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Jiyang Xue1 ,* Ruixiang Li2 ,* Dingding Gao,2 Fenghua Chen,3 Hongjuan Xie1 1Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of China; 2Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 3Department of Ultrasonography, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiyang Xue; Hongjuan XieDepartment of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, People’s Republic of ChinaTel +86-21-20261152Email xuejiyang7635@163.com; xiehongjuan@51mch.comIntroduction: Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes.Methods: AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied.Results: AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial–mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway.Conclusion: The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.Keywords: AMD3100, paclitaxel, nanoparticle, CXCL12/CXCR4 axis, ovarian cancer

Background Avoiding or reducing cardiopulmonary bypass-related injuries of important organs is the eternal topic in the field of cardiovascular surgery. Remote ischemic preconditioning (RIPC) is a promising strategy whose clinical application seems more realistic and extensive compared with other conservative or surgical strategies. However, considering its complex process which involves the expression of a variety of molecules and even genes and little is known about its underlying mechanism after years of researches, new train of thought and method must be developed to explore its potential in clinical application. Long noncoding RNA (LncRNA) is a kind of RNA that has been proven be exert efficacy in the occurrence and development of cardiovascular disease. The differential expression of LncRNAs and their biological effects during RIPC have not been reported. Methods We first verified the protective effect of RIPC on myocardial ischemia-reperfusionby western blot, ELISA and hematoxylin-eosin(HE) staining. Mouse and human LncRNA arrays were used to investigate the expression signatures of LncRNAs and mRNAs in myocardial tissue after RIPC. Homology comparison was used to screen homologous genes in total differentially expressed LncRNAs. Competing endogenous RNA(ceRNA) mechanism analysis helped us find the matching relationship among homologous LncRNA, mRNA and microRNA. Results 554 differentially expresssed mouse LncRNAs(281 up-regulated / 273 down-regulated) and 1392 differentially expresssed human LncRNAs(635 up-regulated / 757 down-regulated) were selected from LncRNA microarrays. Quantitative real-time polymerase chain reaction(qRT-PCR) was used to verify these selected LncRNAs, after homology comparison and ceRNA mechanism analysis, we got a pair of homologous LncRNAs(ENST00000574727 & ENSMUST00000123752), predicted corresponding matching relationship and potential competitive binding sites. Conclusions In this study, we identify a number of differentially expressed LncRNAs, which may be closely related to the regulation of inflammation and cell proliferation. In addition, we take several pairs of homologous LncRNAs as the next research object. By continuously exploring the function and mechanism of these LncRNAs, we hope to unveil the mystery of RIPC and discover a new protective mechanism of cardiovascular ischemia-reperfusion disease.