Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy

Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.

Stratification of portal vein-invaded hepatocellular carcinoma treated with transarterial chemoembolization monotherapy

Purpose:The study aimed to establish a prognostic prediction model and an artificial neural network(ANN)model to determine who will benefit from transarterial chemoembolization(TACE)monotherapy for patients with hepatocellular carcinoma(HCC)invading portal vein.Methods:Treatment-naive patients with HCC and portal vein invasion who were treated with TACE monotherapy at hospital A as training cohort and hospital B as validation cohort were included.The primary endpoint was overall survival(OS).In training cohort,independent risk factors associated with OS were identified by univariate and multivariate analysis.The prognostic prediction(PP)and ANN models based on the independent risk factors were established to find out who will benefit most from TACE monotherapy.The type of portal vein tumor thrombosis was classified based on the Cheng’s Classification.The accuracy of the models was validated in validation cohort.Results:Totally,242 patients(training cohort:n=159;validation cohort:n=83)were included.The median OS was 7.1 and 8.5 months in training and validation cohort,respectively.In training cohort,the PP model was established based on the following five independent risk factors:Cheng’s Classification,Eastern Cooperative Oncology Group score,maximum tumor size,number of HCC nodules,and Child-Pugh stage.PP score of 17.5 was identified as cut-off point and patients were divided into two groups by PP score<17.5 and>17.5 in survival benefit and prognostication(8.8 vs.5.5 months;P<0.001).These five factors were included and ranked based on the importance associated with OS in the ANN model.Both of the two models received high accuracy after validation.Conclusions:Portal vein invaded HCC patients with PP score<17.5 may benefit most from TACE monotherapy.For these patients,TACE monotherapy should be considered.

Precision interventional radiology

The recent interest in precision medicine among interventionists has led to the establishment of the concept of precision interventional radiology(PIR).This concept focuses not only on the accuracy of interventional operations using traditional image-guided techniques,but also on the comprehensive evaluation of diseases.The invisible features extracted from CT,MRI,or US improve the accuracy and specificity of diagnosis.The integration of multi-omics and molecule imaging provides more information for interventional operations.The development and application of drugs,embolic materials,and devices broaden the concept of PIR.Integrating medicine and engineering brings new image-guided techniques that increase the efficacy of interventional operations while reducing the complications of interventional treatment.In all,PIR,an important part of precision medicine,emphasizing the whole disease management process,including precision diagnosis,comprehensive evaluation,and interventional therapy,maximizes the benefits of patients with limited damage.

Fucoidan-based dual-targeting mesoporous polydopamine for enhanced MRI-guided chemo-photothermal therapy of HCC via P-selectin-mediated drug delivery

The development of novel theranostic agents with outstanding diagnostic and therapeutic performances is still strongly desired in the treatment of hepatocellular carcinoma(HCC).Here,a fucoidan-modified mesoporous polydopamine nanoparticle dual-loaded with gadolinium iron and doxorubicin(FMPDA/Gd^(3+)/DOX)was prepared as an effective theranostic agent for magnetic resonance imaging(MRI)-guided chemo-photothermal therapy of HCC.It was found that FMPDA/Gd^(3+)/DOX had a high photothermal conversion efficiency of 33.4%and excellent T1-MRI performance with a longitudinal relaxivity(r1)value of 14.966 m M^(-1)·s^(-1).Moreover,the results suggested that FMPDA/Gd^(3+)/DOX could effectively accumulate into the tumor foci by dual-targeting the tumor-infiltrated platelets and HCC cells,which resulted from the specific interaction between fucoidan and overexpressed p-selectin receptors.The excellent tumor-homing ability and MRI-guided chemo-photothermal therapy therefore endowed FMPDA/Gd^(3+)/DOX with a strongest ability to inhibit tumor growth than the respective single treatment modality.Overall,our study demonstrated that FMPDA/Gd^(3+)/DOX could be applied as a potential nanoplatform for safe and effective cancer theranostics.

Manganese molybdate nanodots with dual amplification of STING activation for“cycle”treatment of metalloimmunotherapy

Certain types of cationic metal ions,such as Mn^(2+)are able to activate immune functions via the stimulator of interferon genes(STING)pathway,showing potential applications in eliciting antitumor immunity.How anionic ions interact with immune cells remains largely unknown.Herein,selecting from a range of cationic and anionic ions,we were excited to discover that MoO_(4)^(2-)could act as a cGAS-STING agonist and further confirmed the capability of Mn^(2+)to activate the cGAS-STING pathway.Inspired by such findings,we synthesized manganese molybdate nanoparticles with polyethylene glycol modification(MMP NDs)for cancer metalloimmunotherapy.Meanwhile,MMP NDs could consume glutathione(GSH)over-expressed in tumors and induce ferroptosis owing to high-valence Mo and Mn to elicit tumor-specific immune responses,which was further amplified by MMP-triggered the cGAS-STING activation.In turn,activated CD8+T cells to secrete high levels of interferonγ(IFN-γ)and reduced GPX4 expression in tumor cells to trigger ferroptosis-specific lipid peroxidation,which constituted a“cycle”of therapy.As a result,the metalloimmunotherapy with systemic administration of MMP NDs offered a remarkable tumor inhibition effect for a variety of tumor models.Our work for the first time discovered the ability of anionic metal ions to activate the immune system and rationally designed bimetallic oxide nanostructures as a multifunctional therapeutic nanoplatform for tumor immunotherapy.

