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J. Biol. Chem., Vol. 280, Issue 16, 15619-15627, April 22, 2005

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Haloperidol-associated Stealth Liposomes

A POTENT CARRIER FOR DELIVERING GENES TO HUMAN BREAST CANCER CELLS^*

Amarnath Mukherjee, Tekkatte Krishnamurthy Prasad¶, Nalam Madhusudhana Rao¶, and Rajkumar Banerjee||

From the Division of Lipid Science & Technology, Indian Institute of Chemical Technology, Hyderabad 500 007, India and the ^¶Centre for Cellular and Molecular Biology, Hyderabad 500 007, India

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.

Received for publication, August 24, 2004 , and in revised form, February 4, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a doctoral research fellowship from the University Grants Commission, Govt. of India.

^|| Recipient of a Department of Science & Technology (DST), Government of India grant for research support provided under a Fast Track Proposal for Young Scientists. To whom correspondence should be addressed: Division of Lipid Science & Technology, Rm. 345, Indian Institute of Chemical Technology, Hyderabad 500 007, India. Tel.: 91-40-2719-3201; Fax: 91-40-2716-0757; E-mail: rkbanerjee{at}yahoo.com.

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