title: A diaCEST MRI approach for monitoring liposomal accumulation in tumors.
abstract: Nanocarrier-based chemotherapy allows preferential delivery of therapeutics to tumors and has been found to improve the efficacy of cancer treatment. However, difficulties in tracking nanocarriers and evaluating their pharmacological fates in patients have limited judicious selection of patients to those who might most benefit from nanotherapeutics. To enable the monitoring of nanocarriers in vivo, we developed MRI-traceable diamagnetic Chemical Exchange Saturation Transfer (diaCEST) liposomes. The diaCEST liposomes were based on the clinical formulation of liposomal doxorubicin (i.e. DOXIL®) and were loaded with barbituric acid (BA), a small, organic, biocompatible diaCEST contrast agent. The optimized diaCEST liposomal formulation with a BA-to-lipid ratio of 25% exhibited 30% contrast enhancement at B1=4.7μT in vitro. The contrast was stable, with ~80% of the initial CEST signal sustained over 8h in vitro. We used the diaCEST liposomes to monitor the response to tumor necrosis factor-alpha (TNF-α), an agent in clinical trials that increases vascular permeability and uptake of nanocarriers into tumors. After systemic administration of diaCEST liposomes to mice bearing CT26 tumors, we found an average diaCEST contrast at the BA frequency (5ppm) of 0.4% at B1=4.7μT while if TNF-α was co-administered the contrast increased to 1.5%. This novel approach provides a non-radioactive, non-metallic, biocompatible, semi-quantitative, and clinically translatable approach to evaluate the tumor targeting of stealth liposomes in vivo, which may enable personalized nanomedicine.
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore 21287, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore 21205, USA; Center for Nanomedicine, The Johns Hopkins University School of Medicine, Baltimore 21287, USA; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore 21205, USA.
authors.forename: Kannie W Y
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Center for Nanomedicine, The Johns Hopkins University School of Medicine, Baltimore 21287, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore 21205, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: The Ludwig Center and Howard Hughes Medical Institute at the Hopkins-Kimmel Comprehensive Cancer Center, Baltimore 21287, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: The Ludwig Center and Howard Hughes Medical Institute at the Hopkins-Kimmel Comprehensive Cancer Center, Baltimore 21287, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Center for Nanomedicine, The Johns Hopkins University School of Medicine, Baltimore 21287, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore 21205, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: Center for Nanomedicine, The Johns Hopkins University School of Medicine, Baltimore 21287, USA.
authors.forename: Himatkumar
authors.initials: H
authors.lastname: Patel
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore 21287, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore 21205, USA.
authors.forename: Guanshu
authors.initials: G
authors.lastname: Liu
authors.affiliation: The Ludwig Center and Howard Hughes Medical Institute at the Hopkins-Kimmel Comprehensive Cancer Center, Baltimore 21287, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: The Ludwig Center and Howard Hughes Medical Institute at the Hopkins-Kimmel Comprehensive Cancer Center, Baltimore 21287, USA.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore 21287, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore 21205, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore 21205, USA; Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore 21205, USA.
authors.forename: Jeff W M
authors.initials: JW
authors.lastname: Bulte
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore 21287, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore 21205, USA.
authors.forename: Peter C M
authors.initials: PC
authors.lastname: van Zijl
authors.affiliation: Center for Nanomedicine, The Johns Hopkins University School of Medicine, Baltimore 21287, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore 21205, USA; Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore 21287, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.affiliation: The Ludwig Center and Howard Hughes Medical Institute at the Hopkins-Kimmel Comprehensive Cancer Center, Baltimore 21287, USA.
authors.forename: Shibin
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore 21287, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore 21205, USA; Center for Nanomedicine, The Johns Hopkins University School of Medicine, Baltimore 21287, USA. Electronic address: mtmcmaho@gmail.com.
authors.forename: Michael T
authors.initials: MT
authors.lastname: McMahon
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D001463:Barbiturates / Q000008:administration & dosage*; D003287:Contrast Media / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D061848:Optical Imaging; D011092:Polyethylene Glycols / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
chemical_list: D000903:Antibiotics, Antineoplastic; D001463:Barbiturates; D003287:Contrast Media; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; C032232:barbituric acid
keywords: Barbituric acid; CEST; Doxorubicin; Liposomes; MRI; Tumor necrosis factor