Desenvolvimento de lipossomas vetorizados ao receptor folato contendo paclitaxel e imatinibe coencapsulados: avaliação da atividade antiproliferativa e da expressão gênica do VEGF em células tumorais
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2014-04-30
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Universidade Federal de Goiás
Resumo
The impact of Nanotechnology is constantly raising in different areas of
science, with the development of new products that bring benefits in comparison with
the alternatives available in the market. When encapsulated in nanoparticles,
anticancer drugs can achieve several advantages, most importantly the possibility of
reducing the amount of drug administered through targeting strategies, which are not
accomplished by conventional medication. Passive targeting is related to leaky
vasculature in pathological sites, and active targeting comprehends the attachment of
specific ligands, anchored in nanoparticles surface, to recognize and bind receptors
overexpressed in cancer cells. Coencapsulation of anticancer drugs in the same
pharmaceutical carrier can coordinate pharmacokinetics of encapsulated drugs. In
the present work, liposomal formulations targeted to folate receptor with paclitaxel
(PTX) and imatinib (IB) coencapsulated were obtained, aiming to combine cytotoxic
and antiangiogenic effects of the drugs, respectively. New analytical method was
developed and validated for simultaneous quantification of IB and PTX. Soy
phosphatidylcholine liposomes were prepared, with cholesterol and DSPEmPEG(
2000), to obtain long circulation particles. DSPE-PEG(2000)-FA was obtained
by an unpublished method of synthesis, and this product was further used in the
formulation by post-insertion technique. Cytotoxic effect and VEGF gene suppression
were studied in vitro in two different cell lines, MCF7 (breast adenocarcnioma) and
PC3 (prostatic adenocarcinoma), after treatment with liposomal vesicles. Analytical
procedures were developed with isocratic elution, 6,5 minutes runs, with linearity,
specificity, precision and accuracy. Quantification limit was 750 Ng/mL and 1000
Ng/mL for IB and PTX, respectively. After extrusion, liposomes had mean diameter
close to 100 nm and low polidispersion index. Post-insertion of folic acid attached to
lipid anchor procedure increased polidispersion, because the procedure lasted 24h.
Drug to lipid ratios were 1:26 and 1:27 (IB and PTX respectively). Lyophilized
formulations containing trehalose remained stable after 60 days of storage in terms
of %EE. Synthesis of DSPE-PEG(2000)-FA was confirmed by RMN, FT-IR and ESIMS
techniques. Liposomal PTX was more cytotoxic (p<0,05) than free drug in MCF7
cell line, after both 24h and 48h of exposion, for all tested concentrations. Targeted
formulation containing folic acid ligand, had more impact on cell viability reduction
(p<0,05) than non targeted liposomes (LPIP), also after 24h. On PC3 cell line cell
viability reduction was greater (p<0,01) when the cells were exposed to targeted
vesicles loaded with 1 and 10 Ng/mL of IB and PTX, after 24 and 48h. VEGF gene
expression was reduced in MCF7 and PC3 (p<0,05), and once more targeted
vesicles showed better results than non-targeted liposomes. It is, thus, plausible to
conclude, through in vitro experiments results, that the attachment of folic acid to
liposomal formulations, resulting in multi-functional liposomes, is an interesting
strategy to achieve enhanced internalization and accumulation of drugs in targeted
cells. This was observed by the enhancement of cytotoxic and antiangiogenic effects
in breast and prostate cell lines.
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PERES FILHO, Marco Júnio. Desenvolvimento de lipossomas vetorizados ao receptor folato contendo paclitaxel e imatinibe coencapsulados: avaliação da atividade antiproliferativa e da expressão gênica do VEGF em células tumorais. 2014. 108 f. Tese (Doutorado em Nanotecnologia Farmacêutica em Rede) - Universidade Federal de Goiás, Goiânia, 2014.