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    The effect of tripterygium glucoside tablet on pharmacokinetics of losartan and its metabolite EXP3174 in rats. Hu Yongsheng,Zhou Xuexue,Shi Hui,Shi Wenyu,Ye Shengjie,Zhang Hai Biomedical chromatography : BMC Losartan and tripterygium glucoside tablet (TGT) are often simultaneously used for reducing urine protein excretion in clinic. However, it is unknown whether there is potential herb-drug interaction between losartan and TGT. The aim of this study was to investigate their potential herb-drug interaction, and clarify the mechanism of the effect of TGT on the pharmacokinetics of losartan and its metabolite EXP3174 in rats. The plasma concentrations of losartan and EXP3174 were determined by LC-MS, and the main pharmacokinetic parameters were calculated. The C , t and AUC of losartan became larger after co-administration, while the C and AUC of EXP3174 became smaller, suggesting that TGT could influence the pharmacokinetics of losartan and EXP3174. The effects of TGT and its main components on the metabolic rate of losartan were further investigated in rat liver microsomes. Results indicated that TGT and its two main ingredients could decrease the metabolic rate of losartan. Therefore, it was speculated that TGT might increase the plasma concentration of losartan and decrease the concentration of EXP3174 by inhibiting the metabolism of losartan. The results could provide references for clinical medication guidance of losartan and TGT to avoid the occurrence of adverse reactions. 10.1002/bmc.3973
    Nanoparticle multivalency counterbalances the ligand affinity loss upon PEGylation. Hennig Robert,Pollinger Klaus,Veser Anika,Breunig Miriam,Goepferich Achim Journal of controlled release : official journal of the Controlled Release Society The conjugation of receptor ligands to shielded nanoparticles is a widely used strategy to precisely control nanoparticle-cell interactions. However, it is often overlooked that a ligand's affinity can be severely impaired by its attachment to the polyethylene glycol (PEG) chains that are frequently used to protect colloids from serum protein adsorption. Using the model ligand EXP3174, a small-molecule antagonist for the angiotensin II receptor type 1 (AT1R), we investigated the ligand's affinity before and after its PEGylation and when attached to PEGylated nanoparticles. The PEGylated ligand displayed a 580-fold decreased receptor affinity compared to the native ligand. Due to their multivalency, the nanoparticles regained a low nanomolar receptor affinity, which is in the range of the affinity of the native ligand. Moreover, a four orders of magnitude higher concentration of free ligand was required to displace PEGylated nanoparticles carrying EXP3174 from the receptor. On average, one nanoparticle was decorated with 11.2 ligand molecules, which led to a multivalent enhancement factor of 22.5 compared to the monovalent PEGylated ligand. The targeted nanoparticles specifically bound the AT1R and showed no interaction to receptor negative cells. Our study shows that the attachment of a small-molecule ligand to a PEG chain can severely affect its receptor affinity. Concomitantly, when the ligand is tethered to nanoparticles, the immense avidity greatly increases the ligand-receptor interaction. Based on our results, we highly recommend the affinity testing of receptor ligands before and after PEGylation to identify potent molecules for active nanoparticle targeting. 10.1016/j.jconrel.2014.07.062
    AXL Overexpression in Tumor-Derived Endothelial Cells Promotes Vessel Metastasis in Patients With Hepatocellular Carcinoma. Chai Zong-Tao,Zhang Xiu-Ping,Ao Jian-Yang,Zhu Xiao-Dong,Wu Meng-Chao,Lau Wan Yee,Sun Hui-Chuan,Cheng Shu-Qun Frontiers in oncology Portal vein tumor thrombus (PVTT) is one of the most serious forms of hepatocellular carcinoma (HCC) vessel metastasis and has a poor survival rate. However, the molecular mechanism of PVTT has not yet been elucidated. In this study, the molecular mechanism of AXL expressed in tumor-derived endothelial cells (TECs) in vessel metastasis was investigated. High AXL expression was observed in TECs, but not in the tumor cells of HCC patients with PVTT and this was associated with poor overall survival (OS) and disease-free survival (DFS). AXL overexpression was positively associated with CD 31 expression both and . AXL promoted the cell proliferation, tube formation, and migration of both TECs and normal endothelial cells (NECs). High expression of AXL in TECs promoted the cell migration, but not the proliferation of HCC cells. Further studies demonstrated that AXL promoted cell migration and tube formation through activation of the PI3K/AKT/SOX2/DKK-1 axis. AXL overexpression in HUVECs promoted tumor growth and liver or vessel metastasis of HCC in xenograft nude mice, which could be counteracted by treatment with R428, an AXL inhibitor. R428 reduced tumor growth and CD 31 expression in HCC in PDX xenograft nude mice. Therefore, AXL over-expression in TECs promotes vessel metastasis of HCC, which indicates that AXL in TECs could be a potential therapeutic target in HCC patients with PVTT. 10.3389/fonc.2021.650963
    Expression of caspase-3 and hypoxia inducible factor 1α in hepatocellular carcinoma complicated by hemorrhage and necrosis. Liang Hui,Wu Jian-Guo,Wang Fei,Chen Bo-Xuan,Zou Shi-Tian,Wang Cong,Luo Shuai-Wu World journal of clinical cases BACKGROUND:Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver. Its onset is latent, and it shows high heterogeneity and can readily experience intrahepatic metastasis or systemic metastasis, which seriously affects patients' quality of life. Numerous studies have shown that hypoxia inducible factor1α (HIF-1α) plays a significant role in the occurrence and development of tumors, as it promotes the formation of intratumoral vessels and plays a key role in their metastasis and invasion. Some studies have reported that caspase-3, which is induced by various factors, is involved in the apoptosis of tumor cells. AIM:To investigate the expression of caspase-3 and HIF-1α and their relationship to the prognosis of patients with primary HCC complicated by pathological changes of hemorrhage and necrosis. METHODS:A total of 88 patients with HCC complicated by pathological changes of hemorrhage and necrosis who were treated at our hospital from January 2017 to December 2019 were selected. The expression of caspase-3 and HIF-1α in HCC and paracancerous tissues from these patients was assessed. RESULTS:The positive expression rate of caspase-3 in HCC tissues was 27.27%, which was significantly lower than that in the paracancerous tissues ( < 0.05), while the positive expression rate of HIF-1α was 72.73%, which was significantly higher than that in the paracancerous tissues ( < 0.05). The positive expression rates for caspase-3 in tumor node metastasis (TNM) stage III and lymph node metastasis tissues were 2.78% and 2.50%, respectively, which were significantly lower than those in TNM stage I-II and non-lymph node metastasis tissues ( < 0.05). The positive expression rates of HIF-1α in TNM stage III, lymph node metastasis, and portal vein tumor thrombus tissues were 86.11%, 87.50%, and 88.00%, respectively, and these values were significantly higher than those in TNM stage I-II, non-lymph node metastasis, and portal vein tumor thrombus tissues ( < 0.05). The expression of caspase-3 and HIF-1α in HCC tissues were negatively correlated ( = - 0.426, < 0.05). The median overall survival time of HCC patients was 18.90 mo (95% CI: 17.20-19.91). The results of the Cox proportional risk regression model analysis showed that TNM stage, portal vein tumor thrombus, lymph node metastasis, caspase-3 expression, and HIF-1α expression were the factors influencing patient prognosis ( < 0.05). CONCLUSION:The expression of caspase-3 decreases and HIF-1α increases in HCC tissues complicated by pathological changes of hemorrhage and necrosis, and these are related to clinicopathological features and prognosis. 10.12998/wjcc.v9.i23.6725
    Immunotherapy and targeted therapy converted radical surgery in an advanced hepatocellular carcinoma with tumor emboi of portal vein and hepatic vein. Huang Xing-Hua,Zhang Xiao-Jin,Jiang Yi,Hu Huan-Zhang Asian journal of surgery 10.1016/j.asjsur.2021.06.044
    Hepatocellular Carcinoma with Portal Vein Tumor Involvement: Best Management Strategies. Liu Po-Hong,Huo Teh-Ia,Miksad Rebecca A Seminars in liver disease Portal vein tumor thrombosis (PVTT) commonly occurs in patients with hepatocellular carcinoma (HCC). Patients with PVTT usually have an aggressive disease course, decreased liver function reserve, limited treatment options, higher recurrence rates after treatment, and, therefore, worse overall survival. Among untreated HCC patients with PVTT, the median overall survival has been reported as low as 2 to 4 months. Historically, many aspects of PVTT have impacted the theoretical and practical safety and efficacy of treatment, for example, disordered blood flow and associated impairment of liver function, heat-sink effects of blood flow in the area of the PVTT, and risk of recurrence due to tumor location in the blood vessel. The current Barcelona Clinic Liver Cancer staging system categorizes HCC patients with PVTT as advanced stage, for which the standard of care is targeted therapy with sorafenib. However, sorafenib is associated with only marginal benefits among patients with PVTT. First-line lenvatinib, which was shown to be noninferior to sorafenib, excluded patients with main portal trunk invasion. Regorafenib and nivolumab, an immune-based therapy, were recently approved in the United States for second-line therapy after sorafenib. Preliminary results for cabozantinib suggest a benefit in the second-/third-line after sorafenib failure. In addition, rapid advances in many fields (surgery, interventional radiology, nuclear medicine, and immunotherapy) have increased the potential treatment options for the management of this complex disease entity. A large portion of the emerging evidence focuses on the broader category of advanced HCC of which PVTT is a subgroup. While many of these studies show promising results, the efficacy among PVTT patients requires validation in prospective studies. Real-world data may help fill the evidence gap for patients not eligible for clinical trials due to common hepatic function requirements. The variety of new treatment advances for the heterogeneous and complex disease entity of HCC with PVTT means that personalized, multidisciplinary management may be necessary to achieve optimal outcomes. In this narrative review, we summarize the evolving management strategies for patients with HCC and PVTT. 10.1055/s-0038-1666805
