title: Amphiphilic Phospholipid-Based Riboflavin Derivatives for Tumor Targeting Nanomedicines.
abstract: Riboflavin (RF) is an essential vitamin for cellular metabolism. Recent studies have shown that RF is internalized through RF transporters, which are highly overexpressed by prostate and breast cancer cells, as well as by angiogenic endothelium. Here, we present an optimized synthesis protocol for preparing tailor-made amphiphilic phospholipid-based RF derivatives using phosphoramidite chemistry. The prepared RF amphiphile-RfdiC14-can be inserted into liposome formulations for targeted drug delivery. The obtained liposomes had a hydrodynamic size of 115 ± 5 nm with narrow size distribution (PDI 0.06) and a zeta potential of -52 ± 3 mV. In vitro uptake studies showed that RfdiC14-containing liposomes were strongly internalized in HUVEC, PC3, and A431 cells, in a specific and transporter-mediated manner. To assess the RF targeting potential in vivo, an amphiphile containing PEG spacer between RF and a lipid was prepared-DSPE-PEG-RF. The latter was successfully incorporated into long-circulating near-infrared-labeled liposomes (141 ± 1 nm in diameter, PDI 0.07, zeta potential of -33 ± 1 mV). The longitudinal μCT/FMT biodistribution studies in PC3 xenograft bearing mice demonstrated similar pharmacokinetics profile of DSPE-PEG-RF-functionalized liposomes compared to control. The subsequent histological evaluation of resected tumors revealed higher degree of tumor retention as well as colocalization of targeted liposomes with endothelial cells emphasizing the targeting potential of RF amphiphiles and their utility for the lipid-containing drug delivery systems.
authors.affiliation: Institute of Chemistry & Biology of Membranes & Nano-objects, CBMN UMR 5248, Bordeaux University , 33600 Pessac, France.
authors.forename: Nataliia
authors.initials: N
authors.lastname: Beztsinna
authors.affiliation: Experimental Molecular Imaging, RWTH Aachen University Clinic , 52056 Aachen, Germany.
authors.forename: Yoanna
authors.initials: Y
authors.lastname: Tsvetkova
authors.affiliation: Gastroenterology and Metabolic Disorders, RWTH Aachen University Clinic , 52056 Aachen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bartneck
authors.affiliation: Experimental Molecular Imaging, RWTH Aachen University Clinic , 52056 Aachen, Germany.
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
authors.affiliation: Experimental Molecular Imaging, RWTH Aachen University Clinic , 52056 Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: Institute of Chemistry & Biology of Membranes & Nano-objects, CBMN UMR 5248, Bordeaux University , 33600 Pessac, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bestel
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine; D010743:Phospholipids / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012256:Riboflavin / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D010743:Phospholipids; D012256:Riboflavin