Correction: A H2O2 self-sufficient nanoplatform with domino effects for thermal-responsive enhanced chemodynamic therapy.

[This corrects the article DOI: 10.1039/C9SC05506A.].

Validity of data extraction in evidence synthesis practice of adverse events: reproducibility study.

OBJECTIVES: To investigate the validity of data extraction in systematic reviews of adverse events, the effect of data extraction errors on the results, and to develop a classification framework for data extraction errors to support further methodological research. DESIGN: Reproducibility study. DATA SOURCES: PubMed was searched for eligible systematic reviews published between 1 January 2015 and 1 January 2020. Metadata from the randomised controlled trials were extracted from the systematic reviews by four authors. The original data sources (eg, full text and ClinicalTrials.gov) were then referred to by the same authors to reproduce the data used in these meta-analyses. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Systematic reviews were included when based on randomised controlled trials for healthcare interventions that reported safety as the exclusive outcome, with at least one pair meta-analysis that included five or more randomised controlled trials and with a 2×2 table of data for event counts and sample sizes in intervention and control arms available for each trial in the meta-analysis. MAIN OUTCOME MEASURES: The primary outcome was data extraction errors summarised at three levels: study level, meta-analysis level, and systematic review level. The potential effect of such errors on the results was further investigated. RESULTS: 201 systematic reviews and 829 pairwise meta-analyses involving 10 386 randomised controlled trials were included. Data extraction could not be reproduced in 1762 (17.0%) of 10 386 trials. In 554 (66.8%) of 829 meta-analyses, at least one randomised controlled trial had data extraction errors; 171 (85.1%) of 201 systematic reviews had at least one meta-analysis with data extraction errors. The most common types of data extraction errors were numerical errors (49.2%, 867/1762) and ambiguous errors (29.9%, 526/1762), mainly caused by ambiguous definitions of the outcomes. These categories were followed by three others: zero assumption errors, misidentification, and mismatching errors. The impact of these errors were analysed on 288 meta-analyses. Data extraction errors led to 10 (3.5%) of 288 meta-analyses changing the direction of the effect and 19 (6.6%) of 288 meta-analyses changing the significance of the P value. Meta-analyses that had two or more different types of errors were more susceptible to these changes than those with only one type of error (for moderate changes, 11 (28.2%) of 39 v 26 (10.4%) 249, P=0.002; for large changes, 5 (12.8%) of 39 v 8 (3.2%) of 249, P=0.01). CONCLUSION: Systematic reviews of adverse events potentially have serious issues in terms of the reproducibility of the data extraction, and these errors can mislead the conclusions. Implementation guidelines are urgently required to help authors of future systematic reviews improve the validity of data extraction.

Proton-Driven Transformable 1 O2 -Nanotrap for Dark and Hypoxia Tolerant Photodynamic Therapy.

Despite the clinical potential, photodynamic therapy (PDT) relying on singlet oxygen (1 O2 ) generation is severely limited by tumor hypoxia and endosomal entrapment. Herein, a proton-driven transformable 1 O2 -nanotrap (ANBDP NPs) with endosomal escape capability is presented to improve hypoxic tumor PDT. In the acidic endosomal environment, the protonated 1 O2 -nanotrap ruptures endosomal membranes via a "proton-sponge" like effect and undergoes a drastic morphology-and-size change from nanocubes (≈94.1 nm in length) to nanospheres (≈12.3 nm in diameter). Simultaneously, anthracenyl boron dipyrromethene-derived photosensitizer (ANBDP) in nanospheres transforms to its protonated form (ANBDPH) and switches off its charge-transfer state to achieve amplified 1 O2 photogeneration capability. Upon 730 nm photoirradiation, ANBDPH prominently produces 1 O2 and traps generated-1 O2 in the anthracene group to form endoperoxide (ANOBDPH). Benefitting from the hypoxia-tolerant 1 O2 -release property of ANOBDPH in the dark, the 1 O2 -nanotrap brings about sustained therapeutic effect without further continuous irradiation, thereby achieving remarkable antitumor performance.

Thrombin Based Photothermal-Responsive Nanoplatform for Tumor-Specific Embolization Therapy.

The specific coagulation in the tumor vasculature has the potential for the ablation of solid tumors by cutting off the blood supply. However, the safe delivery of effective vessel occluding agents in the tumor-specific embolization therapy remains challenging. Herein, it is reported that the photothermal responsive tumor-specific embolization therapy based on thrombin (Thr) is delivered by intravenous injection via the phase-change materials (PCM)-based nanoparticles. The wax sealing profile of PCM enables safe delivery and prevents the preleakage of Thr in the blood circulation. While in the tumor site, the thermal effect induced by IR780 triggers the melting of PCM and rapidly releases Thr to generate coagulation in the tumor blood vessels. Based on the safe delivery and controllable release of Thr, thermal responsive tumor-specific embolization therapy could be achieved with high efficiency and no significant damage to normal organs and tissues. The safe administration of Thr to induce vascular infarction in tumors based on PCM nanoparticles in this work shows a promising strategy for improving the therapeutic specificity and efficacy of coagulation-based tumor therapy.

Small Molecular NIR-II Fluorophores for Cancer Phototheranostics.

Phototheranostics integrates deep-tissue imaging with phototherapy (containing photothermal therapy and photodynamic therapy), holding great promise in early diagnosis and precision treatment of cancers. Recently, second near-infrared (NIR-II) fluorescence imaging exhibits the merits of high accuracy and specificity, as well as real-time detection. Among the NIR-II fluorophores, organic small molecular fluorophores have shown superior properties in the biocompatibility, variable structure, and tunable emission wavelength than the inorganic NIR-II materials. What's more, some small molecular fluorophores also display excellent cytotoxicity when illuminated with the NIR laser. This review summarizes the progress of small molecular NIR-II fluorophores with different central cores for cancer phototheranostics in the past few years, focusing on the molecular structures and phototheranostic performances. Furthermore, challenges and prospects of future development toward clinical translation are discussed.