    Contrast-enhanced ultrasound for the characterization of portal vein thrombosis vs tumor-in-vein in HCC patients: a systematic review and meta-analysis. Chen Jifan,Zhu Jianing,Zhang Chao,Song Yue,Huang Pintong European radiology OBJECTIVES:Portal vein thrombosis (PVT) is a common complication of liver cirrhosis. However, differentiation of thrombosis and tumor-in-vein (TIV) may be challenging. Contrast-enhanced ultrasound (CEUS) is an excellent method for detection of vascularization and could help in the distinction. We performed a systematic review and meta-analysis for evaluating the diagnostic value of CEUS in differentiating between PVT and TIV in hepatocellular carcinoma (HCC) patients. METHODS:PubMed, Embase, Cochrane Library, and Web of Science were searched up to the 5th of May 2019. The study quality was assessed by QUADAS-2 tool. Pooled sensitivity and specificity were calculated by the bivariate random effect model and hierarchical summary receiver-operating characteristic (SROC) curve was plotted. RESULTS:Seven studies including 425 participants were analyzed after screening 986 articles searched from databases. The pooled sensitivity and specificity of CEUS in diagnosing TIV were 0.94 (95%CI, 0.89-0.97) and 0.99 (95%CI, 0.80-1.00), respectively. The area under the curve (AUC) of SROC curve was 0.97 (95%CI, 0.95-0.98). The pooled sensitivity and AUC were consistent across all the subgroups of different subject numbers, country, study design, CEUS contrast agents, and diagnostic criteria. CONCLUSIONS:CEUS is highly efficient in differentiating TIV from PVT and is an alternative or a substitute for CT and/or MRI. TRIAL REGISTRATION:PROSPERO registration number: CRD42019138847 KEY POINTS: • Characterization of portal vein thrombosis (PVT) vs tumor-in-vein (TIV) is critical for HCC staging. • CEUS has an excellent safety profile, provides a real-time analysis without any loss in accuracy compared with CT and MRI. • This meta-analysis demonstrates that contrast-enhanced ultrasound (CEUS) is a suitable method for the detection of PVT and distinction with TIV. 10.1007/s00330-019-06649-z
    A stable and reliable animal model for hepatocellular carcinoma with portal vein tumor thrombus. Chai Zong-Tao,Chen Zhen-Hua,Zhang Xiu-Ping,Feng Jin-Kai,Liu Zong-Han,Cheng Shu-Qun Hepatobiliary & pancreatic diseases international : HBPD INT 10.1016/j.hbpd.2021.03.003
    S100P as a novel biomarker of microvascular invasion and portal vein tumor thrombus in hepatocellular carcinoma. Qi Lu-Nan,Ma Liang,Wu Fei-Xiang,Chen Yuan-Yuan,Xing Wan-Ting,Jiang Zhi-Jun,Zhong Jian-Hong,Chen Zu-Shun,Gong Wen-Feng,Ye Jia-Zhou,Li Hong-Hao,Shang Jin-Jie,Xiang Bang-De,Li Le-Qun Hepatology international BACKGROUND:Portal vein tumor thrombus (PVTT) and microvascular invasion (MVI) are types of intrahepatic vascular metastasis of hepatocellular carcinoma (HCC) and are highly correlated with poor prognosis. However, the underlying biomarkers of PVTT and MVI are unclear. METHODS:We identified a PVTT/MVI-associated gene S100P by cDNA microarray analysis, and assess the potential value of serum S100P measurement in the differential diagnosis of HCC and prediction of MVI status with large retrospective and perspective cohort studies. RESULTS:The mRNA and protein of S100P was increased in HCCs with PVTT or MVI. High S100P immunostaining in tumors was correlated with inferior tumor-free survival. Serum S100P values discriminated patients with HCCs from those with benign liver tumors, and it showed predictive potential of MVI status in both retrospective and perspective cohorts. S100P may regulate HCC tumorigenicity and invasive ability; S100P also was associated with up-regulation of CD44, which may mediate HCC cell adhesion to form PVTT/MVI. CONCLUSIONS:Serum S100P may be a novel differential diagnostic marker for HCC and a potential predictor of MVI status pre-surgery for HCC patients. S100P overexpression in HCC is highly correlated with the formation of PVTT and MVI, which may make S100P as a potential therapeutic target for HCC metastasis. 10.1007/s12072-020-10130-1
    Transcriptome sequencing-based personalized analysis of hepatocellular carcinoma patients with portal vein tumor thrombus. Journal of gastrointestinal oncology BACKGROUND:The mechanism of portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) has been widely studied, and numerous diagnostic and prognostic biomarkers for HCC with PVTT have been identified. We aimed to evaluate the extent to which these biomarkers may aid the personalized precision therapy of HCC with PVTT. METHODS:Matched tissue specimens [primary HCC tumor (PT), adjacent normal (N) liver, and PVTT tissues] were acquired from 3 Chinese HCC patients who underwent surgery at Sun Yat-sen University Cancer Centre between 2019 and 2020. Ribonucleic acid (RNA) sequencing was performed on the 9 tissue samples. GFOLD (generalized fold change) algorithm was used to analyze the differently expressed genes (DEGs) between the PVTT, PT, and normal tissues from each patient. Genes with a P<0.01 and a |GFOLD value| >1 were identified as having significantly different expression. RESULTS:In total, 3,543, 32,472, and 12,901 tumorigenesis-associated genes, and 2,919, 17,679, and 14,825 metastasis-associated genes, were detected in Patient 1 (P1), Patient 2 (P2), and Patient 3 (P3), respectively. We analyzed the expression levels of genes associated with hypoxia, macrophage recruitment and cancer stem cells (CSCs). The results showed that hypoxia and CSCs may have contributed to tumorigenesis but not to metastasis in P1. We also found the hypoxia microenvironment played an important role in tumorigenesis and metastasis in P2, and CSCs may have contributed to metastasis. Additionally, we found that CSCs played critical roles in metastasis but not in tumorigenesis in P3. The results also showed that the long non-coding RNA (lncRNA) Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) was greatly overexpressed in the PTs and PVTT in all 3 patients, and Heart and Neural Crest Derivatives Expressed 2-antisense RNA 1 (HAND2-AS1) was downregulated in PVTT compared with PTs in all 3 patients. Thus, MALAT1 and HAND2-AS1 may be robust biomarkers for metastasis in HCC patients with PVTT. CONCLUSIONS:Tumor-associated macrophages (TAMs)-targeted immunotherapy is a promising therapy for HCC patients with PVTT. LncRNAs MALAT1, and HAND2-AS1 may be promising targets for HCC therapy. 10.21037/jgo-21-162
    Identification of prognostic biomarkers associated with the occurrence of portal vein tumor thrombus in hepatocellular carcinoma. Lin Tong,Lin Zhimei,Mai Peipei,Zhang E,Peng Lisheng Aging The occurrence of portal vein tumor thrombus (PVTT) is strongly correlated to the staging and poor prognosis of hepatocellular carcinoma (HCC) patients. However, the mechanisms of PVTT formation remain unclear. This study aimed to investigate differentially expressed genes (DEGs) between primary tumor (PT) and PVTT tissues and comprehensively explored the underlying mechanisms of PVTT formation. The DEGs between PT and paired PVTT tissues were analyzed using transcriptional data from the Gene Expression Omnibus (GEO) database. The expression, clinical relevance, prognostic significance, genetic alternations, DNA methylation, correlations with immune infiltration, co-expression correlations, and functional enrichment analysis of the DEGs were explored using multiple databases. As result, 12 DEGs were commonly down-expressed in PVTT compared with PT tissues among three datasets. The expression of , , , , , , and was progressively decreased from normal liver, PT, to PVTT tissues, whose up-expression associated with favorable survivals of HCC patients. The genetic alternations and DNA methylation of the DEGs frequently occurred, and several methylated CpG sites of the DEGs significantly correlated with outcomes of HCC patients. The immune infiltration in the tumor microenvironment of HCC was correlated with the expression level of the DEGs. Besides, the DEGs and their co-expressive genes participated in the biological processes of extracellular matrix (ECM) organization and focal adhesion. In summary, this study indicated the dysregulation of ECM and focal adhesion might contribute to the formation of PVTT. And the above seven genes might serve as potential biomarkers of PVTT occurrence and prognosis of HCC patients. 10.18632/aging.202876
    Neoadjuvant Three-Dimensional Conformal Radiotherapy for Resectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Randomized, Open-Label, Multicenter Controlled Study. Wei Xubiao,Jiang Yabo,Zhang Xiuping,Feng Shuang,Zhou Bin,Ye Xiaofei,Xing Hui,Xu Ying,Shi Jie,Guo Weixing,Zhou Dong,Zhang Hui,Sun Huichuan,Huang Cheng,Lu Congde,Zheng Yaxin,Meng Yan,Huang Bin,Cong Wenming,Lau Wan Yee,Cheng Shuqun Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:To compare the survival outcomes of neoadjuvant three-dimensional conformal radiotherapy (RT) followed by hepatectomy with hepatectomy alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). PATIENTS AND METHODS:A randomized, multicenter controlled study was conducted from January 2016 to December 2017 in patients with resectable HCC and PVTT. Patients were randomly assigned to receive neoadjuvant RT followed by hepatectomy (n = 82) or hepatectomy alone (n = 82). The modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines were used to evaluate the therapeutic effects of RT. The primary end point was overall survival. The expression of interleukin-6 (IL-6) in patients' serum before RT and in surgical specimens was correlated with response to RT. RESULTS:In the neoadjuvant RT group, 17 patients (20.7%) had partial remission. The overall survival rates for the neoadjuvant RT group at 6, 12, 18, and 24 months were 89.0%, 75.2%, 43.9%, and 27.4%, respectively, compared with 81.7%, 43.1%, 16.7%, and 9.4% in the surgery-alone group ( < .001). The corresponding disease-free survival rates were 56.9%, 33.0%, 20.3%, and 13.3% versus 42.1%, 14.9%, 5.0%, and 3.3% ( < .001). On multivariable Cox regression analyses, neoadjuvant RT significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone (hazard ratios, 0.35 [95% CI, 0.23 to 0.54; < .001] and 0.45 [95% CI, 0.31 to 0.64; < .001]). Increased expressions of IL-6 in pre-RT serum and tumor tissues were significantly associated with resistance to RT. CONCLUSION:For patients with resectable HCC and PVTT, neoadjuvant RT provided significantly better postoperative survival outcomes than surgery alone. IL-6 may predict response to RT in these patients. 10.1200/JCO.18.02184
    Expression of the chemokine receptor CXCR4 in human hepatocellular carcinoma and its role in portal vein tumor thrombus. Li Nan,Guo Weixing,Shi Jie,Xue Jie,Hu Huasheng,Xie Dong,Wu Mengchao,Cheng Shuqun Journal of experimental & clinical cancer research : CR BACKGROUND:This study was conducted to investigate the expression of CXCR4 in portal vein tumor thrombus (PVTT) tissue and its possible role in the invasiveness of tumor thrombus cells. METHODS:We detected differential expression of CXCR4 between PVTT and hepatocellular carcinoma (HCC) by an immunohistochemical assay. Lentivirus-mediated RNA interference and a migration assay were performed on human primary cells derived from PVTT to study the impact of CXCR4 on the invasiveness of HCC. RESULTS:The expression of CXCR4 in tumor thrombus tissue was higher than that in HCC tissue. The invasion ratio of PVTT cells was significantly decreased (P < 0.05) after being infected with a CXCR4-targeting siRNA lentivirus, indicating that downregulation of CXCR4 by lentivirus-mediated RNA interference significantly impaired the invasive potential of PVTT. CONCLUSIONS:These results indicate that CXCR4 is an effective curative target for hepatocellular carcinomas with PVTT. 10.1186/1756-9966-29-156
    Chinese Expert Consensus on Multidisciplinary Diagnosis and Treatment of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus (2018 Edition). Cheng Shuqun,Chen Minshan,Cai Jianqiang,Sun Juxian,Guo Rongping,Bi Xinyu,Lau Wan Yee,Wu Mengchao Liver cancer Portal vein tumor thrombus (PVTT) is very common, and it plays a major role in the prognosis and clinical staging of hepatocellular carcinoma (HCC). We have published the first version of the Consensus in 2016. Over the past several years, many new evidences for the treatment of PVTT become available especially for the advent of new targeted drugs which have further improved the prognosis of PVTT. So, the Chinese Association of Liver Cancer revised the 2016 version of consensus to adapt to the development of PVTT treatment. Future treatment strategies for HCC with PVTT in China would depend on new evidences from more future clinical trials. 10.1159/000503685
