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

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 136-152页

作者： Xiaoju Guo Xiaoxiao Chen Jiayi Ding Feng Zhang Shunyang Chen Xin Hu Shiji Fang Lin Shen Chenying Lu Zhongwei Zhao Jianfei Tu Gaofeng Shu Minjiang Chen Jiansong Ji Lishui Central Hospital Shaoxing UniversityShaoxing 312000China Zhejiang Key Laboratory of imaging and interventional Medicine Imaging Diagnosis and Interventional Minimally Invasive InstituteThe Fifth Affiliated Hospital of Wenzhou Medical UniversityLishui 323000China Clinical College of The Affiliated Central Hospital School of MedicineLishui UniversityLishui 323000China Key Laboratory of Precision Medicine of Lishui Lishui 323000China

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.

关键词： CaCO3-based nanoparticles Hypoxia attenuation Acidity neutralization Reversal of chemotherapy resistance Enhanced chemo-immunotherapy

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma

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World Journal of Gastroenterology 2024年第17期30卷 2321-2331页

作者： Zhi-Peng Lin Xiao-Long Hu Du Chen Da-Bei Huang Xu-Gong Zou Hai Zhong Sheng-Xiang Xu Yuan Chen Xiao-Qun Li Jian Zhang department of interventional Medicine Zhongshan People’s HospitalZhongshan 528400Guangdong ProvinceChina

BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.

关键词： Hepatocellular carcinoma Hepatic arterial infusion chemotherapy Targeted therapy Immunotherapy Adverse events

Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

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World Journal of Gastroenterology 2024年第4期30卷 318-331页

作者： Yu-Zhe Cao Guang-Lei Zheng Tian-Qi Zhang Hong-Yan Shao Jia-Yu Pan Zi-Lin Huang Meng-Xuan Zuo department of Minimally Invasive interventional Therapy Sun Yat-sen University Cancer CenterGuangzhou 510060Guangdong ProvinceChina department of Minimally Invasive interventional Therapy State Key Laboratory of Oncology in South ChinaGuangzhou 510060Guangdong ProvinceChina department of Minimally Invasive interventional Therapy Guangdong Provincial Clinical Research Center for CancerGuangzhou 510060Guangdong ProvinceChina

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

关键词： Unresectable hepatocellular carcinoma Hepatic arterial infusion chemotherapy Angiogenesis inhibitors Programmed cell death protein 1 Programmed death ligand 1

Self-fueling ferroptosis-inducing microreactors based on p H-responsive Lipiodol Pickering emulsions enable transarterial ferro-embolization therapy

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National Science Review 2024年第1期11卷 74-85页

作者： Chunjie Wang Lei Zhang Zhijuan Yang Dongxu Zhao Zheng Deng Jialu Xu Yumin Wu Yu Hao Ziliang Dong Liangzhu Feng Zhuang Liu Institute of Functional Nano & Soft Materials (FUNSOM) Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices Soochow University Center of interventional Radiology & Vascular Surgery Department of Radiology Zhongda Hospital Medical School Southeast University department of interventional Radiology The First Afflliated Hospital of Soochow University

Lipiodol chemotherapeutic emulsions remain one of the main choices for the treatment of unresectable hepatocellular carcinoma(HCC) via transarterial chemoembolization(TACE). However, the limited stability of Lipiodol chemotherapeutic emulsions would lead to rapid drug diffusion, which would reduce the therapeutic benefit and cause systemic toxicity of administrated chemotherapeutics. Therefore, the development of enhanced Lipiodol-based formulations is of great significance to enable effective and safe TACE treatment. Herein, a stable water-in-oil Lipiodol Pickering emulsion(LPE) stabilized by pH-dissociable calcium carbonate nanoparticles and hemin is prepared and utilized for efficient encapsulation of lipoxygenase(LOX). The obtained LOX-loaded CaCO3&hemin-stabilized LPE(LHCa-LPE) showing greatly improved emulsion stability could work as a pH-responsive and self-fueling microreactor to convert polyunsaturated fatty acids(PUFAs), a main component of Lipiodol, to cytotoxic lipid radicals through the cascading catalytic reaction driven by LOX and hemin, thus inducing ferroptosis of cancer cells. As a result, such LHCa-LPE upon transcatheter embolization can effectively suppress the progression of orthotopic N1S1 HCC in rats. This study highlights a concise strategy to prepare pH-responsive and stable LPE-based self-fueling microreactors, which could serve as bifunctional embolic and ferroptosis-inducing agents to enable proof-of-concept transarterial ferro-embolization therapy of HCC.

关键词： CaCO3 nanoparticles Pickering emulsion ferroptosis lipid peroxidation transarterial ferro-embolization

Ambroxol,the cough expectorant with neuroprotective effects

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Neural Regeneration Research 2024年第11期19卷 2345-2346页

作者： Kristin Patzwaldt Salvador Castaneda-Vega Werner Siemens imaging Center Department of Preclinical Imaging and RadiopharmacyEberhard Karls University TuebingenTuebingenGermany department of Nuclear Medicine and Clinical Molecular imaging University Clinic TuebingenTuebingenGermany

Ambroxol hydrochloride(2-amino-3,5-dibromo-N-methylbenzylamine hydrochloride)has been used as a mucolytic agent in the treatment of respiratory diseases since the late 1970s.Its effects on mucus membranes such as mucus disruption,increased mucus production,and low toxicity profile were addressed in its original German patent in 1966.These first described properties have kept Ambroxol available worldwide and over the counter in the pharmaceutical market to this day.

