title: Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC-MS/MS and Gd-DTPA Using Magnetic Resonance Imaging.
abstract: Successful treatment and diagnosis of neurological diseases depend on reliable delivery of molecules across the blood-brain barrier (BBB), which restricts penetration of pharmaceutical drugs and diagnostic agents into the brain. Thus, developing new noninvasive strategies to improve drug delivery across the BBB is critically needed. This study was aimed at evaluating the activity of HAV6 peptide (Ac-SHAVSS-NH2) in improving brain delivery of camptothecin-glutamate (CPT-Glu) conjugate and gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) contrast agent in Sprague-Dawley rats. Brain delivery of both CPT-Glu and Gd-DTPA was evaluated in an in situ rat brain perfusion model in the presence and absence of HAV6 peptide (1.0 mM). Gd-DTPA (0.6 mmol/kg) was intravenously (iv) administered with and without HAV6 peptide (0.019 mmol/kg) in rats. The detection and quantification of CPT-Glu and Gd-DTPA in the brain were carried out by LC-MS/MS and quantitative magnetic resonance imaging (MRI), respectively. Rats perfused with CPT-Glu in combination with HAV6 had significantly higher deposition of drug in the brain compared to CPT-Glu alone. MRI results also showed that administration of Gd-DTPA in the presence of HAV6 peptide led to significant accumulation of Gd-DTPA in various regions of the brain in both the in situ rat brain perfusion and in vivo studies. All observations taken together indicate that HAV6 peptide can disrupt the BBB and enhance delivery of small molecules into the brain.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Kayann
authors.initials: K
authors.lastname: Tabanor
authors.forename: Phil
authors.initials: P
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Kiptoo
authors.forename: In-Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Erica B
authors.initials: EB
authors.lastname: Sherry
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Cheyenne Sun
authors.initials: CS
authors.lastname: Eagle
authors.affiliation: Mass Spectrometry Laboratory, The University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Williams
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Teruna J
authors.initials: TJ
authors.lastname: Siahaan
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002166:Camptothecin / Q000008:administration & dosage*; D002853:Chromatography, Liquid; D003287:Contrast Media / Q000008:administration & dosage; D016503:Drug Delivery Systems; D019786:Gadolinium DTPA / Q000008:administration & dosage*; D018698:Glutamic Acid / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D003287:Contrast Media; D010446:Peptide Fragments; D018698:Glutamic Acid; D019786:Gadolinium DTPA; D002166:Camptothecin
keywords: Gd-DTPA; HAV peptide; LC−MS/MS; blood−brain barrier (BBB); brain delivery; camptothecin; magnetic resonance imaging (MRI)