title: Synthesis and in vitro evaluation of BBB permeability, tumor cell uptake, and cytotoxicity of a series of carboranylporphyrin conjugates.
abstract: A series of tri[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin conjugates of linear and branched polyamines, glucose, arginine, tri(ethylene glycol), and Tyr-D-Arg-Phe-β-Ala (YRFA) peptide were synthesized. These conjugates were investigated for their BBB permeability in human hCMEC/D3 brain endothelial cells, and their cytotoxicity and uptake were assessed using human glioma T98G cells. For comparison purposes, a symmetric tetra[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin was also synthesized, and its crystal structure was obtained. All porphyrin conjugates show low dark cytotoxicity (IC50>400 μM) and low phototoxicity (IC50>100 μM at 1.5 J/cm2) toward T98G cells. All conjugates were efficiently taken up by T98G cells, particularly the cationic polyamine and arginine conjugates, and were localized in multiple cellular organelles, including mitochondria and lysosomes. All compounds showed relatively low in vitro BBB permeability compared with that of lucifer yellow because of their higher molecular weight, hydrophobicity, and tendency for aggregation in solution. Within this series, the branched polyamine and YRFA conjugates showed the highest permeability coefficient, whereas the glucose conjugate showed the lowest permeability coefficient.
authors.affiliation: Department of Chemistry, Louisiana State University , Baton Rouge, Louisiana 70803, United States.
authors.forename: N V S Dinesh K
authors.initials: NV
authors.lastname: Bhupathiraju
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Hu
authors.forename: Zehua
authors.initials: Z
authors.lastname: Zhou
authors.forename: Frank R
authors.initials: FR
authors.lastname: Fronczek
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: M Graça H
authors.initials: MG
authors.lastname: Vicente
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001896:Boron Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000098:blood supply; D002196:Capillaries / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000378:metabolism; D005947:Glucose / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry; D015388:Organelles / Q000378:metabolism; D010539:Permeability; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011073:Polyamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011166:Porphyrins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001896:Boron Compounds; D009842:Oligopeptides; D017319:Photosensitizing Agents; D011073:Polyamines; D011166:Porphyrins; C412736:tyrosyl-arginyl-phenylalanyl-beta--alanine; C028914:triethylene glycol; D011092:Polyethylene Glycols; D001120:Arginine; D005947:Glucose