Controlled delivery of protein therapeutics remains a challenge. Here, the inclusion of diselenide‐bond‐containing organosilica moieties into the framework of silica to fabricate biodegradable ...mesoporous silica nanoparticles (MSNs) with oxidative and redox dual‐responsiveness is reported. These diselenide‐bridged MSNs can encapsulate cytotoxic RNase A into the 8–10 nm internal pores via electrostatic interaction and release the payload via a matrix‐degradation controlled mechanism upon exposure to oxidative or redox conditions. After surface cloaking with cancer‐cell‐derived membrane fragments, these bioinspired RNase A‐loaded MSNs exhibit homologous targeting and immune‐invasion characteristics inherited from the source cancer cells. The efficient in vitro and in vivo anti‐cancer performance, which includes increased blood circulation time and enhanced tumor accumulation along with low toxicity, suggests that these cell‐membrane‐coated, dual‐responsive degradable MSNs represent a promising platform for the delivery of bio‐macromolecules such as protein and nucleic acid therapeutics.
Diselenide‐bond‐containing organosilica moieties are introduced into the framework of mesoporous silica to fabricate biodegradable mesoporous silica nanoparticles (MSNs) with an oxidative and redox dual‐responsive degradable feature. After surface cloaking with cancer‐cell‐derived membrane fragments, these bioinspired RNase‐A‐loaded MSNs exhibit homologous targeting and immune escape abilities, leading to efficient in vitro and in vivo anti‐cancer performance along with low toxicity.
Chemotherapy causes off‐target toxicity and is often ineffective against solid tumors. Targeted and on‐demand release of chemotherapeutics remains a challenge. Here, cancer‐cell‐membrane‐coated ...mesoporous organosilica nanoparticles (MONs) containing X‐ray‐ and reactive oxygen species (ROS)‐responsive diselenide bonds for controlled release of doxorubicin (DOX) at tumor sites are developed. DOX‐loaded MONs coated with 4T1 breast cancer cell membranes (CM@MON@DOX) show greater accumulation at tumor sites and prolonged blood circulation time versus an uncoated control in mice bearing 4T1 orthotopic mammary tumors. Under low‐dose X‐ray radiation, the DOX‐loaded MONs exhibit carrier degradation‐controlled release via cleavage of diselenide bonds, resulting in DOX‐mediated immunogenic cell death at the tumor site. Combination with a PD‐L1 checkpoint blockade further enhances inhibition of tumor growth and metastasis with low systemic toxicity. Together, the findings show the promise of these biomimetic, radiation‐responsive diselenide‐bond‐bridged MONs in chemo‐immunotherapy.
Biomimetic mesoporous organosilica nanoparticles are tailored for radiation‐responsive delivery of doxorubicin to solid tumors and are combined with a PD‐L1 checkpoint blockade as a chemo‐immunotherapy strategy. Under low‐dose X‐ray radiation, these cancer‐cell‐membrane‐coated nanotherapeutics exhibit degradation‐controlled drug release and induce anti‐tumor immune responses, leading to enhanced tumor regression and metastasis inhibition with low systemic toxicity when combined with anti‐PD‐L1.
We study four quasi-two-body decay processes including D0⁎(2400) as the intermediate state in the perturbative QCD (PQCD) approach. The branching fraction predicted in this work for the decay mode ...B−→D0⁎(2400)0π−→D+π−π− agree with the data from Belle, BaBar and LHCb Collaborations. The PQCD prediction of the branching ratio for the decay B¯0→D0⁎+K−→D0π+K− is consistent with the value given by LHCb. For the decays B¯0→D0⁎+π−→D0π+π− and B−→D0⁎0K−→D+π−K−, the PQCD predicted branch ratios are 2.85−0.80+1.23(ωB)−0.81+1.05(ωDπ)−0.31+0.33(aDπ)−0.05+0.06(ΓD0⁎+)×10−4 and 4.65−1.30+1.89(ωB)−1.24+1.51(ωDπ)+0.40−0.38(aDπ)−0.18+0.22(ΓD0⁎0)×10−5, respectively. We analyze the experimental branching fractions using the ratios RD0⁎0 and RD0⁎+ which are related to the decays with the neutral and charged D0⁎(2400), respectively. The available experimental results for the quasi-two-body decays including D0⁎(2400) are not in agreement with the isospin relation and SU(3) flavor symmetry.
