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Xie X, Zhang Y, Li F, Lv T, Li Z, Chen H, Jia L, Gao Y. Challenges and Opportunities from Basic Cancer Biology for Nanomedicine for Targeted Drug Delivery. Curr Cancer Drug Targets 2019; 19:257-276. [DOI: 10.2174/1568009618666180628160211] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 03/15/2018] [Accepted: 06/22/2018] [Indexed: 12/11/2022]
Abstract
Background:Effective cancer therapy is still a great challenge for modern medical research due to the complex underlying mechanisms of tumorigenesis and tumor metastasis, and the limitations commonly associated with currently used cancer therapeutic options. Nanotechnology has been implemented in cancer therapeutics with immense potential for improving cancer treatment.Objective:Through information about the recent advances regarding cancer hallmarks, we could comprehensively understand the pharmacological effects and explore the mechanisms of the interaction between the nanomaterials, which could provide opportunities to develop mechanism-based nanomedicine to treat human cancers.Methods:We collected related information and data from articles.Results:In this review, we discussed the characteristics of cancer including tumor angiogenesis, abnormalities in tumor blood vessels, uncontrolled cell proliferation markers, multidrug resistance, tumor metastasis, cancer cell metabolism, and tumor immune system that provide opportunities and challenges for nanomedicine to be directed to specific cancer cells and portray the progress that has been accomplished in application of nanotechnology for cancer treatment.Conclusion:The information presented in this review can provide useful references for further studies on developing effective nanomedicine for the treatment of cancer.
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Affiliation(s)
- Xiaodong Xie
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Yingying Zhang
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Fengqiao Li
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Tingting Lv
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Ziying Li
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Haijun Chen
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Lee Jia
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Yu Gao
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
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Meng C, Shen X, Jiang W. Potential biomarkers of HCC based on gene expression and DNA methylation profiles. Oncol Lett 2018; 16:3183-3192. [PMID: 30127913 PMCID: PMC6096098 DOI: 10.3892/ol.2018.9020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 04/19/2018] [Indexed: 12/17/2022] Open
Abstract
The aim of the present study was to identify potential biomarkers of hepatocellular carcinoma (HCC). Three gene expression profiles of GSE95698, GSE49515 and GSE76427 and a DNA methylation profile of GSE73003 were downloaded from the Gene Expression Omnibus (GEO) database, each comprising data regarding HCC and control tissue samples. The differentially expressed genes (DEGs) between the HCC group and the control group were identified using the limma software package. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the overlapping DEGs. The PPI network of the overlapping DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins. A total of 41 DEGs were identified in HCC the group compared with control group. The overlapping DEGs were enriched in 11 GO terms and 3 KEGG pathways. A total of 6,349 DMSs were identified, and 6 of the differentially expressed genes were also differentially methylated [Denticleless protein homolog (DTL), Dual specificity phosphatase 1 (DUSP1), Eomesodermin, Endothelial cell specific molecule 1, Nuclear factor κ-light-chain gene enhancer of activated B cells inhibitor, α (NFKBIA) and suppressor of cytokine signaling 2 (SOCS2)]. The present study suggested that DTL, DUSP1, NFKBIA and SOCS2 may be potential biomarkers of HCC, and the tumor protein 'p53 signaling', 'forkhead box O1' signaling and 'metabolic' pathways may serve roles in the pathogenesis of HCC.
