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Wen Ting Zhu,1,* Xiang Feng Zeng,2,* Hua Yang,2 Meng Lei Jia,1 Wei Zhang,2 Wei Liu,2 Sheng Yao Liu3 1Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, People’s Republic of China; 2Department of Orthopedics, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China; 3Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Liu, Department of Orthopedics, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China, Email lwsurgery@163.com Sheng Yao Liu, Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, People’s Republic of China, Email liushengyao12@163.comBackground: Osteosarcoma is a malignant bone tumor with a high rate of lung metastasis and mortality. It has been demonstrated that resveratrol can inhibit tumor proliferation and metastasis, but its application is limited due to poor water solubility and low bioavailability. In this study, we proposed to prepare folate-modified liposomes loaded with resveratrol to investigate its anti-osteosarcoma effect in vitro and in vivo.Methods: We prepared and characterized resveratrol liposomes modified with folate (denoted as, FA-Res/Lps). The effects of FA-Res/Lps on human osteosarcoma cell 143B proliferation, apoptosis, and migration were investigated by MTT, cell cloning, wound-healing assay, transwell, and flow cytometry. A xenograft tumor and lung metastasis model of osteosarcoma was constructed to study the therapeutic effects of FA-Res/Lps on the growth and metastasis of osteosarcoma in vivo.Results: The FA-Res/Lps were prepared with a particle size of 118.5 ± 0.71 and a small dispersion coefficient of 0.154 ± 0.005. We found that FA-modified liposomes significantly increased resveratrol uptake by osteosarcoma cells 143B in flow cytometric assay, resulting in FA-Res/Lps, which inhibit tumor proliferation, migration and induce apoptosis more effectively than free Res and Res/Lps. The mechanism of action may be associated with the inhibition of JAK2/STAT3 signaling. In vivo imaging demonstrated that FA-modified DiR-modified liposomes significantly increased the distribution of drugs at the tumor site, leading to significant inhibition of osteosarcoma growth and metastasis by FA-Res/Lps. Furthermore, we found that FA-Res/Lps did not cause any adverse effects on mice body weight, liver, or kidney tissues.Conclusion: Taken together, the anti-osteosarcoma effect of resveratrol is significantly enhanced when it is loaded into FA-modified liposomes. FA-Res/Lps is a promising strategy for the treatment of osteosarcoma.Keywords: resveratrol, liposomes, osteosarcoma, lung metastasis, JAK2/STAT3 pathway

Xiao-Min Liu1 *, Wen-Ting Zhu1 *, Meng-Lei Jia,1 Yu-Ting Li,1 Ye Hong,1 Zhong-Qiu Liu,2 Peng-Ke Yan1 1Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhong-Qiu Liu, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China, Email liuzq@gzucm.edu.cn Peng-Ke Yan, Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Email gysyypk@126.comBackground: Transgenic C57BL/6-APC(Min/+) spontaneous cancer mouse model and the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) chemically induced orthotopic colorectal cancer mouse model represented distinct pathogenesis of colorectal cancers. Our previous study revealed that the combination of Rapamycin liposomes (Rapa/Lps) and 5-Fluorouracil (5-FU) has anti-colorectal cancer effects. However, the therapeutic efficacy of Rapa/Lps and 5-FU in other colorectal cancer mice models is yet to be thoroughly explored. The purpose of this study was to investigate the anti-tumor effect of Rapa/Lps combined with 5-FU in vivo and in vitro.Methods: In this study, we evaluated the effect of Rapa/Lps and 5-FU on APC (Min/+) mice and AOM/DSS-induced colorectal cancer mice. The small intestine, colorectum, serum, and plasma of mice in each group were collected following sacrifice to record the number of tumors. HE staining was utilized for observing pathological damage to intestine tissues. Tube formation assay, Transwell assay, wound healing assay, Western Blot were used to explore the anti-angiogenesis effect of drugs in HUVECs.Results: As expected, Rapa/Lps and 5-FU significantly suppressed tumor formation, decreased the number of tumors, and tumor load both in two mouse models, and had no influence on mouse weight. Mechanically, the anti-tumor effect of the drug also was associated in inhibiting angiogenesis and proliferation. Furthermore, we found that Rapa/Lps obviously inhibited HUVECs tube formation and migration.Conclusion: Altogether, we revealed the Rapa/Lps synergism with 5-FU decreased colon and small intestinal tumorigenesis in AOM/DSS-treated and APC (Min/+) mice, respectively, and correlated with anti-angiogenesis.Keywords: rapamycin liposomes, 5-fluorouracil, angiogenesis, APC (Min/+) mice, AOM/DSS, colorectal cancer