To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.
Systematic review and network meta-analysis.
...Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018.
Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group.
36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer.
Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events.
PROSPERO CRD42017082553.
Amplifying the chemotherapy‐driven immunogenic cell death (ICD) for efficient and safe cancer chemoimmunotherapy remains a challenge. Here, a potential ICD nanoamplifier containing diselenide‐bridged ...mesoporous organosilica nanoparticles (MONs) and chemotherapeutic ruthenium compound (KP1339) to achieve cancer chemoimmunotherapy is tailored. KP1339‐loaded MONs show controlled drug release profiles via glutathione (GSH)‐responsive competitive coordination and matrix degradation. High concentration of MONs selectively evoked reactive oxygen species production, GSH depletion, and endoplasmic reticulum stress in cancer cells, thus amplifying the ICD of KP1339 and boosting robust antitumor immunological responses. After the combination of PD‐L1 checkpoint blockade, cancer cell membrane‐cloaked KP1339‐loaded MONs not only regress primary tumor growth with low systemic toxicity, but also inhibit distant tumor growth and pulmonary metastasis of breast cancer. The results have shown the potential of coordination and redox dual‐responsive MONs boosting amplified ICD for cancer chemoimmunotherapy.
Diselenide‐bridged mesoporous organosilica nanoparticles are selected for coordination and redox dual‐responsive delivery of the chemotherapeutic ruthenium compound KP1339. The cancer cell membrane‐cloaked immunogenic cell death nano‐amplifier performs robust suppression on primary and distant tumor growth, as well as pulmonary metastasis of breast cancer with low systematic toxicity when combined with anti‐PD‐L1.
We analyze the quasi-two-body decays B→Kρ→Kππ in the perturbative QCD (PQCD) approach, in which final-state interactions between the pions in the resonant regions associated with the P-wave states ...ρ(770) and ρ′(1450) are factorized into two-pion distribution amplitudes. Adopting experimental inputs for the time-like pion form factors involved in two-pion distribution amplitudes, we calculate branching ratios and direct CP asymmetries of the B→Kρ(770),Kρ′(1450)→Kππ modes. It is shown that agreement of theoretical results with data can be achieved, through which Gegenbauer moments of the P-wave two-pion distribution amplitudes are determined. The consistency between the three-body and two-body analyses of the B→Kρ(770)→Kππ decays supports the PQCD factorization framework for exclusive hadronic B meson decays.
Photodynamic therapy (PDT) is clinically promising in destructing primary tumors but ineffective against distant metastases. This study reports the use of immunogenic nanoparticles mediated ...combination of PDT and magnetic hyperthermia to synergistically augment the anti‐metastatic efficacy of immunotherapy. Janus nanobullets integrating chlorine e6 (Ce6) loaded, disulfide‐bridged mesoporous organosilica bodies with magnetic heads (M‐MONs@Ce6) are tailored for redox/pH‐triggered photosensitizer release accompanying their matrix degradation. Cancer cell membrane cloaking enables favorable tumor‐targeted accumulation and prolonged blood circulation time of M‐MONs@Ce6. The combination of PDT and magnetic hyperthermia has a strong synergy anticancer activity and simultaneously elicits a sequence of immunogenic cell death, resulting in synergistically tumor‐specific immune responses. When combined with anti‐CTLA‐4 antibody, the biomimetic and biodegradable nanoparticle enables the notable eradication of primary and deeply metastatic tumors with low systematic toxicity, thus potentially advancing the development of combined hyperthermia, PDT, and checkpoint blockade immunotherapy to combat cancer metastasis.