Sialic acid-engineered mesoporous polydopamine nanoparticles loaded with SPIO and Fe3+as a novel theranostic agent for T1/T2 dual-mode MRI-guided combined chemo-photothermal treatment of hepatic cancer

diagnostic and therapeutic capability are highly needed for the treatment of hepatic cancer.Herein,we aimed to develop a novel mesoporous polydopamine(MPDA)-based theranostic agent for T1/T2 dual magnetic resonance imaging(MRI)-guided cancer chemo-photothermal therapy.Superparamagnetic iron oxide(SPIO)-loaded MPDA NPs(MPDA@SPIO)was firstly prepared,followed by modifying with a targeted molecule of sialic acid(SA)and chelating with Fe^(3+)(SA-MPDA@SPIO/Fe^(3+) NPs).After that,doxorubicin(DOX)-loaded SA-MPDA@SPIO/Fe^(3+) NPs(SA-MPDA@SPIO/DOX/Fe^(3+))was prepared for tumor theranostics.The prepared SAPEG-MPDA@SPIO/Fe^(3+) NPs were water-dispersible and biocompatible as evidenced by MTT assay.In vitro photothermal and relaxivity property suggested that the novel theranostic agent possessed excellent photothermal conversion capability and photostability,with relaxivity of being r1=4.29 mM1s1 and r2=105.53 mM1s1,respectively.SAPEG-MPDA@SPIO/Fe^(3+) NPs could effectively encapsulate the DOX,showing dual pH-and thermal-triggered drug release behavior.In vitro and in vivo studies revealed that SA-MPDA@SPIO/DOX/Fe^(3+) NPs could effectively target to the hepatic tumor tissue,which was possibly due to the specific interaction between SA and the overexpressed E-selectin.This behavior also endowed SA-MPDA@SPIO/DOX/Fe^(3+)NPs with a more precise T1-T2 dual mode contrast imaging effect than the one without SA modification.In addition,SAPEG-MPDA@SPIO/DOX/Fe^(3+) NPs displayed a superior therapeutic effect,which was due to its active targeting ability and combined effects of chemotherapy and photothermal therapy.These results demonstrated that SAPEG-MPDA@SPIO/DOX/Fe^(3+) NPs is an effective targeted nanoplatform for tumor theranostics,having potential value in the effective treatment of hepatic cancer.

PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE)-a population-based prospective cohort study: rationale, design and baseline participant characteristics

Background and purpose Cardiovascular diseases and dementia are two major diseases in the elderly.Atherosclerosis is associated with future vascular events and cognitive impairment.The PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events(PRECISE)study is a population-based prospective cohort study with comprehensive evaluation of multiterritorial artery stenosis and plaque using advanced vascular imaging techniques and prospective collection of vascular events and cognitive assessments.Methods Between May 2017 and September 2019,the PRECISE study enrolled 3067 community-dwelling adults with ages between 50 and 75 years cluster sampled from six villages and four communities of Lishui city in China.Data are collected in face-to face interviews at baseline,2-year and 4-year follow-up visits.Brain MRI including high-resolution sequences for intracranial and carotidal arteries and CT angiography for thoracoabdominal arteries were performed at baseline and will be rescanned after 4 years.Cardiovascular/cerebrovascular events and cognitive assessment will be prospectively collected after the enrollment.Blood and urine samples were collected and biomarkers were tested at baseline.Results A total of 3067 subjects were enrolled,among which 53.5%were female with an average age of 61.2±6.7 years.Among them,2.8%,8.1%,43.1%and 21.6%had a history of stroke,coronary heart diseases,hypertension and diabetes mellitus,respectively.Conclusions The PRECISE study is a population-based prospective cohort study with comprehensive evaluation of atherosclerotic stenosis and plaque using advanced vascular imaging techniques.Data from this cohort provide us an opportunity to precisely evaluate polyvascular atherosclerosis and its association with future vascular events and cognitive impairment.

Multifunctional Gd-CuS loaded UCST polymeric micelles for MR/PA imaging-guided chemo-photothermal tumor treatment

Hepatocellular carcinoma(HCC)is a life-threatening disease for which there is no effective treatment currently.Novel theranostics simultaneously having excellent imaging and therapeutic functions are highly desired in cancer therapy.Herein,we develop the sialic acid(SA)modified polymeric micelles at an upper critical solution temperature(UCST)of 43℃(sialic acid-poly(ethylene glycol)-poly(acrylamide-co-acrylonitrile),SA-PEG-p(AAm-co-AN)),which further encapsulated with doxorubicin(DOX)and Gd-CuS nanoparticles(Gd-CuS NPs)for chemo-photothermal treatment of HCC guided by magnetic resonance(MR)/photoacoustic(PA)dual-mode imaging.The resultant SA-PEG-p(AAm-co-AN)/DOX/Gd-CuS(SPDG)had an excellent photothermal conversion efficiency,enabling SPDG with an instantaneous release behavior of DOX under near-infrared(NIR)irradiation.This study also revealed that SPDG could actively target to HCC,which was due to that SA had a high affinity with E-selectin overexpressed at the tumor site.Moreover,benefiting from the HCC-targeted ability and NIR light-controlled on-demand delivery of DOX,SPDG showed a superior potential in MR/PA dual-mode imaging-guided chemo-photothermal treatment.Overall,our study reveals that the designed SPDG may be used as an ideal multifunctional nanoplatform for cancer theranostics.