title: Specific antitumor targetable beta-cyclodextrin-poly(ethylene glycol)-folic acid drug delivery bioconjugate.
abstract: The tumor targeting properties of a new drug carrier synthesized by bioconjugation of folic acid (FA) to beta-cyclodextrins through a poly(ethylene glycol) (PEG) spacer (CD-PEG-FA) were investigated. Surface plasmon resonance demonstrated that CD-PEG-FA specifically interacts with immobilized folate binding protein (FBP) while the naked beta-cyclodextrins do not display any specific interaction. In vitro studies demonstrated that CD-PEG-FA was devoid of cell toxicity. [(3)H]-folic acid/CD-PEG-FA competition binding investigations performed with folate receptor overexpressing human epidermal carcinoma KB cells showed that CD-PEG-FA had about 14 times lower tumor cell binding capacity than free folic acid. The carrier cell trafficking properties were investigated using rhodamine-B as fluorescent probe, which possesses 3000 and 4580 M(-)(1) inclusion constants for CD-PEG-FA and beta-cyclodextrins, respectively. Cell-associated fluorescence measurements showed that CD-PEG-FA does not promote the rhodamine-B uptake into non-folate receptor expressing human lung carcinoma MCF7 cells while 19% higher accumulation in KB cells was found with respect to rhodamine-B loaded beta-cyclodextrins. Confocal laser scanning microscopy indicated the presence of cytosolic red fluorescent spots after 2 h of incubation of KB cells with rhodamine-B included CD-PEG-FA. The fluorescent dye resided primarily in small spots, namely, endosomes and multivesicular bodies. At 1 h after pulsed incubation, wider red fluorescent cellular structures appeared as a fusion of previous structures.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padua, Via F. Marzolo, 5-35131 Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Salmaso
authors.forename: Alessandra
authors.initials: A
authors.lastname: Semenzato
authors.forename: Paolo
authors.initials: P
authors.lastname: Caliceti
authors.forename: Johan
authors.initials: J
authors.lastname: Hoebeke
authors.forename: Fabio
authors.initials: F
authors.lastname: Sonvico
authors.forename: Catherine
authors.initials: C
authors.lastname: Dubernet
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000032:analysis* / Q000737:chemistry; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005492:Folic Acid / Q000008:administration & dosage / Q000032:analysis* / Q000737:chemistry; D006801:Humans; D007624:KB Cells; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000032:analysis* / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000032:analysis* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D047392:beta-Cyclodextrins; D011092:Polyethylene Glycols; D005492:Folic Acid; C031215:betadex