期刊
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
卷 1798, 期 3, 页码 433-441出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2009.12.001
关键词
Liposomes; Antagonist G; Targeted delivery; Oligodeoxynucleotide; siRNA; Cancer
资金
- Center for Neuroscience and Cell Biology
- Portuguese Foundation for Science and Technology (FCT) [SFRH/BD/11817/2003, SFRH/BD/33184/ 2007]
- FCT
- POCTI
- FEDER [POCTI/FCB/48487/2002]
- Portugal-Spain capacitation program in nanoscience and nanotechnology [NANO/NMed-AT/0042/2007]
- Fundação para a Ciência e a Tecnologia [NANO/NMed-AT/0042/2007, SFRH/BD/33184/2007, POCTI/FCB/48487/2002, SFRH/BD/11817/2003] Funding Source: FCT
Anticancer systemic gene silencing therapy has been so far limited by the inexistence of adequate carrier systems that ultimately provide an efficient intracellular delivery into target tumor cells. In this respect, one promising strategy involves the covalent attachment of internalizing-targeting ligands at the extremity of PEG chains grafted onto liposomes. Therefore, the present work aims at designing targeted liposomes containing nucleic acids, with small size, high encapsulation efficiency and able to be actively internalized by SCLC cells, using a hexapeptide (antagonist G) as a targeting ligand. For this purpose, the effect of the liposomal preparation method, loading material (ODN versus siRNA) and peptide-coupling procedure (direct coupling versus post-insertion) on each of the above-mentioned parameters was assessed. Post-insertion of DSPE-PEG-antagonist G conjugates into preformed liposomes herein named as stabilized lipid particles, resulted in targeted vesicles with a mean size of about 130 nm, encapsulation efficiency close to 100%, and a loading capacity of approximately 5 nmol siRNA/mu mol of total lipid. In addition, the developed targeted vesicles showed increased internalization in SCLC cells, as. well as in other tumor cells and HMEC-1 microvascular endothelial cells. The improved cellular association, however, did not correlate with enhanced downregulation of the target protein (Bcl-2) in SCLC cells. These results indicate that additional improvements need to be performed in the future, namely by ameliorating the access of the nucleic acids to the cytoplasm of the tumor cells following receptor-mediated endocytosis. (C) 2009 Elsevier B.V. All rights reserved.
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