NIR-II Organic Nanotheranostics for Precision Oncotherapy.

Precision oncotherapy can remove tumors without causing any apparent iatrogenic damage or irreversible side effects to normal tissues. Second near-infrared (NIR-II) nanotheranostics can simultaneously perform diagnostic and therapeutic modalities in a single nanoplatform, which exhibits prominent perspectives in tumor precision treatment. Among all NIR-II nanotheranostics, NIR-II organic nanotheranostics have shown an exceptional promise for translation in clinical tumor treatment than NIR-II inorganic nanotheranostics in virtue of their good biocompatibility, excellent reproducibility, desirable excretion, and high biosafety. In this review, recent progress of NIR-II organic nanotheranostics with the integration of tumor diagnosis and therapy is systematically summarized, focusing on the theranostic modes and performances. Furthermore, the current status quo, problems, and challenges are discussed, aiming to provide a certain guiding significance for the future development of NIR-II organic nanotheranostics for precision oncotherapy.

Recent advances in phase change material based nanoplatforms for cancer therapy.

Cancer has become a severe threat to human life due to its high mortality and metastatic rate. Effective inhibition and killing of cancer cells using chemotherapeutic drugs have been a promising means in clinical cancer therapy. However, the low selectivity, drug-resistance, uncontrollability and serious side effects of chemotherapy significantly limit its further development. There is an urgent need for new treatment strategies to compensate for deficiencies inherent in chemotherapy alone. A growing body of research shows that combined treatment strategies have the potential to overcome this dilemma by achieving significantly enhanced synergistic effects and reduced side effects. Emerging phase change materials (PCMs) create an ideal nanoplatform for cancer combination therapy due to their universal loading properties, stable and temperature-responsive phase transition capability, and excellent natural biocompatibility/biodegradability. The release of therapeutic agents can be precisely controlled through external, non-intrusive stimuli (such as NIR light and ultrasound), avoiding systemic toxicity associated with conventional chemotherapy. Herein, the construction methods and design principles of PCM-based nanoplatforms serving as strict gatekeeper and smart payload delivery systems are discussed in detail. Moreover, the advantages and disadvantages of these nanoplatforms are provided. A suitable discussion and perspective of the remaining challenges and future opportunities for PCM-based nanoplatforms in cancer treatment are also given in conclusion.

A Highly-Efficient Type I Photosensitizer with Robust Vascular-Disruption Activity for Hypoxic-and-Metastatic Tumor Specific Photodynamic Therapy.

Hypoxia severely impedes photodynamic therapy (PDT) efficiency. Worse still, considerable tumor metastasis will occur after PDT. Herein, an organic superoxide radical (O2∙- ) nano-photogenerator as a highly effcient type I photosensitizer with robust vascular-disrupting efficiency to combat these thorny issues is designed. Boron difluoride dipyrromethene (BODIPY)-vadimezan conjugate (BDPVDA) is synthesized and enwrapped in electron-rich polymer-brushes methoxy-poly(ethylene glycol)-b-poly(2-(diisopropylamino) ethyl methacrylate) (mPEG- PPDA) to afford nanosized hydrophilic type I photosensitizer (PBV NPs). Owing to outstanding core-shell intermolecular electron transfer between BDPVDA and mPEG-PPDA, remarkable O2∙- can be produced by PBV NPs under near-infrared irradiation even in severe hypoxic environment (2% O2 ), thus to accomplish effective hypoxic-tumor elimination. Simultaneously, the efficient ester-bond hydrolysis of BDPVDA in the acidic tumor microenvironment allows vadimezan release from PBV NPs to disrupt vasculature, facilitating the shut-down of metastatic pathways. As a result, PBV NPs will not only be powerful in resolving the paradox between traditional type II PDT and hypoxia, but also successfully prevent tumor metastasis after type I PDT treatment (no secondary-tumors found in 70 days and 100% survival rate), enabling enhancement of existing hypoxic-and-metastatic tumor treatment.

A H2O2 self-sufficient nanoplatform with domino effects for thermal-responsive enhanced chemodynamic therapy.

Chemodynamic therapy (CDT), employing Fenton or Fenton-like catalysts to convert hydrogen peroxide (H2O2) into toxic hydroxyl radicals (˙OH) to kill cancer cells, holds high promise in tumor therapy due to its high selectivity. However, the anticancer efficacy is unsatisfactory owing to the limited concentration of endogenous H2O2. Herein, thermal responsive nanoparticles with H2O2 self-sufficiency are fabricated by utilizing organic phase change materials (PCMs) to encapsulate iron-gallic acid nanoparticles (Fe-GA) and ultra-small CaO2. PCMs, acting as the gatekeeper, could be melted down by the hyperthermia effect of Fe-GA under laser irradiation with a burst release of Fe-GA and CaO2. The acidic tumor microenvironment would further trigger CaO2 to generate a large amount of H2O2 and Ca2+. The self-supplied H2O2 would be converted into ˙OH by participating in the Fenton reaction with Fe-GA. Meanwhile, in situ generation of Ca2+ could cause mitochondrial damage and lead to apoptosis of tumor cells. With efficient tumor accumulation illustrated in in vivo photoacoustic imaging, Fe-GA/CaO2@PCM demonstrated a superior in vivo tumor-suppressive effect without inducing systemic toxicity. The study presents a unique domino effect approach of PCM based nanoparticles with thermal responsiveness, H2O2 self-supply, and greatly enhanced CDT effects, showing bright prospects for highly efficient tumor treatment.