Yi-Qing Chen,* Wen-Ting Zhu,* Cai-Yan Lin, Zhong-Wen Yuan, Zhen-Hua Li, Peng-Ke Yan The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng-Ke YanThe Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, People’s Republic of ChinaEmail gysyypk@126.comBackground: Rapamycin is a promising agent for treating tumors, but clinical applications of rapamycin are limited due to its poor water solubility and low bioavailability. This paper constructs a liposome delivery system for rapamycin to improve the effect in treating colorectal cancer.Methods: We prepared the rapamycin liposomes using the ethanol injection method. The cellular uptake and biodistribution were detected by LC-MS and in vivo imaging system. MTT assay, transwell migration experiment, flow cytometry, and Western blot analysis evaluated the antitumor effect of rapamycin liposomes in vitro. Furthermore, HCT-116 tumor-bearing mice were used to assess the therapeutic efficacy of rapamycin liposomes in vivo.Results: The prepared rapamycin liposomes had a particle size of 100± 5.5 nm and with a narrow size distribution. In vitro cellular uptake experiments showed that the uptake of rapamycin liposomes by colorectal cells was higher than that of free rapamycin. Subsequently, in vivo imaging experiments also demonstrated that rapamycin liposomes exhibited higher tumor accumulation. Therefore, the ability of rapamycin liposomes to inhibit tumor proliferation, migration and to induce tumor apoptosis is superior to that of free rapamycin. We also demonstrated in vivo good antitumor efficacy of the rapamycin liposomes in HCT-116 xenograft mice. In addition, rapamycin liposomes and 5-FU can synergistically improve the efficacy of colorectal cancer via the Akt/mTOR and P53 pathways.Conclusion: Collectively, rapamycin liposomes are a potential treatment for colorectal cancer, as it not only improves rapamycin’s antitumor effect but also synergistically enhances 5-FU’s chemotherapy effect.Keywords: rapamycin liposomes, 5-fluorouracil, Akt/mTOR, P53, colorectal cancer

Lian-Tao Li,1–3,* Xun Wang,4,* Wen-Tao Zhu,5,* Guo-Wei Qian,6 Dong-Sheng Pei,1,5 Jun-Nian Zheng1,2 1Cancer Institute, Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 2Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 3Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 4Department of Interventional Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 5Department of Pathology, Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 6Department of Medical Oncology, Shanghai Sixth People’s Hospital, Shanghai 200000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dong-Sheng Pei; Jun-Nian Zheng 84 West Huaihai Road, Xuzhou, Jiangsu, People’s Republic of ChinaTel +8605168558230Email dspei@xzhmu.edu.cn; jnzheng@xzhmu.edu.cnPurpose: DNA methylation plays major regulatory roles in gene transcription. Our previous studies confirmed that Ki-67 promoter is hypomethylated and Sp1 is a transcriptional activator of Ki-67 gene in cancer cells. However, whether Sp1-mediated transcriptional activation of Ki-67 is related to its methylation has not been studied yet.Materials and methods: In this study, we confirmed that methylated CpG binding protein 2 (MBD2) binding to methylated DNA hindered the binding of Sp1 to Ki-67 promoter and then repressed Ki-67 transcription through chromatin immunoprecipitation (ChIP) and quantitative real-time PCR (qRT-PCR). Co-immunoprecipitation (Co-IP), ChIP, methylation-specific PCR (MS-PCR) and Western blot were utilized to analyze the effects of Sp1 binding to Ki-67 promoter on its methylation status.Results: Less DNA methyltransferase 1 (DNMT1) bound to the Ki-67 promoter in MKN45 cells than in HK-2 cells. Histone acetyltransferase p300 that was recruited by Sp1 to Ki-67 promoter could attenuate the methylation level of Ki-67 promoter. Furthermore, higher expression of Sp1 and Ki-67 was related to the overall survival (OS), first progression (FP) and post-progression survival (PPS) in gastric cancer by scrutinizing bioinformatics datasets.Conclusion: Taken together, our findings suggested that hypomethylation of Ki-67 promoter enhanced the binding of Sp1, which in turn maintained hypomethylation of promoter, leading to increase Ki-67 expression in cancer cells. Sp1 and Ki-67 could act promising prognostic biomarkers for clinical diagnosis and treatment of cancer.Keywords: methylation, Ki-67, Sp1, promoter, cancer

