title: Formulation of liposomes functionalized with Lotus lectin and effective in targeting highly proliferative cells.
abstract: Liposomes, used to improve the therapeutic index of new and established drugs, have advanced with the insertion of active targeting. The lectin from Lotus tetragonolobus (LTL), which binds glycans containing alpha-1,2-linked fucose, reveals surface regionalized glycoepitopes in highly proliferative cells not detectable in normally growing cells. In contrast, other lectins localize the corresponding glycoepitopes all over the cell surface. LTL also proved able to penetrate the cells by an unconventional uptake mechanism.
  
  
  
  We used confocal laser microscopy to detect and localize LTL-positive glycoepitopes and lectin uptake in two cancer cell lines. We then constructed doxorubicin-loaded liposomes functionalized with LTL. Intracellular delivery of the drug was determined in vitro and in vivo by confocal and electron microscopy.
  
  
  
  We confirmed the specific localization of Lotus binding sites and the lectin uptake mechanism in the two cell lines and determined that LTL-functionalized liposomes loaded with doxorubicin greatly increased intracellular delivery of the drug, compared to unmodified doxorubicin-loaded liposomes. The LTL-Dox-L mechanism of entry and drug delivery was different to that of Dox-L and other liposomal preparations. LTL-Dox-L entered the cells one by one in tiny tubules that never fused with lysosomes. LTL-Dox-L injected in mice with melanoma specifically delivered loaded Dox to the cytoplasm of tumor cells.
  
  
  
  Liposome functionalization with LTL promises to broaden the therapeutic potential of liposomal doxorubicin treatment, decreasing non-specific toxicity.
  
  
  
  Doxorubicin-LTL functionalized liposomes promise to be useful in the development of new cancer chemotherapy protocols.
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Della Giovampaola
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Capone
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; Program in Physiology & Experimental Biology, Hospital for Sick Children, Toronto, Canada.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Ermini
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Lupetti
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Vannuccini
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Finetti
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donnini
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ziche
authors.affiliation: Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; INSTM, Research Center for Materials Sciences and Technologies, Via G. Giusti 9, 50121 Firenze, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Magnani
authors.affiliation: Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; INSTM, Research Center for Materials Sciences and Technologies, Via G. Giusti 9, 50121 Firenze, Italy.
authors.forename: Gemma
authors.initials: G
authors.lastname: Leone
authors.affiliation: Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; CSGI, Research Center for Colloids and Nanoscience, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, FI, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Rosati
authors.affiliation: Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; CSGI, Research Center for Colloids and Nanoscience, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, FI, Italy. Electronic address: claudia.bonechi@unisi.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bonechi
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003593:Cytoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D000939:Epitopes / Q000008:administration & dosage / Q000737:chemistry; D007887:Fabaceae / Q000378:metabolism*; D006801:Humans; D037102:Lectins / Q000008:administration & dosage* / Q000737:chemistry*; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry*; D008247:Lysosomes / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice
chemical_list: D000939:Epitopes; D037102:Lectins; D008081:Liposomes; D004317:Doxorubicin
keywords: Doxorubicin; Drug delivery; Lotus lectin; NMR; Targeted liposomes