Synergistic antitumoral effect of vinblastine and HSV-Tk/GCV gene therapy mediated by albumin-associated cationic liposomes

Abstract

Despite recent advances in conventional therapeutic approaches for cancer, the frequently observed acquired drug resistance and toxic side effects have limited their clinical application. The main goal of this work was to investigate the combined antitumoral effect of vinblastine with HSV-Tk/GCV "suicide" gene therapy mediated by human serum albumin (HSA)-associated lipoplexes, in mammary adenocarcinoma cells (TSA cells). Our results show that, among the different lipoplex formulations tested, HSA-associated complexes prepared from EPOPC:Chol liposomes, at the (4/1) (+/−) charge ratio, was the most efficient to mediate gene delivery, even in the presence of serum. The simultaneous addition of vinblastine and HSA-EPOPC:Chol/DNA (+/−) (4/1) lipoplexes to TSA cells improved transgene expression more than 10 times. When combined with the HSV-Tk/GCV "suicide" gene therapy mediated by HSA-EPOPC:Chol/DNA (+/−) (4/1) lipoplexes, vinblastine induced a great enhancement in the antitumoral activity in TSA cells. Most importantly, this combined strategy resulted in a significant synergistic effect, thus allowing the use of a much lower dose of the drug to achieve the same therapeutic effect. Overall, our results indicate that this approach has the potential to overcome some major limitations of conventional chemotherapy, and may therefore constitute a promising strategy for future applications in antitumoral therapy.

Increased gene delivery efficiency and specificity of a lipid-based nanosystem incorporating a glycolipid

“…15 Our results demonstrated that the incorporation of lactosyl-PE in the nanocarriers (EPOPC:Chol:lactosyl-PE/DNA) promoted a substantial increase in their biological activity in HepG2 cells (Figures 1 and 2). This enhancing effect was dependent on the amount of lactosyl-PE and on the (+/-) charge ratio of lipoplexes, the highest increase in biological activity being achieved for nanosystems containing 15% of lactosyl-PE and prepared at the 2/1 (+/-) charge ratio.…”

“…21,[24][25][26][27] On the other hand, we have previously shown that the use of cationic liposomes composed of EPOPC and Chol, at a 1:1 molar ratio, results in considerably higher biological activities than those obtained with other lipid-based formulations. [13][14][15][16][17]28 In this regard, the main goal of this work consisted of the development of a new gene delivery lipid-based nanosystem for HCC, targeting the ASGP-R, based on cationic liposomes composed of EPOPC, Chol and lactosyl-PE.…”

“…12,13,14 Our studies have demonstrated that cationic liposomes composed of 1-palmitoyl-2-oleoyl-snglycero-3-ethylphosphocholine (EPOPC) and cholesterol (Chol), at a molar ratio of 1:1, have the ability to mediate efficient gene delivery in different tissues and cells lines. 13,15 Lipoplexes prepared with these cationic liposomes were shown to exhibit higher levels of transfection than those obtained with nanosystems prepared with other cationic liposome formulations. 15 In addition, EPOPC, which is a derivative of a natural lipid (phosphatidylcholine), has revealed lower cytotoxicity due the presence of ester linkages and, therefore is suitable for clinical applications of gene therapy.…”

“…13,15 Lipoplexes prepared with these cationic liposomes were shown to exhibit higher levels of transfection than those obtained with nanosystems prepared with other cationic liposome formulations. 15 In addition, EPOPC, which is a derivative of a natural lipid (phosphatidylcholine), has revealed lower cytotoxicity due the presence of ester linkages and, therefore is suitable for clinical applications of gene therapy. 13,[15][16][17] Liver has several characteristics that make it very attractive for application of gene therapy, namely the presence of the asialoglycoprotein receptor (ASGP-R).…”

“…15 In addition, EPOPC, which is a derivative of a natural lipid (phosphatidylcholine), has revealed lower cytotoxicity due the presence of ester linkages and, therefore is suitable for clinical applications of gene therapy. 13,[15][16][17] Liver has several characteristics that make it very attractive for application of gene therapy, namely the presence of the asialoglycoprotein receptor (ASGP-R). ASGP-R is an integral membrane protein specifically expressed in hepatocytes and overexpressed in tumoral hepatocytes, [18][19][20] allowing the development of therapies targeted to these cells.…”