    Challenging the Treatment Paradigm: Selecting Patients for Surgical Management of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus. Nevarez Nicole M,Yopp Adam C Journal of hepatocellular carcinoma Portal vein tumor thrombus (PVTT) remains a common presentation in patients with hepatocellular carcinoma (HCC). Approximately 30-50% of patients newly diagnosed with HCC will present with a concomitant PVTT. Current guidelines recommend systemic therapy for treatment of HCC with PVTT. Real-world application of partial hepatectomy in HCC patients with PVTT has increased over the past two decades, as perioperative complications have declined. However, it is unclear if there is an association between the extent of PVTT and overall survival and rates of recurrence and whether the perioperative morbidity outweighs these potential benefits. Partial hepatectomy with en bloc resection of PVTT in second-order branches and distal can offer significant benefits in carefully selected patients; however, once the HCC-associated PVTT extends into first-order portal venous branches or more proximal into the superior mesenteric vein, the risks of surgical resection outweigh the benefits. The aim of this review is to determine which patients with HCC presenting with PVTT benefit from surgical resection. We will discuss the classification systems of PVTT and review both outcome and perioperative measures in patients undergoing partial hepatectomy with extirpation of HCC-related PVT. 10.2147/JHC.S291530
    Determination of portal vein tumor thrombus blood supply using in vivo cellular magnetic resonance imaging in a rabbit model. Zhang Xiuming,Wu Bei,Guo Zhen,Gao Yang,Xi Wei,Yu Hui,Feng Guodong,Zhang Jingyuan,Shen Wenrong,Chen Jun Cancer management and research This study aimed to investigate the anatomic configuration of the blood vessels that contribute to portal vein tumor thrombus (PVTT), a common complication of hepatocellular carcinoma, in VX2 rabbits. Peripheral blood mononuclear cells (MNCs) were isolated and labeled using superparamagnetic iron oxide particles in vitro. Twenty-four rabbits were injected with the VX2 tumor via the portal vein to establish the PVTT model. The rabbits (n=6/treatment group) were randomly assigned into four groups. Rabbits of groups A, B and C received an infusion of iron-labeled MNCs via the hepatic artery, the portal vein or the auricular vein, respectively, whereas rabbits of group D received an injection of normal saline via the auricular vein 7 days after the injection of VX2 tumors. MRI was performed, and the signal intensity (SI) of the PVTTs was measured on T2-weighted images (T2WIs) 1 day after the transfusion of iron-labeled cells. The SI of PVTTs, as measured on T2WIs, in rabbits of groups A, B, C and D was 241.400 (172.350, 364.825), 221.150 (203.775, 318.225), 590.200 (363.325, 728.875) and 568.050 (474.725, 705.150), respectively. Our data showed a significant decrease in the SI of PVTTs in rabbits of groups A and B compared with rabbits of groups C and D (group A vs group C, U=4.000, =0.025; group A vs group D, U=2.000, =0.010; group B vs group C, U=4.000, =0.025; group B vs group D, U=1.000, =0.006). There was no significant difference in the SI of PVTTs in rabbits of group A and B. Our results indicated that the portal vein and the hepatic artery supplied blood flow to the PVTT in rabbits. 10.2147/CMAR.S197231
    The evaluation of anti-angiogenic effects of Endostar on rabbit VX2 portal vein tumor thrombus using perfusion MSCT. Feng Guoquan,Lei Zhen,Wang Dongqing,Xu Na,Wei Qiang,Li Dinuo,Liu Jingyi Cancer imaging : the official publication of the International Cancer Imaging Society BACKGROUND:There were many treatments for hepatocellular carcinoma with portal vein tumor thrombus (PVTT), in which targeted anti-angiogenic drug therapy is becoming a popular research topic. However, an objective and non-invasive method that can evaluate the treatment effects is still lacking. METHODS:Eighteen New Zealand white rabbits implanted with VX2 tumor thrombus in portal vein were randomly assigned into 3 groups: Endostar, saline, or control, six in each group. Multi-slice CT (MSCT) perfusion scanning was performed to measure the differences in blood flow (TBF), tissue blood volume (TBV), and capillary permeability time the surface (PS) before and after Endostar treatment, between Endostar and saline treatment. Two weeks after treatment, both Endostar and saline groups underwent CT perfusion scan. The rabbits then were sacrificed by air embolism, and specimens of tumor thrombosis were collected. Immunohistochemistry assay was also performed to compare the expression of vascular endothelial growth factor (VEGF) in PVTT after Endostar, saline and placebo treatment. RESULTS:In Endostar group, PVTT CT perfusion parameters (TBF, TBV, PS) significantly decreased after the treatment (p <0.05). Post-treatment PVTT CT perfusion parameters (TBF, TBV, PS) were significantly lower in Endostar group than in Saline group (p <0.05). VEGF is mainly expressed in cytoplasma. After Endostar treatment, the expression of VEGF in PVTT was markedly reduced. There was also significant difference on post-treatment VEGF protein expression measured by Immunohistochemistry assay between Endostar group and control group (p <0.05). Post-treatment PVTT CT perfusion parameters (TBF, TBV, PS) were positively correlated with VEGF protein expression in all 3 groups (rs > 0, p <0.05). CONCLUSIONS:Multi-slice CT perfusion imaging can evaluate the anti-angiogenic effects of Endostar for the VX2 tumor thrombus in portal vein, and provide quantitative functional information. 10.1186/1470-7330-14-17
    Apatinib treatment of advanced hepatocellular carcinoma with portal vein and inferior vena cava tumor thrombus: A case report. Yang XueGang,Wu Ge,Xu GuoHui Medicine RATIONALE:Hepatocellular carcinoma (HCC) is a highly invasive cancer associated with vascular invasion. The survival of advanced HCC is very poor. In this case study, we describe the efficacy and safety of apatinib in patient with advanced HCC as the first-line therapy. PATIENT CONCERNS:A 46-year-old male complained of abdominal distention and pain for half a month. DIAGNOSES:HCC patient with portal vein and inferior vena cava tumor thrombus. INTERVENTIONS:The apatinib alone was used as first-line therapy. OUTCOMES:Intrahepatic tumors, portal vein, and inferior vena cava tumor thrombus were diminished. The patient achieved partial response (PR) soon after the treatment, and progression-free survival (PFS) was 12.5 months. During the entire process, the alpha-fetoprotein (AFP) continued to decrease. LESSONS:Apatinib alone may be a safe and effective therapy for HCC patients with portal vein and inferior vena cava tumor thrombus. However, it is warranted further investigation in the future prospective randomized clinical studies. 10.1097/MD.0000000000014582
    The multidisciplinary management of hepatocellular carcinoma with portal vein tumor thrombus. Qiu Guoteng,Xie Kunlin,Jin Zhaoxing,Jiang Chuang,Liu Hu,Wan Haifeng,Huang Jiwei Bioscience trends Portal vein tumor thrombus (PVTT) is one of the most common complications of hepatocellular carcinoma (HCC), which refers to the advanced stage of HCC and indicates an extremely poor prognosis. Monotherapy cannot effectively prolong the survival benefit of patients with HCC-PVTT characterized by a high recurrence rate. With great progress in the area of immune and molecular targeted therapy, there comes a promising era of multidisciplinary management of HCC. Survival benefits can be achieved based on accurate diagnosis, staging, and multidisciplinary management. Additionally, in terms of the presence of controversy about the standard treatment algorithm and the absence of universal treatment guidelines, a multidisciplinary management program may afford the best hope for HCC-PVTT patients via appropriate implement of various treatment protocols. 10.5582/bst.2021.01173
    Better surgical treatment method for hepatocellular carcinoma with portal vein tumor thrombus. Peng Shu-You,Wang Xu-An,Huang Cong-Yun,Li Jiang-Tao,Hong De-Fei,Wang Yi-Fang,Xu Bin World journal of gastroenterology Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is a disease that is not uncommon, but the treatments vary drastically between Eastern and Western countries. In Europe and America, the first line of treatment is systemic therapy such as sorafenib and the surgical treatment is not a recommend option. While an increasing number of studies from China and Japan have suggested that surgical treatment results in better outcomes when compared to transcatheter arterial chemoembolization (TACE), sorafenib, or other nonsurgical treatments, and two classification systems, Japanese Vp classification and Chinese Cheng's classification, were very useful to guide the surgical treatment. We have also found that surgical treatment may be more effective, as we have performed surgical treatment for HCC-PVTT patients over a period of approximately 15 years and achieved good results with the longest surviving time being 13 years and onward. In this study, we review the efficacy and principles of current surgical treatments and introduce our new, more effective surgical technique named "thrombectomy first", which means the tumor thrombus in the main portal vein, the bifurcation or the contralateral portal vein should be removed prior to liver resection. Thus, compression and crushing of PVTT during the operation could be avoided and new intrahepatic metastases caused by tumor thrombus to the remnant liver minimized. The new technique is even beneficial to the prognosis of Cheng's classification Types III and IV PVTT. The vital tips and tricks for the surgical approach are described. 10.3748/wjg.v24.i40.4527
    Spontaneous Regression of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus. Koya Yudai,Suzuki Tomohiro,Tai Mayumi,Ichii Osamu,Matsuhashi Nobuo,Ejiri Yutaka,Shibata Michihiko,Harada Masaru Case reports in gastroenterology An 83-year-old man underwent transcatheter arterial chemoembolization (TACE) for a 20-mm hepatocellular carcinoma (HCC) in Couinaud's segment 4. Computed tomography (CT) 4 months after TACE showed tumor thrombus in the portal vein in addition to diffuse metastases and arterioportal shunts in the left lobe. Although we performed the best supportive care, the tumor thrombus in the portal vein and tumors in the left lobe had completely disappeared on CT 16 months after the TACE. Rapidly grown portal vein tumor thrombus and arterioportal shunt might be the causes of spontaneous regression of HCC, probably associated with tumor hypoxia. 10.1159/000490661
    Nano-immunotherapy for each stage of cancer cellular immunity: which, why, and what? Zuo Shiyi,Song Jiaxuan,Zhang Jingxuan,He Zhonggui,Sun Bingjun,Sun Jin Theranostics Immunotherapy provides a new avenue for combating cancer. Current research in anticancer immunotherapy is primary based on T cell-mediated cellular immunity, which can be divided into seven steps and is named the cancer-immunity cycle. Unfortunately, clinical applications of cancer immunotherapies are restricted by inefficient drug delivery, low response rates, and unmanageable adverse reactions. In response to these challenges, the combination of nanotechnology and immunotherapy (nano-immunotherapy) has been extensively studied in recent years. Rational design of advanced nano-immunotherapies requires in-depth consideration of "which" immune step is targeted, "why" it needs to be further enhanced, and "what" nanotechnology can do for immunotherapy. However, the applications and effects of nanotechnology in the cancer-immunity cycle have not been well reviewed. Herein, we summarize the current developments in nano-immunotherapy for each stage of cancer cellular immunity, with special attention on the which, why and what. Furthermore, we summarize the advantages of nanotechnology for combination immunotherapy in two categories: enhanced efficacy and reduced toxicity. Finally, we discuss the challenges of nano-immunotherapy in detail and provide a perspective. 10.7150/thno.59953