Ming Shao,1,* Weitao Zhu,2,* Xianping Lv,1 Qiankun Yang,1 Xin Liu,1 Ying Xie,1 Ping Tang,3 Ling Sun3 1Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China; 2Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China; 3Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China *These authors contributed equally to this work Purpose: As the deadliest gynecological malignancy, ovarian cancer ranks as a major cause of disease-related deaths to women worldwide and is treated with transurethral resection or systemic chemotherapy. However, traditional chemotherapeutic drug in antitumor therapy has shown unavoidable limitations, such as poor curative effects, systemic toxicity and development of drug resistance, leading to failure of tumor inhibition and recurrence. This study aims to explore an innovative method to enhance the clinical efficiency of ovarian cancer.Materials and methods: Using MTT assay, the cell viability was detected under different culture systems. Western blot was used to examine the expression of P-gp in doxorubicin-resistant and wild-type A2780/SKOV3 cells. We used confocal to examine the drug concentration under different culture conditions. Also, flow cytometry was used to detect the drug absorption at the determined time points under different culture systems. Using nude mice model, we evaluated the killing efficacy of chemotherapeutic drugs with or without nanoparticle encapsulation. ELISA was used to examine the levels of creatinine, alanine aminotransferase and aspartate aminotransferase in plasma.Results: We found that pretreatment of chloroquine (CQ) as chemosensitizer markedly enhanced the anticancer effects in ovarian cancer. We also provided evidence that CQ efficiently increase the pH value of lysosomes in tumor cells, leading to the reverse of drug sequestration induced by lysosomes. To further improve the pharmacokinetics profiles and avoid the systemic toxicity caused by chemotherapeutic agents, we encapsulated CQ and chemotherapeutic drugs by polymeric nanoparticles methoxy poly(ethylene glycol)-poly(L-lactic acid). Codelivery of CQ and chemotherapeutic agents by nanocarrier revealed enhanced anticancer effects compared with the free drug delivery by tail vein injection. More importantly, accumulated drugs, prolonged drug circulation and reduced organic damages were observed in nanoparticles delivery.Conclusion: Codelivery of CQ and chemotherapeutic drugs by methoxy poly(ethylene glycol)-poly(L-lactic acid) could significantly improve the anticancer effects and might have important potency in clinical applications for ovarian cancer therapy. Keywords: ovarian cancer, chloroquine, cisplatin, MPEG-PLA, nanoparticles

Wen-Ting Zhu,1,2,* Sheng-Yao Liu,3,* Lei Wu,1,2 Hua-Li Xu,4 Jun Wang,1,2 Guo-Xin Ni,3,5 Qing-Bing Zeng1,2 1Biomaterial Research Center, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; 2Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; 3Department of Orthopeadics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, China; 4Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; 5Department of Rehabilitation Medicine, First Affiliated Hospital, Fujian Medical University, Fuzhou, China *These authors contributed equally to this work Background: It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future. Materials and methods: In this study, CUR-loaded methoxy polyethylene glycol–polylactide (CUR/mPEG–PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently. Results: The average size of CUR/mPEG–PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067–0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG–PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG–PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG–PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG–PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax. Conclusion: The mPEG–PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG–PLA micelles have promising clinical potential in treating NSCLC. Keywords: curcumin, mPEG–PLA, polymeric micelles, A549 cells, HUVECs, angiogenesis

Xiaoyi Wang, Ying Wang, Xiaoyuan Feng, Ying Lu, Yu Zhang, Wenwen Wang, Wentao Zhu School of Management, Beijing University of Chinese Medicine, Beijing, People’s Republic of China Objective: The aim of the study was to evaluate the effectiveness, safety, and cost associated with Wenxin keli in the treatment of cardiovascular diseases based on meta-analysis. Methods: The terms “Wenxin keli” and “Wenxin” were used as the search terms in the PubMed, ProQuest, Springer, the Cochrane Library, CNKI (China National Knowledge Infrastructure), VIP (Chinese Scientific Journals Database), and Wan fang electronic databases (from January 2000 to October 2015). Relevant print journals and conference papers were also searched. Studies on randomized controlled trials (RCTs) of Wenxin keli used in the treatment of cardiovascular diseases were screened, and its indications were classified. Meta-analysis of these studies was conducted using the RevMan 5.2 software. Results: A total of 49 RCTs (n=4,610) were included, 29 of which focused on arrhythmia, seven on angina, seven on heart failure, two on viral myocarditis, and four on menopausal syndrome. Analysis of the therapeutic indications of Wenxin keli showed that it was comparatively more curative and effective than other available treatments for cardiovascular diseases. Conclusion: Wenxin keli showed better clinical efficacy in the treatment of arrhythmia, angina, and heart failure; however, more high-quality evidence is needed to support its use in the clinical setting. Keywords: Wenxin keli, cardiovascular disease, meta-analysis, systematic review

Zhu WT, Liu SY, Wu L, et al. Int J Nanomedicine. 2017;12:2621–2634. On page 2623, under the heading ‘Entrapment effciency (EE) and DL’, the sentence “Acetonitrile/2.5% acetic acid (58/42, v/v) was used as eluent at a flow rate of 1 mL/min” should read “Acetonitrile/0.25% acetic acid (58/42, v/v) was used as eluent at a flow rate of 1 mL/min”. On page 2623, under the heading ‘Cellular uptake of CUR/mPEG–PLA micelles’, first paragraph, the sentence “Subsequently, cells were stained with Hoechst 33258 for 5 minutes, subsequently washed with PBS and fixed with cold 4% paraformaldehyde for 10 minutes” should read "Subsequently, cells were fixed with cold 4% paraformaldehyde for 10 minutes and stained with Hoechst 33258 for 5 minutes”. Read the original article