关键词： protective agent German

Enhancing competency of clinical research nurses:A comprehensive training and evaluation framework

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World Journal of Clinical Cases 2024年第7期12卷 1378-1381页

作者： Yang-Xi Liu Yi Xu Tumor interventional department Taizhou Municipal HospitalTaizhou 318099Zhejiang ProvinceChina

The Sun et al's training program for clinical research nurses(CRNs)in the World Journal of Clinical Cases is a comprehensive and scientific approach.It includes structured frameworks for CRN training,aiming to improve CRN competency.This program emphasizes practical abilities,updates training content,and improves evaluation methods.The cultivation of CRN talents focuses on enhancing the training system,establishing a multifaceted evaluation framework,and continuously refining the training programs.Regular feedback and evalua-tion are essential to improve CRNs'competency in practical settings.

关键词： Clinical research nurse Framework Nurse Operations Practice Structure

Gene expression profiles contribute to robustly predicting prognosis in hepatocellular carcinoma

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Genes & Diseases 2024年第2期11卷 593-596页

作者： Long Liu Yuhui Wang Yuyuan Zhang Siyuan Weng Hui Xu Zaoqu Liu Xinwei Han department of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Prenatal Diagnosis Center The Third Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China department of interventional Radiology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China interventional Institute of Zhengzhou University ZhengzhouHenan 450052China interventional Treatment and Clinical Research Center of Henan Province ZhengzhouHenan 450052China

Hepatocellular carcinoma(HCC)is characterized by both inter-and intra-tumor heterogeneity and has distinct clinical outcomes.1 A promising clinical tool to perform patient stratification,prognosis evaluation,and treatment recommendations is indispensable.Here,we enrolled a total of 1595 tumor patients from 13 independent cohorts,including seven cohorts with survival data,four cohorts with immunotherapy information,and two cohorts with transcatheter arterial chemoembolization(TACE)and Sorafenib information,respectively(Table S1).Using 96 algorithms combinations derived from 10 popular machinelearning approaches,a novel framework was constructed and described in Figure S1.Firstly,a total of 26 stable consensus prognostic genes were screened in seven cohorts harboring complete survival information via univariate Cox regression analysis(Fig.S2A).

关键词： prognosis clinical arterial

Silencing of peroxiredoxin 2 suppresses proliferation and Wnt/β-catenin pathway,and induces senescence in hepatocellular carcinoma

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Oncology Research 2024年第1期32卷 213-226页

作者： XUEGANG YANG XIANHONG XIANG GUOHUI XU SHI ZHOU TIANZHI AN ZHI HUANG department of interventional Radiology Sichuan Cancer Hospital and InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaRadiation Oncology Key Laboratory of Sichuan ProvinceChengdu610041China department of interventional Radiology The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou510080China department of interventional Radiology Affiliated Hospital of Guizhou Medical UniversityGuiyang550004China School of Basic Medical Science Guizhou Medical UniversityGuiyang550002China

Hepatocellular carcinoma(HCC),a common malignancy worldwide,still lacks effective clinical treatment.The study aimed to investigate the oncogenes that affect the progression of HCC and their possible mechanisms.In our study,we initially confirmed a higher level of PRDX2 in the bile of HCC patients compared to those with choledocholithiasis by 2-DE,LC-MS,and ELISA.Subsequently,we demonstrated the high expression of peroxiredoxin 2(PRDX2)in HCC based on the TCGA database and clinical sample analysis.Furthermore,PRDX2 overexpression enhanced the viability of HCC cells.And PRDX2 silencing induced senescence of HCC cells.In vivo,knockdown of PRDX2 significantly reduced the weight of xenograft tumors.PRDX2 also was found to activate the Wnt/β-catenin pathway by inducingβ-catenin nuclear translocation.Consequently,we proved that silencing PRDX2 could inhibit proliferation and Wnt/β-catenin pathway while promoting senescence in HCC cells.

关键词： Peroxiredoxin 2 Hepatocellular carcinoma Wnt/β-catenin pathway Senescence Proliferation

Blood-brain barrier pathology in cerebral small vessel disease

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Neural Regeneration Research 2024年第6期19卷 1233-1240页

作者： Ruxue Jia Gemma Solé-Guardia Amanda J.Kiliaan department of Medical imaging Anatomy Radboud University Medical Center Donders Institute for Brain Cognition & Behavior Center for Medical Neuroscience Preclinical Imaging Center PRIME Radboud Alzheimer Center

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly. Although at first it was considered innocuous, small vessel disease is nowadays regarded as one of the major vascular causes of dementia. Radiological signs of small vessel disease include small subcortical infarcts, white matter magnetic resonance imaging hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy; however, great heterogeneity in clinical symptoms is observed in small vessel disease patients. The pathophysiology of these lesions has been linked to multiple processes, such as hypoperfusion, defective cerebrovascular reactivity, and blood-brain barrier dysfunction. Notably, studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease. Therefore, the purpose of this review is to provide a new foundation in the study of small vessel disease pathology. First, we discuss the main structural domains and functions of the blood-brain barrier. Secondly, we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease. Finally, we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

关键词： blood-brain barrier dysfunction cerebral blood flow cerebral hypoperfusion endothelial dysfunction hypertension inflammation magnetic resonance imaging neurovascular unit oxidative stress small vessel disease tight junctions transcytosis