    Synthesis of Multifunctional Nanoparticles for the Combination of Photodynamic Therapy and Immunotherapy. Lee Mei-Hwa,Thomas James L,Li Jin-An,Chen Jyun-Ren,Wang Tzong-Liu,Lin Hung-Yin Pharmaceuticals (Basel, Switzerland) Programmed death-ligand 1 protein (PD-L1) has been posited to have a major role in suppressing the immune system during pregnancy, tissue allografts, autoimmune disease and other diseases, such as hepatitis. Photodynamic therapy uses light and a photosensitizer to generate singlet oxygen, which causes cell death (phototoxicity). In this work, photosensitizers (such as merocyanine) were immobilized on the surface of magnetic nanoparticles. One peptide sequence from PD-L1 was used as the template and imprinted onto poly(ethylene--vinyl alcohol) to generate magnetic composite nanoparticles for the targeting of PD-L1 on tumor cells. These nanoparticles were characterized using dynamic light scattering, high-performance liquid chromatography, Brunauer-Emmett-Teller analysis and superconducting quantum interference magnetometry. Natural killer-92 cells were added to these composite nanoparticles, which were then incubated with human hepatoma (HepG2) cells and illuminated with visible light for various periods. The viability and apoptosis pathway of HepG2 were examined using a cell counting kit-8 and quantitative real-time polymerase chain reaction. Finally, treatment with composite nanoparticles and irradiation of light was performed using an animal xenograft model. 10.3390/ph14060508
    Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer. Huang Kuan-Wei,Hsu Fu-Fei,Qiu Jiantai Timothy,Chern Guann-Jen,Lee Yi-An,Chang Chih-Chun,Huang Yu-Ting,Sung Yun-Chieh,Chiang Cheng-Chin,Huang Rui-Lin,Lin Chu-Chi,Dinh Trinh Kieu,Huang Hsi-Chien,Shih Yu-Chuan,Alson Donia,Lin Chun-Yen,Lin Yung-Chang,Chang Po-Chiao,Lin Shu-Yi,Chen Yunching Science advances While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)-cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2-encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8 T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy. 10.1126/sciadv.aax5032
    NIR-absorbing Prussian blue nanoparticles for transarterial infusion photothermal therapy of VX2 tumors implanted in rabbits. Pang Huajin,Tian Chen,He Genghan,Zhang Di,Yang Jinghong,Zhang Qianbing,Liu Ruiyuan Nanoscale Nanomaterial-related photothermal therapy has been intensively investigated for treatment of hepatocellular carcinoma (HCC). However, owing to the low specificity to tumors and easy excretion from the systemic circulation, the low dose of photoactive nanomaterials in solid tumors severely hinders the photothermal therapy applications for HCC. Herein, an innovative strategy for transarterial infusion photothermal therapy (TAIPPT) of VX2 tumors implanted in rabbits is reported. NIR-absorbing Prussian blue nanoparticles were prepared by microemulsion methods, which demonstrate excellent photothermal therapy capacity and satisfactory biocompatibility. Prussian blue nanoparticles are transarterially infused into VX2 tumors and irradiated for photothermal therapy. TAIPPT achieves fast and efficient delivery of nanoparticles into tumors and complete ablation by one-time transarterial infusion treatment. Furthermore, TAIPPT could activate the immune cells in rabbits and inhibit distant tumors. Our findings describe a promising strategy for tumor eradication and may benefit future clinical HCC patients. 10.1039/d1nr01394g
    Homotypic Cell Membrane-Cloaked Biomimetic Nanocarrier for the Targeted Chemotherapy of Hepatocellular Carcinoma. Liu Xiaojun,Sun Yingxue,Xu Shushen,Gao Xiaonan,Kong Fanpeng,Xu Kehua,Tang Bo Theranostics Hepatocellular carcinoma (HCC) has been reported to be the third most common malignant tumor and has the highest rate of mortality. To increase the chemotherapy efficacy of HCC, a drug delivery system featured with desirable active targeting ability, delivery efficiency and immune evasion is in high demand. We have developed a drug nanocarrier by utilizing a homotypic cancer cell membrane for targeted chemotherapy of HCC. Structurally, the homotypic HepG2 cell membrane was used as the cloak, and a poly (lactic--glycolic acid) (PLGA) nanoparticle as the core, resulting in the nanocarrier . The nanoparticles exhibit excellent targeting ability toward HepG2 cells. Doxorubicin (Dox) carried by possesses high delivery efficiency and a remarkable therapeutic effect. In experiments, delivers Dox directly to the tumor lesion of nude mice, and tumor volume decreases by approximately 90% after treatment. We have developed a drug nanocarrier by utilizing a homotypic cancer cell membrane for targeted chemotherapy of HCC with excellent active targeting ability. This biomimetic platform not only effectively treats HCC but also provides a sound strategy for the treatment of other cancers changes in the corresponding homotypic cancer cell membrane. 10.7150/thno.34837
    Platelet membrane-coated nanoparticles for targeted drug delivery and local chemo-photothermal therapy of orthotopic hepatocellular carcinoma. Wu Long,Xie Wei,Zan Hui-Ming,Liu Zhongzhong,Wang Ganggang,Wang Yanfeng,Liu Wei,Dong Wenfei Journal of materials chemistry. B Specific targeted drug delivery and controllable release of drugs at tumor regions are two of the main challenges for hepatocellular carcinoma (HCC) therapy, particularly post metastasis. Herein, we present a platelet membrane-facilitated local chemo-photothermal therapy strategy, in which polypyrrole (PPy) nanoparticles act as photothermal agents and along with antitumor drug doxorubicin (DOX) are encapsulated into platelet membranes (PLT-PPy-DOX). The particles are endowed with immune evasiveness and tumor targeting abilities from platelet membranes, and are then intravenously injected into an orthotopic mouse model of HCC. As expected, the PLT-PPy-DOX nanoplatforms were abundant in the tumor tissues. Hyperthermia was generated under laser irradiation (808 nm) not only to ablate tumor cells directly but also to increase the triggered release of DOX. This combination of local chemotherapy and photothermal therapy demonstrated excellent antitumor efficiency in suppressing primary tumor growth and inhibiting tumor metastases. This localized therapy which adopts biocompatible natural cell membranes and good biodegradable organic photothermal agents may provide new insights into designing biomimetic nano-vehicles for personalized therapy of HCC. 10.1039/d0tb00735h
    Hybrid membrane camouflaged copper sulfide nanoparticles for photothermal-chemotherapy of hepatocellular carcinoma. Ji Bai,Cai Hongqiao,Yang Yang,Peng Fenghui,Song Meiyu,Sun Kaiju,Yan Fei,Liu Yahui Acta biomaterialia Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Biomimetic nanoparticles (NPs) coated with cell membranes show enhanced biocompatibility and specificity for homotypic cells, and have gained considerable attention for targeted anti-tumor therapy. We constructed cancer cell-macrophage hybrid membrane-coated near infrared (NIR)-responsive hollow copper sulfide nanoparticles encapsulating sorafenib and surface modified with anti-VEGFR (CuS-SF@CMV NPs). These CuS-SF@CMV NPs expressed the characteristic membrane proteins of both cancer cells and macrophages, and selectively accumulated in cancer cells in vitro and tumors in vivo, compared to the CuS NPs. In addition, the CuS-SF@CMV NPs achieved synergistic photo-thermal and chemotherapy in cancer cells upon NIR irradiation, with 94.3% inhibition of tumor growth in a murine hepatoma model. While the initial increase in temperature rapidly killed the tumor cells, sorafenib and the anti-VEGFR antibody sustained the tumor killing effect by respectively inhibiting tumor cell proliferation and angiogenesis via the Ras/Raf/MEK/ERK and PI3K/AKT pathways. Taken together, the CuS-SF@CMV NPs have immune evasion, tumor cell targeting and drug loading capacities, along with an inherent photo-thermal conversion ability, making them ideal for synergistic photo-thermal/chemo therapy against HCC. STATEMENT OF SIGNIFICANCE: We created cancer cell-macrophage hybrid membrane-coated hollow CuS NPs encapsulating sorafenib and surface modified with anti-VEGFR antibodies (CuS-SF@CMV). These CuS-SF@CMV NPs enhanced synergistic PTT and chemotherapy against hepatoma cells through homotypic cell targeting, immune escape and inhibition of a tumorigenic signaling pathway. A long-term inhibition of tumor growth and metastasis was achieved owing to the rapid destruction of the cancer cells through photo-thermal conversion by the CuS NPs, and sustained clearance of the tumor cells by sorafenib and anti-VEGFR antibodies. Our findings suggest that CuS-SF@CMV NPs present great treating effects in preclinical models of HCC, providing the framework for further study in clinical trials to improve patient outcome in hepatocellular carcinoma. 10.1016/j.actbio.2020.04.046
    In vitro and in vivo anti-metastatic effect of the alkaliod matrine from Sophora flavecens on hepatocellular carcinoma and its mechanisms. Dai Meiqin,Chen Nana,Li Jinzhou,Tan Lizhuan,Li Xiaojuan,Wen Jiayong,Lei Linsheng,Guo Dan Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUNDS:Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer with high metastasis and recurrence rates. Hypoxia-induced miRNAs and HIF-1α are demonstrated to play essential roles in tumor metastasis. Matrine (CHNO), an alkaloid extracted from Sophora flavescens Aiton, has been used as adjuvant therapy for liver cancer in China. The anti-metastasis effects of matrine on HCC and the underlying mechanisms remain poorly understood. PURPOSE:We aimed to investigate the effects of matrine on metastasis of HCC both in vitro and in vivo, and explored whether miR-199a-5p and HIF-1α are involved in the action of matrine. METHODS:MTT method, colony formation, wound healing and matrigel transwell assays were performed to evaluate the effects of matrine on cell proliferation, migration and invasion. Nude mice xenograft model and immunohistochemistry (IHC) assay were employed to investigate the anti-metastatic action of matrine in vivo. Quantitative real-time PCR, western blot and dual luciferase reporter assay were conducted to determine the underlying mechanisms of matrine. RESULTS:Matrine exerted stronger anti-proliferative action on Bel7402 and SMMC-7721 cells under hypoxia than that in normoxia. Both matrine and miR-199a-5p exhibited significant inhibitory effects on migration, invasion and EMT in Bel7402 and SMMC-7721 cells under hypoxia. Further study showed that miR-199a-5p was downregulated in HCC cell lines, and this microRNA was identified to directly target HIF-1α, resulting in decreased HIF-1α expression. Matrine induced miR-199a-5p expression, decreased HIF-1α expression and inhibited metastasis of Bel7402 and SMMC-7721 cells, while miR-199a-5p knockdown reversed the inhibitory effects of matrine on cell migration, invasion, EMT and HIF-1α expression. In vivo, matrine showed significant anti-metastatic activity in the nude mouse xenograft model. H&E and IHC analysis indicated that lung and liver metastasis nodules were reduced, and the protein expression of HIF-1α and Vimentin were significantly decreased by i.p injection of matrine. CONCLUSIONS:Matrine exhibits significant anti-metastatic effect on HCC, which is attributed to enhanced miR-199a-5p expression and subsequently impaired HIF-1α signaling and EMT. These findings suggest that miR-199a-5p is a potential therapeutic target of HCC, and matrine may represent a promising anti-metastatic medication for HCC therapy. 10.1016/j.phymed.2021.153580
