title: Evaluation of unnatural cyclic amino acids as boron delivery agents for treatment of melanomas and gliomas.
abstract: Unnatural cyclic amino acids (UNAAs) are a new class of boron delivery agents that are in a pre-clinical stage of evaluation. In the present study, the biodistribution of racemic forms of the cis- and trans-isomers of the boronated UNAA 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) and 1-amino-3-boronocycloheptanecarboxylic acid (ABCHC) were evaluted in B16 melanoma bearing mice and this was compared to l-p-boronophenylalanine (BPA). Boron concentrations were determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES) at 2.5h following intraperitoneal (i.p.) injection of the test agents at a concentration equivalent to 24mg/B/kg. While all compounds attained comparable tumor boron concentrations, the tumor/blood (T/Bl) boron concentration ratios were far superior for both cis-ABCPC and cis-ABCHC compared to BPA (T/Bl=16.4, and 15.1 vs. 5.4). Secondary ion mass spectrometry (SIMS) imaging revealed that the cis-ABCPC delivered boron to the nuclei, as well as the cytoplasm of B16 cells. Next, a biodistribution study of cis-ABCPC and BPA was carried out in F98 glioma bearing rats following i.p. administration. Both compounds attained comparable tumor boron concentrations but the tumor/brain (T/Br) boron ratio was superior for cis-ABCPC compared to BPA (6 vs. 3.3). Since UNAAs are water soluble and cannot be metabolized by tumor cells, they could be potentially more effective boron delivery agents than BPA. Our data suggest that further studies are warranted to evaluate these compounds prior to the initiation of clinical studies.
authors.affiliation: The Ohio State University, Department of Pathology, 4132 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA. Electronic address: rolf.barth@osumc.edu.
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.affiliation: University of Tennessee, Department of Chemistry, 611 Buehler Hall, Knoxville, TN 37996, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Kabalka
authors.affiliation: The Ohio State University, Department of Pathology, 4132 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.affiliation: The Ohio State University, Department of Pathology, 4132 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Tianyao
authors.initials: T
authors.lastname: Huo
authors.affiliation: The Ohio State University, Department of Pathology, 4132 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Nakkula
authors.affiliation: University of Tennessee, Department of Chemistry, 611 Buehler Hall, Knoxville, TN 37996, USA.
authors.forename: Aarif L
authors.initials: AL
authors.lastname: Shaikh
authors.affiliation: Cornell University, Department of Biomedical Engineering, Ithaca, NY 14853, USA.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Haider
authors.affiliation: Cornell University, Department of Biomedical Engineering, Ithaca, NY 14853, USA.
authors.forename: Subhash
authors.initials: S
authors.lastname: Chandra
mesh_terms: D000598:Amino Acids, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000818:Animals; D001896:Boron Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D045744:Cell Line, Tumor; D004337:Drug Carriers; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000532:radiotherapy; D008545:Melanoma / Q000378:metabolism* / Q000532:radiotherapy; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000598:Amino Acids, Cyclic; D001896:Boron Compounds; D004337:Drug Carriers
keywords: Gliomas; Melanomas; Unnatural cyclic amino acids