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Liposomes as vehicles of delivery of the lncRNA INXS to tumor cells in vitro and in vivo to induction of apoptosis

Grant number: 14/25481-4
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): February 01, 2015
Effective date (End): September 30, 2016
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Sergio Verjovski Almeida
Grantee:Felipe Genova Panicio
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:14/03620-2 - Characterization of the mechanisms of action of long non-coding RNAs involved with gene activation programs in human cells, AP.TEM

Abstract

Noncoding RNAs redefined the understanding of gene regulation. One of the groups of these molecules is the long noncoding RNAs (lncRNAs, > 200nt) that represent important agents in gene regulation. The INXS is one of these lncRNAs that participates in the regulation of the alternative splicing of exon 2 from BCL-X mRNA, a gene from the Bcl-2 family. INXS converts the anti-apoptotic isoform BCL-XL into the pro-apoptotic isoform BCL-XS. An increase of INXS in the cells induces an increase of the pro-apoptotic form BCL-XS, which increases 8- to 10-fold the apoptosis in vitro. An intratumoral injection of a plasmid expressing INXS in vivo decreased 10-fold the volume of xenografted tumors in mice. This property will be explored here to ask the question: Can a lncRNA be used as an injectable intravenous agent against cancer? To improve the mechanism with which the INXS is taken to the tumors, we intend to use cationic nontoxic liposomes complexed with this lncRNA. To specifically direct the liposomes to tumors, we will place the peptide GE11 at the liposomes' surface. GE11 has similar properties to EGF, however without inducing growth or neoangiogenesis. The target tumors have the property of EGF-R over-expression on their surfaces, making these receptors a good target. In parallel we intend to comparatively test the liposomes containing the expression plasmid pCEP-4-INXS used in the previous study. Tests will be done first for the construction of isolated liposomes loaded with lncRNA INXS, following by obtaining these liposomes with GE11 peptide on their surface, and moving to in vitro assays on cells and in vivo assays on animals with tumors.