Abstract
Sigma receptors are membrane-bound proteins that are overexpressed in certain human malignancies including breast cancer. These receptors show very high affinity for various sigma ligands including neuroleptics like haloperidol. We hypothesized that in associating haloperidol-linked lipid into the cationic lipid-DNA complex, we can specifically target and deliver genes to breast cancer cells that overexpress sigma receptors. In the present study, haloperidol was chemically modified to conjugate at the distal end of the polyethylene glycollinked phospholipid, which was then incorporated into the cationic liposome known to condense and deliver genes inside cells. The resulting haloperidol-conjugated targeted lipoplex showed at least 10-fold higher (p < 0.001) reporter gene expression in MCF-7 cells than control lipoplex. The reporter gene expression of the targeted lipoplex was significantly blocked by haloperidol (p < 0.001) and by another sigma ligand, 1,3-ditolylguanidine (p < 0.001) in the majority of cationic lipid to DNA charge ratios (+/-). Spironolactone-mediated sigma receptor down-regulation enabled MCF-7 to show 10-fold lower transgene expression with targeted lipoplex compared with that obtained in spironolactone-untreated cells. The targeted lipoplex generated nonspecific gene expression in sigma receptor-nonexpressing human cancer cells such as Hela, KB, HepG2, and Chinese hamster ovary cells. Moreover, the transgene expression remained unabated in physiologically relevant serum concentrations. This is the first study to demonstrate that haloperidol-targeted gene delivery systems can mediate efficient targeting of genes to sigma receptor-overexpressing breast cancer cells, thereby becoming a novel class of therapeutics for the treatment of human cancers.
Highlights
Sigma receptors are membrane-bound proteins that are overexpressed in certain human malignancies including breast cancer
This is the first study to demonstrate that haloperidol-targeted gene delivery systems can mediate efficient targeting of genes to sigma receptor-overexpressing breast cancer cells, thereby becoming a novel class of therapeutics for the treatment of human cancers
In comparison to spironolactone-untreated MCF-7 cells, the extent of transfection is in general low, and there was barely any statistical significance between the treated and untreated groups in spironolactonepretreated cells. These results show that the HP-associated lipoplex does not show targeted delivery of genes to sigma receptor-depleted MCF-7 cells and for targeting purposes the HP-associated lipoplex needs overexpression of sigma receptors
Summary
Sigma receptors are membrane-bound proteins that are overexpressed in certain human malignancies including breast cancer These receptors show very high affinity for various sigma ligands including neuroleptics like haloperidol. The transgene expression remained unabated in physiologically relevant serum concentrations This is the first study to demonstrate that haloperidol-targeted gene delivery systems can mediate efficient targeting of genes to sigma receptor-overexpressing breast cancer cells, thereby becoming a novel class of therapeutics for the treatment of human cancers. The physiological roles of these receptors in normal tissues are not yet clear, a diverse set of human tumors, such as melanoma, non-small cell lung carcinoma, breast tumors of neural origin, and prostate cancer overexpress sigma receptors [7,8,9,10,11,12,13]. A non-immunogenic, small molecular weight sigma ligand carrying an anisamide moiety was used as a targeting ligand in a drug-carrying liposomal system to target anticancer drugs to sigma receptor-expressing prostate cancer cells in the xenograft tumor mice model [19]
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