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Affiliation(s)
- Chao Meng
- Department of Clinical Laboratory, Tianjin Second People's Hospital, Tianjin 300192, P.R. China
- Tianjin Institute of Hepatology, Tianjin 300192, P.R. China
| | - Xiaomin Shen
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, P.R. China
| | - Wentao Jiang
- Department of Liver Transplantation, Tianjin First Center Hospital, Tianjin 300192, P.R. China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, P.R. China
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Zhu ML, Xu XL, Wang XJ, Zhang NN, Lu KJ, Qi J, Jin FY, Liu D, Du YZ. Sialic-Acid-Anchored Micelles: A Hierarchical Targeting Device for Enhanced Tumor Tissue Accumulation and Cellular Internalization. Mol Pharm 2018; 15:4235-4246. [PMID: 30110551 DOI: 10.1021/acs.molpharmaceut.8b00649] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Targeted drug delivery systems (TDDS) have attracted wide attention for their reduced drug side effects and improved antitumor efficacy in comparison with traditional preparations. While targeting moieties in existing TDDS have principally focused on recognition of receptors on the surface of tumor cells, accumulation into tumor tissue only could be performed by enhanced permeability and retention effects and active transportation into tumor cells. Doxorubicin (DOX)-loaded sialic acid-dextran (Dex)-octadecanoic acid (OA) micelles (SA-Dex-OA/DOX) were designed for targeting hepatocellular carcinoma effectively. The synthesized conjugates could self-aggregate to form micelles with a critical micelle concentration of 27.6 μg·mL-1 and diameter of 54.53 ± 3.23 nm. SA-Dex-OA micelles incorporated with 4.36% DOX-loading content could prolong in vitro drug release to 96 h with 80% of final release. Cellular transportation studies revealed that SA-Dex-OA micelles mediated more efficient DOX delivery into Bel-7402 cells than those without SA modification. In vivo biodistribution testing demonstrated that SA-Dex-OA/ICG micelles showed 3.05-fold higher accumulation into Bel-7402 tumors. The recognition of overexpressed E-selectin in inflammatory tumor vascular endothelial cells led to a large accumulation of SA-Dex-OA/ICG micelles into tumor tissue, and the E-selectin upregulated on the surface of tumor cells contributed to active cellular transportation into tumor cells. Accordingly, SA-Dex-OA/DOX exhibited prior suppression of Bel-7402 tumor growth greater than that of Dex-OA/DOX micelles and free DOX (the tumor inhibition: 79.2% vs 61.0 and 51.3%). These results suggest that SA-functionalized micelles with dual targeting properties have high potential for liver cancer therapy.
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Affiliation(s)
- Meng-Lu Zhu
- The Fourth Affiliated Hospital , Zhejiang University School of Medicine , Yiwu 322000 , China
| | - Xiao-Ling Xu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences , Zhejiang University , 866 Yu-Hang-Tang Road , Hangzhou 310058 , China
| | - Xiao-Juan Wang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences , Zhejiang University , 866 Yu-Hang-Tang Road , Hangzhou 310058 , China
| | - Nan-Nan Zhang
- Lishui Hospital , Zhejiang University School of Medicine , Lishui 323000 , China
| | - Kong-Jun Lu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences , Zhejiang University , 866 Yu-Hang-Tang Road , Hangzhou 310058 , China
| | - Jing Qi
- Institute of Pharmaceutics, College of Pharmaceutical Sciences , Zhejiang University , 866 Yu-Hang-Tang Road , Hangzhou 310058 , China
| | - Fei-Yang Jin
- Institute of Pharmaceutics, College of Pharmaceutical Sciences , Zhejiang University , 866 Yu-Hang-Tang Road , Hangzhou 310058 , China
| | - Di Liu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences , Zhejiang University , 866 Yu-Hang-Tang Road , Hangzhou 310058 , China
| | - Yong-Zhong Du
- Institute of Pharmaceutics, College of Pharmaceutical Sciences , Zhejiang University , 866 Yu-Hang-Tang Road , Hangzhou 310058 , China
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Fang Y, Yang W, Cheng L, Meng F, Zhang J, Zhong Z. EGFR-targeted multifunctional polymersomal doxorubicin induces selective and potent suppression of orthotopic human liver cancer in vivo. Acta Biomater 2017; 64:323-333. [PMID: 29030307 DOI: 10.1016/j.actbio.2017.10.013] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 09/13/2017] [Accepted: 10/09/2017] [Indexed: 02/07/2023]
Abstract