    Matrine suppresses lung metastasis of human hepatocellular carcinoma by directly targeting matrix metalloproteinase-9. Zhang Juyuan,Gao Yuan,Han Hui,Zou Changlin,Feng Yu,Zhang Hui Biochemical and biophysical research communications Matrine is a natural compound derived from Radix Sophora flavescens which is a commonly used Chinese herb. Herein, we report that matrine may inhibit lung metastasis in liver cancer in mice. Invasion chamber assay, scratch-wound assay and orthotopic liver tumor implantation mice were introduced to investigate the potential pharmacological effects of matrine on human hepatocellular carcinoma (HCC). Our results showed that matrine at non-toxic dose could significantly suppress PLC/PRF/5 and MHCC97L cells migration and invasion. Furthermore, matrine treatment (5 mg/kg/day) significantly decreased lung metastasis in orthotopic HCC mouse models. Quantitative polymerase chain reaction, gelatin zymography and immunoblotting assay indicated that matrine could inhibit the activity of matrix metalloproteinase-9 without down-regulating its protein expression in HCC. The docking approach, site-directed mutagenesis, and surface plasmon resonance were applied to identify residues involved in matrine binding in matrix metalloproteinase-9. The biophysical and cell-based assays showed that Pro415, Arg424 residue might contribute to the binding affinity of matrine on matrix metalloproteinase-9 activity. In conclusion, matrine might be a promising anti-cancer agent for inhibiting HCC metastasis. 10.1016/j.bbrc.2019.04.063
    Arsenite-loaded albumin nanoparticles for targeted synergistic chemo-photothermal therapy of HCC. Zhang Ke,Li Dan,Zhou Bin,Liu Jiani,Luo Xiangjie,Wei Ruixue,Wang Lizhu,Hu Xiaojun,Su Zhongzhen,Lin Hongyu,Gao Jinhao,Shan Hong Biomaterials science Arsenic trioxide (ATO, AsO), an active ingredient of traditional Chinese medicine, has been approved by the U.S. Food and Drug Administration as an effective therapeutic agent for acute promyelocytic leukemia (APL). However, the application of ATO in treating advanced solid tumors like hepatocellular carcinoma (HCC) is still restricted by limited therapeutic efficacy and insufferable side effects. To solve this problem, we reported a general and facile strategy using human serum albumin (HSA) as a template for synthesizing a series of ATO-based nanoparticles with uniform single-albumin size. Then, we prepared a multifunctional drug delivery system (MDDS) based on MnAs/HSA termed MnAs/ICG/HSA-RGD, and tested its efficacy both and . Our results revealed that the photothermal effect of MnAs/ICG/HSA-RGD can not only cause irreversible damage to the tumor but also accelerate the discharge of As and Mn ions, enabling responsive chemotherapy and magnetic resonance imaging. Interestingly, the expression of HSP90, vimentin, and MMP-9 in tumor cells was inhibited during the treatment, resulting in less metastasis and recurrence. Moreover, no apparent side effect has been observed during the treatment. Therefore, MnAs/ICG/HSA-RGD can be considered as a promising option for HCC with excellent therapeutic efficacy and minimum side effects. 10.1039/d1bm01374b
    Ultrasound-Driven Biomimetic Nanosystem Suppresses Tumor Growth and Metastasis through Sonodynamic Therapy, CO Therapy, and Indoleamine 2,3-Dioxygenase Inhibition. Zhang Da,Lin Ziguo,Zheng Youshi,Song Jibin,Li Juan,Zeng Yongyi,Liu Xiaolong ACS nano The rational design of nanoplatforms to bypass reticuloendothelial system (RES) clearance, enhance spatiotemporal controllability, and boost host immune responses to achieve synergized tumor-targeted therapeutic purpose is highly desired. Herein, a biomimetic nanosystem is developed for tumor-targeted delivery of singlet oxygen (O) and carbon monoxide (CO) in response to exogenous stimulus ultrasound (US) and endogenous stimulus hydrogen peroxide (HO) in tumor microenvironment, respectively. Taking advantages of tumor homing and RES evasion abilities of the macrophage membrane coating, our designed nanosystem shows excellent accumulation at the tumor site and effective suppression of tumor growth through US/HO-generated O and CO to induce cell apoptosis and mitochondrial dysfunction. Furthermore, our nanosystem can induce significant tumor immunogenic death by O/CO therapy, then can achieve effective immune responses and long-term immune memory through the combination of indoleamin 2,3-dioxygenase (IDO) signal blocking to effectively against tumor rechallenge and prevent lung metastasis. Taken together, the here-presented therapeutic strategy based on sonodynamic/CO therapy and IDO signaling inhibition might provide a promising perspective for synergistically treating cancer in future clinical translations. 10.1021/acsnano.0c03833
    Imaging of Cancer Immunotherapy: Current Approaches and Future Directions. Nishino Mizuki,Hatabu Hiroto,Hodi F Stephen Radiology Cancer immunotherapy using immune-checkpoint inhibitors has emerged as an effective treatment option for a variety of advanced cancers in the past decade. Because of the distinct mechanisms of immunotherapy that activate the host immunity to treat cancers, unconventional immune-related phenomena are encountered in terms of tumor response and progression, as well as drug toxicity. Imaging plays an important role in objectively characterizing immune-related tumor responses and progression and in detecting and monitoring immune-related adverse events. Moreover, emerging data suggest a promise for molecular imaging that can visualize the specific target molecules involved in immune-checkpoint pathways. In this article, the background and current status of cancer immunotherapy are summarized, and the current methods for imaging evaluations of immune-related responses and toxicities are reviewed along with their limitations and pitfalls. Emerging approaches with molecular imaging are also discussed as a future direction to address unmet needs. 10.1148/radiol.2018181349
    Nanohybrid liposomal cerasomes with good physiological stability and rapid temperature responsiveness for high intensity focused ultrasound triggered local chemotherapy of cancer. Liang Xiaolong,Gao Jing,Jiang Lingdong,Luo Jianwen,Jing Lijia,Li Xiaoda,Jin Yushen,Dai Zhifei ACS nano The high intensity focused ultrasound (HIFU) and thermosensitive cerasomes (HTSCs) were successfully assembled by employing cerasome-forming lipid (CFL) in combination with the component lipids of conventional low temperature sensitive liposomes (LTSLs) including 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG-2000) and 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (MSPC). The HTSCs showed spherical shape with a mean diameter around 200 nm, exhibiting good biocompatibility. Both hydrophilic and lipophilic drugs can be efficiently encapsulated into HTSCs. In addition, the release rate of HTSCs could be conveniently adjusted by varying the molar ratios of CFL to DPPC. The drug loaded HTSCs showed much longer blood circulation time (half-life >8.50 ± 1.49 h) than conventional LTSLs (0.92 ± 0.17 h). An in vitro study demonstrated that the drug loaded HTSCs are highly stable at 37 °C and show a burst release at 42 °C, providing a capability to act synergistically against tumors. We found that the HTSCs with a proportion of 43.25% of CFL could release more than 90% hydrophilic drugs in 1 min at an elevated temperature of 42 °C generated by HIFU exposure. After intravenous injection of doxorubicin (DOX) loaded HTSCs at 5 mg DOX/kg, followed by double HIFU sonication, the tumor growth of the adenocarcinoma (MDA-MB-231) bearing mice could be significantly inhibited. Therefore, the drug loaded HTSCs combined with HIFU hold great potential for efficient local chemotherapy of cancer due to the ability to deliver high concentration of chemotherapy drugs directly to the tumor, achieve maximum therapeutic efficacy and minimal side effects, and avoid the damage to the healthy tissues caused by systemic administration of drugs. 10.1021/nn507482w
    Applications of Micro/Nanotechnology in Ultrasound-based Drug Delivery and Therapy for Tumor. Sun Suhui,Wang Ping,Sun Sujuan,Liang Xiaolong Current medicinal chemistry Ultrasound has been broadly used in biomedicine for both tumor diagnosis as well as therapy. The applications of recent developments in micro/nanotechnology promote the development of ultrasound-based biomedicine, especially in the field of ultrasound-based drug delivery and tumor therapy. Ultrasound can activate nano-sized drug delivery systems by different mechanisms for ultrasound- triggered on-demand drug release targeted only at the tumor sites. Ultrasound Targeted Microbubble Destruction (UTMD) technology can not only increase the permeability of vasculature and cell membrane via sonoporation effect but also achieve in situ conversion of microbubbles into nanoparticles to promote cellular uptake and therapeutic efficacy. Furthermore, High Intensity Focused Ultrasound (HIFU), or Sonodynamic Therapy (SDT), is considered to be one of the most promising and representative non-invasive treatment for cancer. However, their application in the treatment process is still limited due to their critical treatment efficiency issues. Fortunately, recently developed micro/nanotechnology offer an opportunity to solve these problems, thus improving the therapeutic effect of cancer. This review summarizes and discusses the recent developments in the design of micro- and nano- materials for ultrasound-based biomedicine applications. 10.2174/0929867327666200212100257
    Platelets as platforms for inhibition of tumor recurrence post-physical therapy by delivery of anti-PD-L1 checkpoint antibody. Han Xiao,Chen Jiawen,Chu Jiacheng,Liang Chao,Ma Qingle,Fan Qin,Liu Zhuang,Wang Chao Journal of controlled release : official journal of the Controlled Release Society Cancer local physical therapy (PT) by using heat, cold, electrical stimulation, irradiation or ultrasound to treat tumor is accepted as alternative choice for cancer patients. However, local recurrence and metastasis after such treatments remains to be the major cause of treatment failure and mortality. Therefore, it is necessary to develop a therapeutic strategy to inhibit local recurrence and metastasis. Inspired by the excellent inflammatory targeting ability of platelets, here we expect that the monoclonal antibody against programmed-death ligand 1 (aPDL1) engineered platelets could inhibit tumor local recurrence effectively, by facilitating transport of anti-PD-L1 antibodies to the ablated area with residue tumors. Using triple-negative breast carcinomas (4T1) bearing mouse model, we proved that antibody-coupled platelets could effectively target incompletely ablated tumor with thermal ablation (TA). We found the release of anti-PD-L1 can be triggered upon the platelets activation, together with many pro-inflammatory cytokines. The release of anti-PD-L1 is likely due to the dissociation of platelets upon the activation. Our findings approved that our platelet-based platform could facilitate the delivery of immune checkpoint antibody to tumor residues and remarkably prevent tumor recurrence after ablation. Moreover, this platelet-based delivery strategy may be extended to the targeted delivery of therapeutics post other types of local therapies including photodynamic therapy, high-intensity-focused-ultrasound ablation therapy, and even radiotherapy. 10.1016/j.jconrel.2019.05.008