Janus magnetic nanoparticles are designed for redox‐/pH‐triggered photosensitizer release accompanying their matrix degradation. Cancer cell membrane cloaking improves combined photodynamic therapy and magnetic hyperthermia in a remarkable anticancer manner, which is harnessed for synergistic tumor‐specific immune response to integrate with cytotoxic T lymphocyte‐associated antigen‐4 antibody for notable eradication of primary and metastatic tumors with low systematic toxicity.
To explore the mechanisms through which hypoxic tumor microenvironment (TME) modulates the transition of tumor‐associated macrophages (TAMs). The migration ability of RAW264.7 macrophages was ...determined by transwell assay. Flow cytometric, western blot and immunofluorescence analyses of CD206 further validated the M2 polarization of macrophages. Immunofluorescence, western blot and qRT‐PCR were performed to detect the expression of neuropilin‐1 (Nrp‐1) and carbonic anhydrase IX (CAIX). An intermittent hypobaric hypoxia (IH) animal model was established to evaluate the role of hypoxia in activating M2‐like TAMs in vivo. We also used immunohistochemistry to analyze the association between CAIX, CD163+ macrophages and Nrp‐1 in a series of 72 human cervical cancer specimens. We found that the hypoxic cervical TME educated the recruited macrophages to transform into the M2 phenotype. Nrp‐1 expression was significantly increased in hypoxia‐primed cervical cancer cells. Blocking Nrp‐1 expression prevented hypoxic cells from recruiting and polarizing macrophages towards the M2 phenotype. Hypoxia exposure significantly increased the expression of Nrp‐1 as well as the infiltration of macrophages in vivo. Consistently, immunochemical staining in serial tissue sections of cervical cancer revealed upregulated levels of Nrp‐1 in CAIX‐positive hypoxic regions along with a concurrent significant elevation of M2 macrophages. Nrp‐1 and M2‐like TAMs were related to the malignant properties of cervical cancer, such as the FIGO stage and lymph node metastasis. Nrp‐1 plays critical roles in hypoxic TME‐induced activation and pro‐tumoral effects of TAMs in cervical cancer. Interfering with Nrp‐1 may be a potential therapeutic strategy in treating cervical cancer.
Cancer immunotherapy is limited by the immune escape of tumor cells and adverse effects. Photo-immunotherapy, the combination of immunotherapy and phototherapy (such as photodynamic therapy (PDT) and ...photothermal therapy (PTT)), can improve the effectiveness of immunotherapy in cancer treatment. Here, we first explored mesoporous hexagonal core-shell zinc porphyrin-silica nanoparticles (MPSNs), which are composed of a zinc porphyrin core and a mesoporous silica shell, and exhibit high laser-triggered photodynamic and photothermal activity, as well as outstanding drug loading capacity. In other words, MPSNs can be used not only as excellent photosensitizers for photo-immunotherapy, but also as an ideal drug carrier to achieve more efficient synergy. After loading with R837 (imiquimod, a toll-like receptor-7 agonist), MPSNs@R837 will elicit high-efficiency immunogenic cell death via PDT and PTT, and promote dendritic cell maturation after the PH-responsive release of R837, thereby, inducing tumor-specific immune responses. When combined with a programmed death ligand-1 checkpoint blockade, the photo-immunotherapy system markedly restrains primary tumors and metastatic tumors with negligible systemic toxicity. Therefore, the therapeutic strategy of integrating PTT, PDT and checkpoint blockade, shows great potential for suppressing cancer metastasis.
A transition‐metal‐free visible‐light‐promoted radical phosphorylation/cyclization of N‐allylbenzamides with phosphine oxides for the synthesis of phosphoryl‐substituted dihydroisoquinolones was ...developed under room temperature. This protocol features mild reaction conditions, simple operation, broad substrate scope as well as scale‐up ability.
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