Liver cancer is a globally leading malignancy that has a poor five-year survival rate of less than 20%. The systemic chemotherapeutics are generally ineffective for liver cancers partly due to fast clearance and low tumor uptake. Here, we report that GE11 peptide functionalized polymersomal doxorubicin (GE11-PS-DOX) effectively targets and inhibits epidermal growth factor receptor (EGFR)-positive SMMC7721 orthotopic human liver tumor xenografts in mice. GE11-PS-DOX with a GE11 surface density of 10% displayed a high drug loading of 15.4 wt%, a small size of 78 nm, and glutathione-triggered release of DOX. MTT assays, flow cytometry and confocal microscopy studies revealed that GE11-PS-DOX mediated obviously more efficient DOX delivery into SMMC7721 cells than the non-targeting PS-DOX and clinically used liposomal doxorubicin (Lipo-DOX) controls. The in vivo studies showed that GE11-PS-DOX had a long circulation time and an extraordinary accumulation in the tumors (13.3 %ID/g). Interestingly, GE11-PS-DOX caused much better treatment of SMMC7721 orthotopic liver tumor-bearing mice as compared to PS-DOX and Lipo-DOX. The mice treated with GE11-PS-DOX (12 mg DOX equiv./kg) exhibited a significantly improved survival rate (median survival time: 130 days versus 70 and 38 days for PS-DOX at 12 mg DOX equiv./kg and Lipo-DOX at 6 mg DOX equiv./kg, respectively) and achieved 50% complete regression. Notably, GE11-PS-DOX induced obviously lower systemic toxicity than Lipo-DOX. EGFR-targeted multifunctional polymersomal doxorubicin with improved efficacy and safety has a high potential for treating human liver cancers. STATEMENT OF SIGNIFICANCE Liver cancer is one of the top five leading causes of cancer death worldwide. The systemic chemotherapeutics and biotherapeutics generally have a low treatment efficacy for hepatocellular carcinoma partly due to fast clearance and/or low tumor uptake. Nanomedicines based on biodegradable micelle and polymersomes offer a most promising treatment for malignant liver cancers. Their clinical effectiveness remains, however, suboptimal owing to issues like inadequate systemic stability, low tumor accumulation and selectivity, and poor control over drug release. Here we report that GE11 peptide-functionalized, disulfide-crosslinked multifunctional polymersomal doxorubicin (GE11-PS-DOX) can effectively suppress the growth of orthotopic SMMC7721 human liver tumors in nude mice. They showed significantly decreased systemic toxicity and improved mouse survival rate with 3.4-fold longer median survival time as compared to clinically used pegylated liposomal doxorubicin (Lipo-DOX) and achieving 50% complete regression. GE11-PS-DOX, based on PEG-PTMC is biodegradable, nontoxic, and easy to prepare, appears as a safe, robust, versatile and all-function-in-one nanoplatform that has a high potential in targeted chemotherapy of EGFR expressed hepatocellular carcinoma.
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Yahya SMM, Fathy SA, El-Khayat ZA, El-Toukhy SE, Hamed AR, Hegazy MGA, Nabih HK. Possible Role of microRNA-122 in Modulating Multidrug Resistance of Hepatocellular Carcinoma. Indian J Clin Biochem 2017; 33:21-30. [PMID: 29371766 DOI: 10.1007/s12291-017-0651-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/11/2017] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular primary liver cancer characterized by rapid progression, besides, resistance to traditional chemotherapeutic agents. It has been shown that microRNAs play critical roles in regulation of tumor cell sensitivity to drugs through modulating the expression of genes involved in drug transport. The present study investigated whether restoration of miR-122 in HCC cells could alter the cell cycle distribution and the expression of multidrug resistance (MDR)-related genes (ABCB1, ABCC1, ABCG2 and ABCF2). After overexpression of miR-122 in HepG2 cells treated or untreated with doxorubicin doses, total RNAs and protein extracts were isolated for application of QRT-PCR and western blotting techniques. Moreover, cell cycle distribution was monitored by flow cytometry. Our results revealed that, the over expression of miR-122 in HepG2 cells treated or untreated with doxorubicin could modulate the sensitivity of cells to chemotherapeutic drug through downregulation of MDR-related genes, ABCB1 and ABCF2. Interpretation of cell cycle distribution revealed that, the anti-proliferative effect of miR-122 is associated with the accumulation of cells in G0/G1 phase. Moreover, treatment with miR-122 and doxorubicin resulted in high percentage of HCC cells in G0/G1 phase. Taken together, our findings revealed that, overexpression of miR-122 inhibited HCC cell growth by inducing cell cycle arrest and this arrest is associated with down-regulation of MDR-related genes.