    High Intensity Focused Ultrasound-Responsive and Ultrastable Cerasomal Perfluorocarbon Nanodroplets for Alleviating Tumor Multidrug Resistance and Epithelial-Mesenchymal Transition. Ma Xiaotu,Yao Meinan,Shi Jiyun,Li Xiaoda,Gao Yu,Luo Qi,Hou Rui,Liang Xiaolong,Wang Fan ACS nano Hypoxia is a hostile hallmark of most solid tumors, which often leads to multidrug resistance (MDR) and causes the failure of chemotherapy. Hypoxia also promotes epithelial-mesenchymal transition (EMT), leading to acceleration of tumor metastasis. Many chemotherapeutic drugs can further exacerbate hypoxia and thus promote metastasis. Therefore, relieving hypoxia is necessary for chemotherapy to inhibit both MDR and EMT. Herein, highly stable cerasomal perfluorocarbon nanodroplets with an atomic layer of polyorganosiloxane surface and pH-sensitive tumor-targeting peptide (D-vPCs-O) were fabricated to co-deliver oxygen and therapeutic drug, doxorubicin. High-intensity focused ultrasound (HIFU) was utilized to trigger the co-release of doxorubicin and oxygen and simultaneously enhance ultrasound imaging, therefore achieving imaging-guided drug delivery. Mild-temperature HIFU (M-HIFU) not only triggered oxygen release from nanodroplets but also slightly elevated tumor temperature to accelerate tumor blood flow. The oxygen release and temperature elevation jointly relieved tumor hypoxia and alleviated MDR, which greatly enhanced the drug therapeutic efficacy as compared to clinically used doxorubicin and Doxil. Overall side effects were also largely reduced owing to the ultrastable drug loading of cerasome. The improvement of insufficient chemotherapy and the relief of tumor hypoxia corporately down-regulated TGF-β1, leading to the alleviation of EMT, and therefore significantly inhibited tumor metastasis. When "D-vPCs-O + M-HIFU" was utilized as a neoadjuvant chemotherapy, nanodroplets down-regulated heat shock proteins, reducing tumor relapse after the high-temperature HIFU (H-HIFU)-mediated hyperthermia ablation. The chemo-hyperthermia therapy totally eradicated tumors without any relapse or metastasis, providing a promising way to treat the triple-negative breast cancer, which is highly malignant, easily metastatic, and lacks effective treatments. 10.1021/acsnano.0c07287
    Assessment of Gold Nanoparticle-Mediated-Enhanced Hyperthermia Using MR-Guided High-Intensity Focused Ultrasound Ablation Procedure. Devarakonda Surendra B,Myers Matthew R,Lanier Mathew,Dumoulin Charles,Banerjee Rupak K Nano letters High-intensity focused ultrasound (HIFU) has gained increasing popularity as a noninvasive therapeutic procedure to treat solid tumors. However, collateral damage due to the use of high acoustic powers during HIFU procedures remains a challenge. The objective of this study is to assess the utility of using gold nanoparticles (gNPs) during HIFU procedures to locally enhance heating at low powers, thereby reducing the likelihood of collateral damage. Phantoms containing tissue-mimicking material (TMM) and physiologically relevant concentrations (0%, 0.0625%, and 0.125%) of gNPs were fabricated. Sonications at acoustic powers of 10, 15, and 20 W were performed for a duration of 16 s using an MR-HIFU system. Temperature rises and lesion volumes were calculated and compared for phantoms with and without gNPs. For an acoustic power of 10 W, the maximum temperature rise increased by 32% and 43% for gNPs concentrations of 0.0625% and 0.125%, respectively, when compared to the 0% gNPs concentration. For the power of 15 W, a lesion volume of 0, 44.5 ± 7, and 63.4 ± 32 mm was calculated for the gNPs concentration of 0%, 0.0625%, and 0.125%, respectively. For a power of 20 W, it was found that the lesion volume doubled and tripled for concentrations of 0.0625% and 0.125% gNPs, respectively, when compared to the concentration of 0% gNPs. We conclude that gNPs have the potential to locally enhance the heating and reduce damage to healthy tissue during tumor ablation using HIFU. 10.1021/acs.nanolett.7b00272
    Designing intelligent nano-bomb with on-demand site-specific drug burst release to synergize with high-intensity focused ultrasound cancer ablation. Mai Xiaoxuan,Chang Yanzhou,You Yuanyuan,He Lizhen,Chen Tianfeng Journal of controlled release : official journal of the Controlled Release Society High intensity focused ultrasound (HIFU) has been widely used in clinical treatment of cervical cancer for its non-invasiveness and sharp treatment margins with very low complication rates. However, how to intensify the therapeutic efficacy of HIFU by specifically focusing the ultrasound energy on targeting pathological tissues is still a bottleneck for it to realize successful cancer ablation. Herein, a multifunctional organic-inorganic hybrid nanovesicles, by coating ultrathin silica shell on the surface of poly (lactic-co-glycolic acid) (PLGA) loaded with perfluorocarbon (PFOB), hydrophobic antitumor ruthenium complex (RuPOP) and superparamagnetic FeO, has been designed to achieve synchronous ultrasound (US)/magnetic resonance imaging (MR) dual mode imaging-guided HIFU-triggered chemotherapy. The introduction of PFOB in this nanosystem could cause phase transition and make it gasification to cause collapse of the outer ultrathin silicon shell under HIFU irradiation, which results in enhanced intensive mechanical stress during blasting and enhanced therapeutic effect. The blasting behavior of this nanosystem triggered by HIFU also induced the on-demand RuPOP burst release in tumor site, thus maximizing the inhibition on residual tumor induced by inhomogeneous HIFU ablation. Taken together, this treatment strategy could overcome the inevitable tumor recurrence and significantly reduces systemic side effects of HIFU, thus could be further developed for noninvasive cancer therapy. 10.1016/j.jconrel.2020.09.051
    Polylactic acid nano- and microchamber arrays for encapsulation of small hydrophilic molecules featuring drug release via high intensity focused ultrasound. Gai Meiyu,Frueh Johannes,Tao Tianyi,Petrov Arseniy V,Petrov Vladimir V,Shesterikov Evgeniy V,Tverdokhlebov Sergei I,Sukhorukov Gleb B Nanoscale Long term encapsulation combined with spatiotemporal release for a precisely defined quantity of small hydrophilic molecules on demand remains a challenge in various fields ranging from medical drug delivery, controlled release of catalysts to industrial anti-corrosion systems. Free-standing individually sealed polylactic acid (PLA) nano- and microchamber arrays were produced by one-step dip-coating a PDMS stamp into PLA solution for 5 s followed by drying under ambient conditions. The wall thickness of these hydrophobic nano-microchambers is tunable from 150 nm to 7 μm by varying the PLA solution concentration. Furthermore, small hydrophilic molecules were successfully in situ precipitated within individual microchambers in the course of solvent evaporation after sonicating the PLA@PDMS stamp to remove air-bubbles and to load the active substance containing solvent. The cargo capacity of single chambers was determined to be in the range of several picograms, while it amounts to several micrograms per cm. Two different methods for sealing chambers were compared: microcontact printing versus dip-coating whereby microcontact printing onto a flat PLA sheet allows for entrapment of micro-air-bubbles enabling microchambers with both ultrasound responsiveness and reduced permeability. Cargo release triggered by external high intensity focused ultrasound (HIFU) stimuli is demonstrated by experiment and compared with numerical simulations. 10.1039/c7nr01841j
    Nano-Enhanced Drug Delivery and Therapeutic Ultrasound for Cancer Treatment and Beyond. Tharkar Priyanka,Varanasi Ramya,Wong Wu Shun Felix,Jin Craig T,Chrzanowski Wojciech Frontiers in bioengineering and biotechnology While ultrasound is most widely known for its use in diagnostic imaging, the energy carried by ultrasound waves can be utilized to influence cell function and drug delivery. Consequently, our ability to use ultrasound energy at a given intensity unlocks the opportunity to use the ultrasound for therapeutic applications. Indeed, in the last decade ultrasound-based therapies have emerged with promising treatment modalities for several medical conditions. More recently, ultrasound in combination with nanomedicines, i.e., nanoparticles, has been shown to have substantial potential to enhance the efficacy of many treatments including cancer, Alzheimer disease or osteoarthritis. The concept of ultrasound combined with drug delivery is still in its infancy and more research is needed to unfold the mechanisms and interactions of ultrasound with different nanoparticles types and with various cell types. Here we present the state-of-art in ultrasound and ultrasound-assisted drug delivery with a particular focus on cancer treatments. Notably, this review discusses the application of high intensity focus ultrasound for non-invasive tumor ablation and immunomodulatory effects of ultrasound, as well as the efficacy of nanoparticle-enhanced ultrasound therapies for different medical conditions. Furthermore, this review presents safety considerations related to ultrasound technology and gives recommendations in the context of system design and operation. 10.3389/fbioe.2019.00324
    Triptolide and celastrol loaded silk fibroin nanoparticles show synergistic effect against human pancreatic cancer cells. Ding Baoyue,Wahid Md Arif,Wang Zhijun,Xie Chen,Thakkar Arvind,Prabhu Sunil,Wang Jeffrey Nanoscale Pancreatic cancer is a lethal disease with a dreadful 5-year survival rate of only 5%. In spite of several treatment options, the prognosis still remains extremely poor. Therefore, novel therapy strategies with combinations of drugs are urgently required to combat this fatal disease. Triptolide (TPL) and celastrol (CL), two main compounds in traditional Chinese medicine isolated from Thunder God Vine, have a broad range of bioactivities including anticancer activity. Silk fibroin (SF), a naturally occurring protein with several unique properties, is an ideal carrier material. In this study, we prepared TPL and CL loaded silk fibroin nanoparticles (TPL-SFNPs and CL-SFNPs) by a modified desolvation method and evaluated their synergistic effects against human pancreatic cancer cells. Both SFNPs were characterized for particle size and zeta potential. The entrapment efficiency, drug loading, and drug release profiles were evaluated by HPLC. The cytotoxicity and synergistic effect of SFNPs were investigated in MIA PaCa-2 and PANC-1 human pancreatic cells. The results showed that the particle sizes of TPL-SFNPs and CL-SFNPs were 166.4 ± 4.6 nm and 170.4 ± 2.3 nm, with a mean zeta potential -27.2 ± 2.0 mV and -25.5 ± 2.57 mV, respectively. TPL-SFNPs and CL-SFNPs have a drug loading of 57.0 ± 4.7 μg mg and 63.5 ± 3.8 μg mg along with an encapsulation efficiency of 81.8 ± 2.8% and 87.0 ± 5.1%, respectively. Drug release studies revealed that a rapid release of the drugs from SFNPs was observed at pH 4.5 (lysosomal pH) and a delayed release was observed at pH 7.4 (plasma pH). TPL-SFNPs (IC 3.80 and 4.75 nM) and CL-SFNPs (IC 0.38 and 0.64 μM) were 2-3 fold more potent against MIA PaCa-2 and PANC-1 cells than free TPL (IC 11.25 and 11.58 nM) and CL (IC 0.84 and 1.23 μM). Furthermore, co-treatment with TPL-SFNPs and CL-SFNPs increased the growth inhibition of the same cells significantly in comparison with TPL-SFNPs or CL-SFNPs alone. Almost all combination index (CI) values, calculated using the CompuSyn software, were <1, suggesting that the growth inhibition effect of TPL-SFNPs in combination with CL-SFNPs was synergistic rather than additive, further suggesting that this novel combination may offer a potential treatment for pancreatic cancer. 10.1039/c7nr03016a
