing and treating tumors. However, the poor solubility in aqueous medium and low 1O2 quantum yields of NIR dyes restrict their application in PDT (photodynamic therapy) research. Herein, a novel nanosystem with modifying the NIR dyes and encapsulating perfluorocarbon is reported for improving the PDT effectiveness of NIR dyes. By adding the PEG2000-SH and the C13 carbon chain to a NIR representative dye IR780, the new formed material PEG-IR780-C13 shows good solubility in water. Then PFTBA was encapsulated into PEG-IR780-C13 to form a nanosystem (PFTBA@PEG-IR780-C13). When exposed to laser irradiation, the nanosystem showed enhanced production of 1O2 and significantly increased PDT both in vivo and in vitro. Therefore, this work provides an approach for design and application of NIR dyes.

Overcome the limitation of hypoxia against photodynamic therapy to treat cancer cells by using perfluorocarbon nanodroplet for photosensitizer delivery.

The low oxygen concentration limits the therapeutic efficacy of photodynamic therapy in treating cancer cells in hypoxia, since the cytotoxic 1O2 can't be effectively generated in this condition. To overcome this, we load photosensitizer into perfluorocarbon nanodroplet, which has a high oxygen capacity to enrich O2 for photodynamic consumption. Under the well-controlled hypoxic condition, we test its efficacy both in vitro and in vivo. This method can be successfully used for destroying cancer cells in hypoxic condition.

Erythrocyte membrane nanoparticles improve the intestinal absorption of paclitaxel.

Paclitaxel (PTX) is a cytotoxic chemotherapy drug with encouraging activity in human malignancies. However, free PTX has a very low oral bioavailability due to its low aqueous solubility and the gastrointestinal drug barrier. In order to overcome this obstacle, we have designed erythrocyte membrane nanoparticles (EMNP) using sonication method. The permeability of PTX by EMNP was 3.5-fold (Papp = 0.425 nm/s) and 16.2-fold (Papp = 394.1 nm/s) higher than free PTX in MDCK-MDR1 cell monolayers and intestinal mucosal tissue, respectively. The in vivo pharmacokinetics indicated that the AUC0-t (µg/mL·h) and Cmax (µg/mL) of EMNP were 14.2-fold and 6.0-fold higher than that of free PTX, respectively. In summary, the EMNP appears to be a promising nanoformulation to enhance the oral bioavailability of insoluble and poorly permeable drugs.

Novel GATAD2B loss-of-function mutations cause intellectual disability in two unrelated cases.

GATA zinc finger domain-containing 2B (GATAD2B) is a subunit of the methyl-CpG-binding protein-1 complex (MECP1), which deacetylates methylated nucleosomes and regresses transcriptional activity. Recently, GATAD2B has been elucidated as a candidate gene in patients with intellectual disability (ID). In this study, we identified two novel heterozygous frameshift mutations of GATAD2B in two unrelated ID cases through next-generation sequencing (NGS). Both of the mutations c.80_81insGATGT and c.552_555delGAAA cause truncated proteins that might be detrimental to neurodevelopment. We performed western blotting and observed a reduction in the target protein compared with normal controls. This is the first report of GATAD2B in Chinese ID patients. Our findings will broaden the spectrum of GATAD2B mutations and facilitate genetic diagnosis and counseling.

NIR Light-Activated Drug Release for Synergetic Chemo-Photothermal Therapy.

Nanocarriers like PEGylated liposomes have achieved enhanced drug accumulation in tumors and reduced systemic side effects, but failed to actively release the carried drug into cancer cells. To obtain improved therapeutic efficacy, we designed a novel liposome that was inserted by the amphiphilic agent PEG-IR780-C13 (PIC-Lipo) and encapsulated therapeutic agent doxorubicin (DOX), termed as DOX@PIC-Lipo. Upon NIR laser irradiation, the novel liposomes could generate hyperthermia and facilitate the release of encapsulated DOX from PIC-Lipo, which were confirmed by photothermal curves and the DOX release assay in vitro, respectively. In addition, the enhanced DOX release and sufficient hyperthermia have performed synergetic therapeutic efficacy both in vitro and in vivo. Therefore, DOX@PIC-Lipo might provide an active strategy to release the loaded drug for synergetic chemo-photothermal combined therapy.

Liposome encapsulated perfluorohexane enhances radiotherapy in mice without additional oxygen supply.

BACKGROUND: To investigate the effect of perfluorochemical preparations in enhancing radiotherapy, perfluocarbon nanoparticles were by encapsulating perfluorohexane into liposome [lip(PFH)]. METHODS: After intravenous injection, lip(PFH) could accumulate in the tumor site over time, with a prominent accumulation in tumor 24 h post injection. X-ray was delivered to the tumor site 24 h after the injection of lip(PFH) under room air. The experimental mice were randomized into four groups: control (saline), lip(PFH) (lip(PFH) only), X-ray (X-ray only), and lip(PFH) + X-ray (lip(PFH) with X-ray radiation). Tumor volume and histology were monitored to assess treatment efficacy. RESULTS: Tumor growth was significantly reduced in mice received lip(PFH) and X-ray compared with X-ray only. The histological data also revealed more destruction of tumor tissue in lip(PFH) + X-ray group compared with X-ray only. In addition, lip(PFH) did not show any significant tissue damage to major organs or induce significant liver/kidney dysfunction. CONCLUSIONS: Lip(PFH) could accumulate in the tumor site and enhance radiotherapy without additional oxygen supply.

A novel de novo POGZ mutation in a patient with intellectual disability.

POGZ, the gene encoding pogo transposable element-derived protein with zinc-finger domain, has been implicated in autism spectrum disorder and it is widely expressed in the human tissues, including the brain. Intellectual disability (ID) is highly heterogeneous neurodevelopment disorder and affects ~2-3% of the general population. Here we report the identification of a novel frameshift mutation in the coding region of the POGZ gene (c.1277_1278insC), which occurred de novo in a Chinese patient with ID. In silico analysis and western blotting revealed this frameshift mutation generating truncated protein in peripheral blood lymphocytes, and this may disrupt several important domains of POGZ gene. Our finding broadens the spectrum of POGZ mutations and may help to understand the molecular basis of ID and aid genetic counseling.

Photothermal Ablation of in Situ Renal Tumor by PEG-IR780-C13 Micelles and Near-Infrared Irradiation.

PEG-IR780-C13 micelles have been demonstrated to be a novel photothermal agent with tumor-targeting property. This study was designed to explore the feasibility of applying PEG-IR780-C13 micelles and near-infrared (NIR) irradiation for thermal ablation of renal tumor by using an in situ tumor model. In addition, the potential thermal injury to normal renal tissue was evaluated. PEG-IR780-C13 micelles were intended to accumulate in renal tumor after systemic delivery. In vitro results revealed that PEG-IR780-C13 micelles were uptaken by RENCA cells mainly through caveola-mediated endocytosis and mainly distributed in late endosomes and lysosomes. Upon NIR irradiation, PEG-IR780-C13 micelles generated heat effectively both in vitro and in vivo, exhibiting a promising photothermal therapeutic property. The photothermal effect of PEG-IR780-C13 micelles could effectively destroy RENCA cells in vitro and adequately inhibit growth of in situ renal tumor in vivo. Meanwhile, PEG-IR780-C13 micelles mediated photothermal therapy (PTT) resulting in only limited injury to normal renal tissue surrounding tumor sites. Our data indicated that PEG-IR780-C13 micelles mediating PTT could generate tumor-specific heat for destruction of renal tumor in a minimally invasive way, providing a novel strategy for thermal ablation of renal tumor.