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Guangzhou, China

Wang D.,Copenhagen University | Wu L.-P.,Copenhagen University | Wu L.-P.,Guangzhou RiboBio Co.
Materials Science and Engineering C | Year: 2016

Billions of dollars have been invested in the therapeutic application of nucleic acid-based agents in humans in recent years. There are inspirable data from ongoing clinical trial for different diseases. However, in order to widely apply nucleic acid in prevention, diagnosis and treatment of age-related disease, such as neurodegeneration and disorders, suitable, safe and effective drug delivery nanocarriers have to been developed to overcome the blood brain barrier (BBB), which is the most inflexible barrier in human body. Here, we highlight the structure and function of barriers in the central nervous system (CNS) and summary several types of nanomaterials which can be potentially used in the brain delivery nucleic acid. © 2016 Elsevier B.V.

Zhou L.,Chinese Academy of Sciences | Zhou L.,University of Chinese Academy of Sciences | Chen Z.,Chinese Academy of Sciences | Wang F.,Chinese Academy of Sciences | And 3 more authors.
Acta Biomaterialia | Year: 2013

A non-viral siRNA carrier composed of mono-methoxy-poly (3-hydroxybutyrate-co-4-hydroxybutyrate)-block-polyethylene glycol-block-linear polyethyleneimine (mP3/4HB-b-PEG-b-lPEI) was synthesized using 1800 Da linear polyethyleneimine and evaluated for siRNA delivery. Our study demonstrated that siRNA could be efficiently combined with mP3/4HB-b-PEG-b-lPEI (mAG) co-polymer and was protected from nuclease degradation. The combined siRNA were released from the complexes easily under heparin competition. The particle size of the mAG/siRNA complexes was 158 nm, with a ζ-potential of around 28 mV. Atomic force microscopy images displayed spherical and homogeneously distributed complexes. The mAG block co-polymer displayed low cytotoxicity and efficient cellular uptake of Cy3-siRNA in A549 cells by flow cytometry and confocal microscopy. In vitro transfection efficiency of the block co-polymer was assessed using siRNA against luciferase in cultured A549-Luc, HeLa-Luc, HLF-Luc, A375-Luc and MCF-7-Luc cells. A higher transfection efficiency and lower cytotoxicity was obtained by mAG block co-polymer in five cell lines. Furthermore, a remarkable improvement in luciferase gene silencing efficiency of the mAG complex (up to 90-95%) over that of Lipofectamine™ 2000 (70-82%) was observed in HLF-Luc and A375-Luc cells. Additionally, a mAG/p65-siRNA complex also showed a better capability than Lipofectamine™ 2000/p65-siRNA complex to drastically reduce the p65 mRNA level down to 10-16% in HeLa, U251 and HUVEC cells at an N/P ratio of 70. Crown Copyright © 2013 Published by Elsevier Ltd. on behalf of Acta Materialia Inc. All rights reserved.

Liang P.,Chinese Academy of Sciences | Zhang H.,Chinese Academy of Sciences | Zhang H.,Hefei University of Technology | Wang G.,Chinese Academy of Sciences | And 4 more authors.
Traffic | Year: 2013

NF-κB/p65 is retained in the cytoplasm until it is activated in response to stress. Nuclear import of p65 is regulated by importin α in a nuclear localization signal (NLS)-dependent manner. However, the role of importin β family members in the nuclear translocation of p65 is largely unclear. In this study, using high-content siRNA screening, we identified three of 17 importin β family members that are involved in the nuclear import of p65. Our data showed that knockdown of KPNB1, XPO7 and IPO8 reduced the amount of nuclear p65 following tumor necrosis factor-α (TNF-α) stimulation, resulting in lower NF-κB activity. KPNB1 was the major importin β receptor for p65 import, and this import was dependent on the NLS of p65. However, NLS-mutated p65 still entered the nucleus and bound to XPO7 and IPO8. Interestingly, among the six members of the importin α family, KPNA2 was most important for p65 import. Taken together, our results show that the import of p65 mainly relies on the canonical KPNA2/KPNB1 pathway; however, p65 is also imported by an alternative pathway that is independent of its NLS. Redundant importin receptors are likely to maintain the important function of p65 according to need. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Zhou L.,Chinese Academy of Sciences | Zhou L.,University of Chinese Academy of Sciences | Chen Z.,Chinese Academy of Sciences | Chi W.,Chinese Academy of Sciences | And 4 more authors.
Biomaterials | Year: 2012

A class of non-viral siRNA vectors consisting of biodegradable poly(hydroxyalkanoates) (PHA) grafted onto branched poly(ethyleneimine) (bPEI, 25kDa) was synthesized and evaluated for siRNA delivery. The mPHA- g-bPEI copolymers were synthesized through Michael addition between acrylated mono-methoxy-poly(hydroxyalkanoates) (mPHA-acrylated) and bPEI with various block length poly(hydroxyalkanoates) from 1300 to 2900Da. Our research showed that mPHA- g-bPEI copolymers could effectively bind siRNA, protect it from degradation by nucleases and efficiently release the complexed siRNA in the presence of low concentrations of polyanionic heparin. The particle size of mPHA- g-bPEI/siRNA complexes was <200nm with ζ-potential between 33 and 43mV. mPHA- g-bPEI copolymers displayed low cytotoxicity compared to unmodified bPEI and efficient cellular uptake of Cy3-siRNA in A549 cells by flow cytometry and confocal microscopy. siRNA delivery efficiency of the copolymers was assessed by siRNA against luciferase in cultured A549-Luc and MCF-7-Luc cells. Those mPHA- g-bPEI copolymers revealed a higher transfection efficiency and lower cytotoxicity than bPEI in two cell lines. Furthermore, a remarkable knockdown of luciferase expression of mPHA- g-bPEI (mAP2) complex (up to 85%) invitro was found to be equivalent to that of commercially available transfection agent Lipofectamine™ 2000. © 2011 Elsevier Ltd.

Liu X.,Southern Medical University | Wang W.,Guangzhou RiboBio Co. | Samarsky D.,Guangzhou RiboBio Co. | Liu L.,Southern Medical University | And 16 more authors.
Nucleic Acids Research | Year: 2014

RNAi technology is taking strong position among the key therapeutic modalities, with dozens of siRNA-based programs entering and successfully progressing through clinical stages of drug development. To further explore potentials of RNAi technology as therapeutics, we engineered and tested VEGFR2 siRNA molecules specifically targeted to tumors through covalently conjugated cyclo(Arg-Gly-Asp-d-Phe-Lys[PEG-MAL]) (cRGD) peptide, known to bind αvβ3 integrin receptors. cRGD-siRNAs were demonstrated to specifically enter and silence targeted genes in cultured αvβ3 positive human cells (HUVEC). Microinjection of zebrafish blastocysts with VEGFR2 cRGD-siRNA resulted in specific inhibition of blood vessel growth. In tumor-bearing mice, intravenously injected cRGD-siRNA molecules generated no innate immune response and bio-distributed to tumor tissues. Continuous systemic delivery of two different VEGFR2 cRGD-siRNAs resulted in down-regulation of corresponding mRNA (55 and 45%) and protein (65 and 45%) in tumors, as well as in overall reduction of tumor volume (90 and 70%). These findings demonstrate strong potential of cRGD-siRNA molecules as anti-tumor therapy. © 2014 The Author(s).

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