title: Liposomes Containing Lipid-Soluble Zn(II)-Bis-dipicolylamine Derivatives Show Potential To Be Targeted to Phosphatidylserine on the Surface of Cancer Cells.
abstract: Here we used a lipid-soluble Zn(II)-bis-dipicolylamine derivative as a membrane component to develop liposomal carriers that have potential to be targeted to phosphatidylserine (PS) rich surfaces on cancer cells and to preferentially kill cancer cells without using anticancer drugs. This DPA derivative (abbreviated as DPA-Cy3[22,22]) contains the fluorophore cyanine 3 (Cy3) and two 22-carbon chains that can be anchored into liposomal membrane bilayers. DPA-Cy3[22,22]/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) unilamellar vesicles (∼150 nm) showed selective binding to PS-containing liposomes as demonstrated by anion exchange chromatography. This binding does not result in vesicle fusion or aggregation. Flow cytometry showed that DPA-Cy3[22,22]/POPC liposomes have preferential binding to MCF-7 breast cancer cells over MCF-12A noncancer cells due to 3-7 times more PS exposures on MCF-7. The extent of liposome binding with MCF-7 cells was increased by two times after cells were pretreated with the apoptotic inducer camptothecin, which increased PS exposure to the cell surface. Moreover, our flow cytometry data also suggest that local cell membrane perturbations may occur upon liposome binding and internalization. This implies that DPA-Cy3[22,22]/POPC liposomes alone may have a PS-dependent cytotoxic effect. This assertion was supported by the cell proliferation assay, which showed that 9.1 mol % DPA-Cy3[22,22]/POPC liposomes exert cytotoxicity on MCF-7 cells 3.5 times higher than that on MCF-12A cells. These results indicate that DPA-Cy3[22,22]-containing liposomes hold great promise as efficient nano drug carriers.
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, The Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania 19140, United States.
authors.forename: Umme
authors.initials: U
authors.lastname: Ayesa
authors.affiliation: Molecular Targeting Technologies, Inc. , West Chester, Pennsylvania 19380, United States.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Gray
authors.affiliation: Molecular Targeting Technologies, Inc. , West Chester, Pennsylvania 19380, United States.
authors.forename: Koon Y
authors.initials: KY
authors.lastname: Pak
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, The Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania 19140, United States.
authors.forename: Parkson Lee-Gau
authors.initials: PL
authors.lastname: Chong
mesh_terms: D000588:Amines / Q000008:administration & dosage* / Q000737:chemistry*; D000838:Anions / Q000737:chemistry; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry*; D061986:MCF-7 Cells; D008561:Membrane Fusion / Q000187:drug effects; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy*; D010713:Phosphatidylcholines / Q000737:chemistry; D010718:Phosphatidylserines / Q000378:metabolism*; D010848:Picolinic Acids / Q000008:administration & dosage* / Q000737:chemistry*; D053835:Unilamellar Liposomes / Q000737:chemistry; D015032:Zinc / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: C501847:2,2'-dipicolylamine; D000588:Amines; D000838:Anions; D004337:Drug Carriers; D008051:Lipid Bilayers; D008081:Liposomes; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D010848:Picolinic Acids; D053835:Unilamellar Liposomes; D015032:Zinc; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: MCF-7 cancer cells; binding to anionic membranes; confocal microscopy; cytotoxicity; flow cytometry; fluorescence; nanocarriers; targeted delivery