    Manganese/iron-based nanoprobes for photodynamic/chemotherapy combination therapy of tumor guided by multimodal imaging. Fan Shanshan,Zhang Yu,Tan Haisong,Xue Cuili,He Yu,Wei Xiangyu,Zha Yiqian,Niu Jiaqi,Liu Yanlei,Cheng Yingsheng,Cui Daxiang Nanoscale Early diagnosis of tumors is crucial in selecting appropriate treatment options to achieve the desired therapeutic effect, but it is difficult to accurately diagnose cancer by a single imaging modality due to technical constraints. Therefore, we synthesized a type of Fe3O4 nanoparticle with manganese dioxide grown on the surface and then prepared it by loading photosensitive drugs and traditional Chinese medicine monomers to create an integrated diagnosis/treatment multifunctional nanoplatform: Fe3O4@MnO2-celastrol (CSL)/Ce6. This nanoplatform can have full advantage of the tumor microenvironment (TME) characteristics of hypoxia (hypoxia), acidic pH (acidosis), and increased levels of reactive oxygen species (e.g., H2O2), even outside the TME. Specific imaging and drug release can also enhance tumor therapy by adjusting the hypoxic state of the TME to achieve the combined effect of chemotherapy (CT) and photodynamic therapy (PDT). Moreover, the obtained Fe3O4@MnO2-CSL/Ce6 has H2O2- and pH-sensitive biodegradation and can release the anticancer drug celastrol (CSL) and photosensitizer Ce6 in TME and simultaneously generate O2 and Mn2+. Therefore, the "dual response" synergistic strategy also confers specific drug release on nanomaterials, relieves tumor hypoxia and antioxidant capacity, and achieves significant optimization of CT and PDT. Furthermore, the resulting Mn2+ ions and Fe3O4 nanoparticles can be used for T1/T2 magnetic resonance imaging on tumor-bearing mice, and the released Ce6 can simultaneously provide fluorescence imaging functions. Therefore, Fe3O4@MnO2-CSL/Ce6 realized the synergistic treatment of PDT and CT under multimodal near-infrared fluorescence/photoacoustic (photoacoustic) imaging monitoring, showing its great potential in the accurate medical treatment of tumors. 10.1039/d0nr08831e
    The Anticancer Properties of Herba Epimedii and Its Main Bioactive Componentsicariin and Icariside II. Chen Meixia,Wu Jinfeng,Luo Qingli,Mo Shuming,Lyu Yubao,Wei Ying,Dong Jingcheng Nutrients Cancer is one of the leading causes of deaths worldwide. Compounds derived from traditional Chinese medicines have been an important source of anticancer drugs and adjuvant agents to potentiate the efficacy of chemotherapeutic drugs and improve the side effects of chemotherapy. Herba Epimedii is one of most popular herbs used in China traditionally for the treatment of multiple diseases, including osteoporosis, sexual dysfunction, hypertension and common inflammatory diseases. Studies show Herba Epimedii also possesses anticancer activity. Flavonol glycosides icariin and icariside II are the main bioactive components of Herba Epimedii. They have been found to possess anticancer activities against various human cancer cell lines in vitro and mouse tumor models in vivo via their effects on multiple biological pathways, including cell cycle regulation, apoptosis, angiogenesis, and metastasis, and a variety of signaling pathways including JAK2-STAT3, MAPK-ERK, and PI3k-Akt-mTOR. The review is aimed to provide an overview of the current research results supporting their therapeutic effects and to highlight the molecular targets and action mechanisms. 10.3390/nu8090563
    Astragaloside IV derived from Astragalus membranaceus: A research review on the pharmacological effects. Zhang Jianqin,Wu Chuxuan,Gao Li,Du Guanhua,Qin Xuemei Advances in pharmacology (San Diego, Calif.) Decoctions prepared from the roots of Astragali Radix are known as "Huangqi" and are widely used in traditional Chinese medicine for treatment of viral and bacterial infections, inflammation, as well as cancer. Astragaloside IV (AS-IV), one of the major compounds from the aqueous extract of Astragalus membranaceus, is a cycloartane-type triterpene glycoside chemical. To date, many studies in cellular and animal models have demonstrated that AS-IV possesses potent protective effects in cardiovascular, lung, kidney and brain. Based on studies over the past several decades, this review systematically summarizes the pharmacological effects, pharmacokinetics and the toxicity of AS-IV. We analyze in detail the pharmacological effects of AS-IV on neuroprotection, liver protection, anti-cancer and anti-diabetes, attributable to its antioxidant, anti-inflammatory, anti-apoptotic properties, and the roles in enhancement of immunity, attenuation of the migration and invasion of cancer cells and improvement of chemosensitivity of chemotherapy drugs. In addition, the latest developments in the combination of AS-IV and other active ingredients of traditional Chinese medicine or chemical drugs are detailed. These pharmacological effects are associated with multiple signaling pathways, including the Raf-MEK-ERK pathway, EGFR-Nrf2 signaling pathway, Akt/PDE3B signaling pathway, AMPK signaling pathway, NF-κB signaling pathway, Nrf2 antioxidant signaling pathways, PI3K/Akt/mTOR signaling pathway, PKC-α-ERK1/2-NF-κB pathway, IL-11/STAT3 signaling pathway, Akt/GSK-3β/β-catenin pathway, JNK/c-Jun/AP-1 signaling pathway, PI3K/Akt/NF-κB pathway, miRNA-34a/LDHA pathway, Nox4/Smad2 pathway, JNK pathway and NF-kB/PPARγ pathway. This review will provide an overall understanding of the pharmacological functions of astragaloside IV on neuroprotection, liver protection, anti-cancer and anti-diabetes. In light of this, AS-IV will be a potent alternative therapeutic agent for treatment of the above mentioned diseases. 10.1016/bs.apha.2019.08.002
    Quercetin Remodels the Tumor Microenvironment To Improve the Permeation, Retention, and Antitumor Effects of Nanoparticles. Hu Kaili,Miao Lei,Goodwin Tyler J,Li Jun,Liu Qi,Huang Leaf ACS nano Our previous work demonstrated that Wnt16 expression in cisplatin-damaged tumor-associated fibroblasts is a key factor contributing to cisplatin resistance in malignancies. Natural antifibrotic compounds with low toxicities are promising candidates to downregulate Wnt16 expression, improving the antitumor effect of cisplatin nanoparticles. Upon screening several natural chemicals, we found that a dietary flavonoid, quercetin, significantly suppresses Wnt16 expression in activated fibroblasts. To facilitate drug delivery, we have prepared a targeted lipid/calcium/phosphate nanoparticle formulation consisting of a prodrug of quercetin, i.e., quercetin phosphate, with a high loading efficiency (26.6% w/w). This quercetin nanoparticle with a particle size of around 35 nm significantly improved the bioavailability and metabolic stability of the parent quercetin. Quercetin phosphate is released from the nanoparticles and converted back to the parent quercetin under physiological conditions. Following systemic administration of quercetin phosphate nanoparticles, a significant downregulation in Wnt16 expression was observed and further yielded a synergistic antitumor effect with cisplatin nanoparticles in a stroma-rich bladder carcinoma model. The α-SMA-positive fibroblast and collagen within the tumor decreased significantly after combination treatment. This suggests that the remodeling of the tumor microenvironment induced by quercetin plays a critical role in promoting the synergy. Indeed, our data further confirmed that quercetin phosphate alone significantly remodeled the tumor microenvironment and increased the penetration of second-wave nanoparticles into the tumor nests. Collectively, quercetin phosphate nanoparticles may be a safe and effective way to improve therapeutic treatment for desmoplastic tumors. 10.1021/acsnano.7b01522
    Astragaloside III Enhances Anti-Tumor Response of NK Cells by Elevating NKG2D and IFN-γ. Chen Xingmeng,Chen Xi,Gao Junxiao,Yang Han,Duan Yue,Feng Yuxin,He Xin,Gong Xiaoqun,Wang Hanjie,Wu Xiaoli,Chang Jin Frontiers in pharmacology Natural killer (NK) cells play an irreplaceable role in the development of colon cancer, in which antitumor function of NK cells was impaired. Astragaloside III is a natural compound from Astragalus that has been shown to have immunomodulatory effects in various systems. However, few studies have evaluated the antitumor effects of Astragaloside III through stimulating systemic immunity and regulating NK cells. In this study, flow cytometry, immunohistochemical analysis, and immunofunctional assays were performed to elucidate the functions of Astragaloside III in restoring antitumor function of NK cells. We demonstrated that Astragaloside III significantly elevated the expression of natural killer group 2D (NKG2D), Fas, and interferon-γ (IFN-γ) production in NK cells, leading to increased tumor-killing ability. Experiments in cell co-culture assays and CT26-bearing mice model further confirmed that Astragaloside III could effectively impede tumor growth by increasing infiltration of NK cells into tumor and upregulating the antitumor response of NK cells. We further revealed that Astragaloside III increased IFN-γ secretion of NK cells by enhancing the expression of transcription factor T-bet. In conclusion, the effective anti-tumor function of Astragaloside III was achieved through up-regulation of the immune response of NK cells and elevation of NKG2D, Fas, and IFN-γ production. 10.3389/fphar.2019.00898
    Prospective therapeutic potential of Tanshinone IIA: An updated overview. Ansari Mohammad Azam,Khan Farheen Badrealam,Safdari Haaris Ahsan,Almatroudi Ahmad,Alzohairy Mohammad A,Safdari Mohammadreza,Amirizadeh Mehran,Rehman Suriya,Equbal Mohammad Javed,Hoque Mehboob Pharmacological research In the past decades, the branch of complementary and alternative medicine based therapeutics has gained considerable attention worldwide. Pharmacological efficacy of various traditional medicinal plants, their products and/or product derivatives have been explored on an increasing scale. Tanshinone IIA (Tan IIA) is a pharmacologically active lipophilic component of Salvia miltiorrhiza extract. Tan IIA shares a history of high repute in Traditional Chinese Medicine. Reckoning with these, the present review collates the pharmacological properties of Tan IIA with a special emphasis on its therapeutic potential against diverse diseases including cardiovascular diseases, cerebrovascular diseases, cancer, diabetes, obesity and neurogenerative diseases. Further, possible applications of various therapeutic preparations of Tan IIA were discussed with special emphasis on nano-based drug delivery formulations. Considering the tremendous advancement in the field of nanomedicine and the therapeutic potential of Tan IIA, the convergence of these two aspects can be foreseen with great promise in clinical application. 10.1016/j.phrs.2020.105364