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Affiliation(s)
- Shaymaa M M Yahya
- 1Hormones Department, National Research Centre, Dokki, Giza, 12622 Egypt
| | - Shadia A Fathy
- 2Biochemistry Department, Ain Shams University, Cairo, Egypt
| | | | | | - Ahmed R Hamed
- 4Pharmaceutical Research Group, Center of Excellence for Advanced Sciences and Phytochemistry Department National Research Centre, Dokki, Giza, Egypt
| | | | - Heba K Nabih
- 3Medical Biochemistry Department, National Research Centre, Cairo, Egypt
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New Tools for Molecular Therapy of Hepatocellular Carcinoma. Diseases 2015; 3:325-340. [PMID: 28943628 PMCID: PMC5548255 DOI: 10.3390/diseases3040325] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/15/2015] [Accepted: 10/22/2015] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, arising from neoplastic transformation of hepatocytes or liver precursor/stem cells. HCC is often associated with pre-existing chronic liver pathologies of different origin (mainly subsequent to HBV and HCV infections), such as fibrosis or cirrhosis. Current therapies are essentially still ineffective, due both to the tumor heterogeneity and the frequent late diagnosis, making necessary the creation of new therapeutic strategies to inhibit tumor onset and progression and improve the survival of patients. A promising strategy for treatment of HCC is the targeted molecular therapy based on the restoration of tumor suppressor proteins lost during neoplastic transformation. In particular, the delivery of master genes of epithelial/hepatocyte differentiation, able to trigger an extensive reprogramming of gene expression, could allow the induction of an efficient antitumor response through the simultaneous adjustment of multiple genetic/epigenetic alterations contributing to tumor development. Here, we report recent literature data supporting the use of members of the liver enriched transcription factor (LETF) family, in particular HNF4α, as tools for gene therapy of HCC.
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Lyra-González I, Flores-Fong LE, González-García I, Medina-Preciado D, Armendáriz-Borunda J. MicroRNAs dysregulation in hepatocellular carcinoma: Insights in genomic medicine. World J Hepatol 2015; 7:1530-1540. [PMID: 26085912 PMCID: PMC4462691 DOI: 10.4254/wjh.v7.i11.1530] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 12/22/2014] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading primary liver cancer and its clinical outcome is still poor. MicroRNAs (miRNAs) have demonstrated an interesting potential to regulate gene expression at post-transcriptional level. Current findings suggest that miRNAs deregulation in cancer is caused by genetic and/or epigenetic, transcriptional and post-transcriptional modifications resulting in abnormal expression and hallmarks of malignant transformation: aberrant cell growth, cell death, differentiation, angiogenesis, invasion and metástasis. The important role of miRNAs in the development and progression of HCC has increased the efforts to understand and develop mechanisms of control overt this single-stranded RNAs. Several studies have analyzed tumoral response to the regulation and control of deregulated miRNAs with good results in vitro and in vivo, proving that targeting aberrant expression of miRNAs is a powerful anticancer therapeutic. Identification of up and/or down regulated miRNAs related to HCC has led to the discovery of new potential application for detection of their presence in the affected organism. MiRNAs represent a relevant new target for diagnosis, prognosis and treatment in a wide variety of pathologic entities, including HCC. This manuscript intends to summarize current knowledge regarding miRNAs and their role in HCC development.
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