3rd meeting of young researchers at UP 1 - IJUP - Universidade do ...

Development and characterisation of polymeric nanoparticles
containing siRNAs for antiapoptotic proteins
A. Sá 1 , D. Costa 1 , G.M. Almeida 2 , F. Santos-Silva 2 , R.T. Lima 2,3 , R. Pereira 1,4 , M.
Teixeira 1,5 ,
M.H. Vasconcelos 2,3 and C-M. Barbosa 2,6
1 CEQUIMED-UP, Centro de Química Medicinal da Universidade do Porto, Porto, Portugal
2 Institute of Molecular Pathology and Immunology of the University of Porto – IPATIMUP, Porto,
Portugal
3 Laboratório de Microbiologia, Faculdade de Farmácia da Universidade do Porto, Portugal
4 Faculdade de Ciências e Tecnologias da Saúde, Universidade Lusófona de Humanidades e
Tecnologias, Lisboa, Portugal
5 Instituto Superior de Ciências da Saúde-Norte, Gandra PRD, Portugal
6 Laboratório de Tecnologia Farmacêutica, Faculdade de Farmácia da Universidade do Porto, Portugal.
RNAi with small-interfering RNAs (siRNAs) is a conserved mechanism of post-transcriptional
gene silencing which is highly gene-specific, potent and therefore potentially relevant as a
therapeutical tool to overcome resistance to anticancer drugs. Indeed, siRNAs have been
successfully used to downregulate the expression of targeted mRNAs in cancer cell lines (1).
However, the successful delivery and physical stability of these small double-stranded RNA
molecules has several obstacles: siRNAs are negatively charged hydrophilic molecules that
show instability in biological fluids leading to a poor bioavailability and they show poor
intracellular penetration.
Incorporation of siRNA in nanoparticulate systems offers a good protection of these molecules
against metabolization, because in this form they are completely isolated from the nuclease
rich environment in vivo. Moreover, the use of a carrier system, such as a nanoparticles,
improves the intracellular delivery of siRNA molecules (2).
The development of polymeric nanoparticles for drug delivery is an area already under
development at CEQUIMED-UP (3). The main goal of this project, which is currently under
development, is to incorporate selected siRNAs for anti-apoptotic proteins into biodegradable
polymeric nanoparticles as tools for gene silencing in order to circumvent cancer drug
resistance.
Optimized delivery of siRNAs, which have been designed to downregulate antiapoptotic
proteins, encapsulated into nanoparticles, may represent a putative therapeutic strategy towards
chemotherapeutic sensitization of chemoresistant cancers.
References:
[1] Lima, R.T., Guimarães, J.E. and Vasconcelos, M.H. (2007), Overcoming K562Dox resistance to
STI571 (Gleevec) by downregulation of P-gp expression using siRNAs. Cancer Therapy, 5, 67-76.
[2] de Martimprey, H., Vauthier, C., Malvy, C. and Couvreur, P. (2009) Polymer nanocarriers for the
delivery of small fragments of nucleic acids: oligonucleotides and siRNA. European Journal of
Pharmaceutics and Biopharmaceutics, 71(3), 490-504.
[3] Teixeira, M., Alonso, M.J., Pinto, M.M. and Barbosa, C.M. (2005) Development and
characterization of PLGA nanospheres and nanocapsules containing xanthone and 3-methoxyxanthone.
European Journal of Pharmaceutics and Biopharmaceutics, 59(3), 491-500.
446 3 rd meeting of young researchers at UP