    Nano-realgar suppresses lung cancer stem cell growth by repressing metabolic reprogramming. Yang Fei-Ran,Zhao Yu-Feng,Hu Xi-Wen,Liu Zong-Kai,Yu Xiao-Dan,Li Chang-Yang,Li Xiu-Rong,Li Hui-Jie Gene BACKGROUND:Recent studies in cancer biology suggest that metabolic glucose reprogramming is a potential target for cancer treatment. However, little is known about drug intervention in the glucose metabolism of cancer stem cells (CSCs) and its related underlying mechanisms. METHODS:The crude realgar powder was Nano-grinded to meets the requirements of Nano-pharmaceutical preparations, and Nano-realgar solution (NRS) was prepared for subsequent experiments. Isolation and characterization of lung cancer stem cells (LCSCs) was performed by magnetic cell sorting (MACS) and immunocytochemistry, respectively. Cell viability and intracellular glucose concentration were detected by MTT assay and glucose oxidase (GOD) kit. Protein expressions related to metabolic reprogramming was detected by ELISA assay. Determination of the expression of HIF-1α and PI3K/Akt/mTOR pathways was carried out by RT-PCR and western blotting analysis. A subcutaneous tumor model in BALB/c-nu mice was successfully established to evaluate the effects of Nano-realgar on tumor growth and histological structure, and the expression of HIF-1α in tumor tissues was measured by immunofluorescence. RESULTS:Nano-realgar inhibits cell viability and induces glucose metabolism in LCSCs, and inhibits protein expression related to metabolic reprogramming in a time- and dose-dependent manner. Nano-realgar downregulated the expression of HIF-1α and PI3K/Akt/mTOR pathways in vitro and in vivo. Nano-realgar inhibits tumor growth and changes the histological structure of tumors through in vivo experiments and consequently inhibits the constitutive activation of HIF-1α signaling. CONCLUSIONS:These results reveal that Nano-realgar inhibits tumor growth in vitro and in vivo by repressing metabolic reprogramming. This inhibitory effect potentially related to the downregulation HIF-1α expression via PI3K/Akt/mTOR pathway. 10.1016/j.gene.2021.145666
    Nano-herb medicine and PDT induced synergistic immunotherapy for colon cancer treatment. Wu Xiaoli,Yang Han,Chen Xingmeng,Gao Junxiao,Duan Yue,Wei Daohe,Zhang Jinchao,Ge Kun,Liang Xing-Jie,Huang Yuanyu,Feng Sizhou,Zhang Rongli,Chen Xi,Chang Jin Biomaterials A variety of therapies have been developed and used for the treatment of colon cancer, however, the high mortality rate remains high and more effective strategies are still in urgent needs. In this study, an immunotherapy approach that is composed of innate immune activator Astragaloside III (As) and the photodynamic therapy (PDT) reagent chlorine e6 (Ce6) ((As + Ce6)@MSNs-PEG), was developed for colon cancer treatment. We showed that (As + Ce6)@MSNs-PEG could effectively activate NK cells and inhibit the proliferation of tumor cells in vitro. It could also effectively reach tumor sites, induce infiltration of immune cells into the tumor, and enhance the cytotoxicity of natural killer cells and CD8 T cells in vivo. Without obvious side effects, (As + Ce6)@MSNs-PEG treatment significantly inhibited tumor growth and extended the lifespan of tumor-bearing mice. Further results revealed that treatment of (As + Ce6)@MSNs-PEG led to enhanced IFN secretion by immune cells and increased T-box transcription factor (T-bet), which is highly expressed by T cells. Therefore, (As + Ce6)@MSNs-PEG may serve as an effective and safe platform for combinatory use with nano-herb medicine and PDT to provide a new therapy for colon cancer treatment. 10.1016/j.biomaterials.2021.120654
    Realgar Nanoparticles Inhibit Migration, Invasion and Metastasis in a Mouse Model of Breast Cancer by Suppressing Matrix Metalloproteinases and Angiogenesis. Xiaoxia Xi,Jing Sun,Dongbin Xi,Yonggang Tian,Jingke Zhang,Yanying Zhang,Hulai Wei Current drug delivery BACKGROUND:Realgar, a traditional Chinese medicine, has shown antitumor efficacy in several tumor types. We previously showed that realgar nanoparticles (nano-realgar) had significant antileukemia, anti-lung cancer and anti-liver cancer effects. In addition, the anti-tumor effects of nanorealgar were significantly better than those of ordinary realgar. OBJECTIVE:To explore the inhibitory effects and molecular mechanisms of nano-realgar on the migration, invasion and metastasis of mouse breast cancer cells. METHODS:Wound-healing migration assays and Transwell invasion assays were carried out to determine the effects of nano-realgar on breast cancer cell (4T1) migration and invasion. The expression levels of matrix metalloproteinase (MMP)-2 and -9 were measured by Western blot. A murine breast cancer metastasis model was established, administered nano-realgar for 32 days and monitored for tumor growth and metastasis by an in vivo optical imaging system. Finally, living imaging and hematoxylin and eosin (HE) staining were used to measure the morphology and pathology of lung and liver cancer cell metastases, respectively. Angiogenesis was assessed by CD34 immunohistochemistry. RESULTS:Nano-realgar significantly inhibited the migration and invasion of breast cancer 4T1 cells and the expression of MMP-2 and -9. Meanwhile, nano-realgar effectively suppressed the abilities of tumor growth, metastasis and angiogenesis in the murine breast cancer metastasis model in a time- and dosedependent manner. CONCLUSION:Nano-realgar significantly inhibited migration and invasion of mouse breast cancer cells in vitro as well as pulmonary and hepatic metastasis in vivo, which may be closely correlated with the downexpression of MMP-2 and -9 and suppression of tumor neovascularization. 10.2174/1567201817666200115105633
    A Modern Technology Applied in Traditional Chinese Medicine: Progress and Future of the Nanotechnology in TCM. Yan Guojun,Wang Yonglin,Han Xinxin,Zhang Qian,Xie Hui,Chen Jun,Ji De,Mao Chunqin,Lu Tulin Dose-response : a publication of International Hormesis Society The application of nanotechnology to traditional Chinese medicine (TCM) enabled the development of Chinese medicine in the international society. The pharmacodynamics of TCM is not only depending on its chemical constituents but also related to its physical state such as particle size. Indeed, there is some new pesticide effect that appeared when the medicine was being made into nanophase. The application of nanotechnology to TCM can expand the use of a range of Chinese medicinal materials. In this review, we introduce the concept of nanometer TCM. We also review the preparation methods, advantages, and development tendency of Nano-TCM; furthermore, we analyze the problems in the process of development of Nano-TCM and put forward varies possible solutions to solve this problems, thereby providing new thought for the development of Nano-TCM. 10.1177/1559325819872854
    Traditional Chinese medicine-combination therapies utilizing nanotechnology-based targeted delivery systems: a new strategy for antitumor treatment. Ma Zhe,Fan Yuqi,Wu Yumei,Kebebe Dereje,Zhang Bing,Lu Peng,Pi Jiaxin,Liu Zhidong International journal of nanomedicine Cancer is a major public health problem, and is now the world's leading cause of death. Traditional Chinese medicine (TCM)-combination therapy is a new treatment approach and a vital therapeutic strategy for cancer, as it exhibits promising antitumor potential. Nano-targeted drug-delivery systems have remarkable advantages and allow the development of TCM-combination therapies by systematically controlling drug release and delivering drugs to solid tumors. In this review, the anticancer activity of TCM compounds is introduced. The combined use of TCM for antitumor treatment is analyzed and summarized. These combination therapies, using a single nanocarrier system, namely codelivery, are analyzed, issues that require attention are determined, and future perspectives are identified. We carried out a systematic review of >280 studies published in PubMed since 1985 (no patents involved), in order to provide a few basic considerations in terms of the design principles and management of targeted nanotechnology-based TCM-combination therapies. 10.2147/IJN.S197889
    Nano Traditional Chinese Medicine: Current Progresses and Future Challenges. Huang Yi,Zhao Yinglan,Liu Fang,Liu Songqing Current drug targets Nano traditional Chinese medicine (nano TCM) refers to bioactive ingredients, bioactive parts, medicinal materials or complex prescription, being approximately 100 nm in size, which are processed by nanotechnology. Nano TCM is a product of the TCM modernization, and is an application of nanotechnology in the field of TCM. This article reviews literatures on researches of nano TCM, which were published in the past 15 years. Different nanotechnologies have been used in preparation of Nano TCM in view of the varying aims of the study. The mechanical crushing technology is the main approach for nanolization of TCM material and complex prescription, and nanoparticulate drug delivery systems is the main approach for nanolization of bioactive ingredients or bioactive parts in TCM. Nano TCM has a number of advantages, for example, enhancing the bioavailability of TCM, reducing the adverse effects of TCM, achieving sustained release, attaining targeted delivery, enhancing pharmacological effects and improving the administration route of TCM. However, there are still many problems that must be resolved in nano TCM research. The main challenges to nano TCM include the theory system of TCM modernization, preparation technology, safety and stability, etc.
    A Nano-Traditional Chinese Medicine Against Lymphoma That Regulates the Level of Reactive Oxygen Species. Zhao Qiangqiang,Li Jian,Wu Bin,Shang Yinghui,Huang Xueyuan,Dong Hang,Liu Haiting,Gui Rong,Nie Xinmin Frontiers in chemistry Jolkinolide B (JB) is a bioactive compound isolated from a Chinese herbal medicine that exerts antitumor activity. However, the anti-lymphoma effect of JB and its mechanism are yet to be revealed. Because free JB has poor pharmacokinetics and weak antitumor efficacy, we opted to use black phosphorus quantum dot (BPQD) nanomaterials as a drug loading platform to synthesize a nano-traditional Chinese medicine (nano-TCM) called BPQDs@JB. Compared with free JB, Raji cells administrated with BPQDs@JB exhibited the cell viability of 19.85 ± 1.02%, and the production of intracellular reactive oxygen species (ROS) was promoted. Likewise, BPQDs@JB was capable of rising the apoptosis rate of Raji cells to 34.98 ± 1.76%. In nude mice transplanted tumor model administrated with BPQDs@JB, the tumor tissue sections administrated with BPQDS@JB achieved a conspicuous red fluorescence, demonstrating the presence of most ROS production in the BPQDS@JB. TUNEL achieved a number of positive (brown) nuclei , revealing that BPQDS@JB could significantly induce tumor tissue apoptosis. As revealed from the mentioned results, BPQDs@JB can generate considerable ROS and interfere with the redox state to inhibit tumor. In brief, BPQDs@JB may be adopted as a treatment option for lymphoma. 10.3389/fchem.2020.00565
    The combination of nanotechnology and traditional Chinese medicine (TCM) inspires the modernization of TCM: review on nanotechnology in TCM-based drug delivery systems. Drug delivery and translational research Fast development of combination of nanotechnology with traditional Chinese medicine (TCM) broadens the field of application of TCM. Besides, it increases the research ideas and contributes to TCM modernization. As expected, TCM will be developed into the nanodrug delivery system by nanotechnology with careful design, which will enhance the medicinal value of TCM to cure and prevent disease based on benefits brought by nanometer scale. Here, formulations, relevant preparations methods, and characteristics of nano-TCM were introduced. In addition, the main excellent performances of nano-TCM were clearly elaborated. What is more, the review was intended to address the studies committed to application of nanotechnology in TCM over the years, including development of Chinese medicine active ingredients, complete TCM, and Chinese herbal compounds based on nanotechnology. Finally, this review discussed the safety of nano-TCM and presented future development trends in the way to realize the modernization of TCM. Overall, using the emerging nanotechnology in TCM is promising to promote progress of TCM in international platform. Recent researches on modernization of traditional Chinese medicine (TCM) urged by nanotechnology are introduced, and formulations, advantages, and applications of nano-TCM are reviewed to provide strong proofs. 10.1007/s13346-021-01029-x