Type
Text
Type
Dissertation
Advisor
Sitharaman, Balaji | Frame, Mary | Shroyer, Kenneth | Moore, William | Button, Terry.
Date
2015-08-01
Keywords
Biomedical engineering | Blood Pool, Contrast agent, Graphene, Magnetic resonance Imaging, Manganese
Department
Department of Biomedical Engineering.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/76992
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Magnetic resonance imaging (MRI) contrast agents (CA) are increasingly being used to enhance the contrast between normal and diseased tissues, and to help detect various anatomical and functional abnormalities in MRI scans. Today, 40-50% of the MRI procedures worldwide are performed with CAs, majority of them being gadolinium chelate based agents (GBCA). Theory suggests that the relaxivity (a quantitative measure of CA efficacy) of current clinical CAs is sub-optimal, and predicts the possibility of developing new contrast agents with relaxivities up to one to two orders of magnitude greater (depending on the magnetic field), that can allow the same clinical MRI performance at substantially lower dosages (micro or nanomolar dose), enabling advanced MRI applications such as cellular/molecular imaging and blood pool imaging. Also, the recent discovery and association with nephrogenic systemic fibrosis in patients with renal insufficiency has fostered concern and Food and Drug Administration restrictions on the clinical use of GBCA. Therefore, there is a need for a next-generation T1 MRI CA that show lower toxicity profile, and possess greater relaxivity than current clinical CAs. Herein, towards the goal of developing a safe and more efficacious T1 MRI CA, I demonstrate a novel nanoparticle MRI CA comprising of manganese (Mn2+) intercalated graphene nanoplatelets functionalized with dextran (hereafter called, Mangradex) with focus on the study of formulation development and in vivo safety and efficacy. The results suggest that Mangradex formulation is hydrophilic, water dispersible (up to 100 mg/ml), and forms stable colloidal dispersions in deionized water, that are iso-osmol and is-viscous to blood. The relaxometry and MRI phantom study suggest that graphene sheets in Mangradex amplify its r1 relaxivity by up to ~ 20X greater than current clinical CAs. Acute toxicity and respiratory/cardiovascular safety pharmacology study performed for 1 day and 30 days in Wistar rats following single intravenous dose of Mangradex between 1-500 mg/kg, suggested that the maximum tolerated dose was (MTD) 50 mg/kg ≤ MTD ≤ 125 mg/kg, and Mangradex nanoparticles eliminate mainly through feces within 24 hours. Sub-acute toxicological assessment performed on rats intravenously injected with Mangradex formulations at 1, 50 or 100 mg/kg dosages 3 times per week for three weeks indicated that doses ≤ 50 mg/kg could serve as potential therapeutic doses. Whole body 7 Tesla MRI performed on mice following intravenous injections of Mangradex at 25 mg/kg (455 nanomoles Mn2+/kg; ~2 orders of magnitude lower than the paramagnetic ion concentration in a typical clinical dose) showed persistent (up to at least 2 hours) contrast enhancement in the vascular branches. Taken together, these results lay the foundations for its further development as a vascular and cellular/ molecular imaging probe. | 150 pages
Recommended Citation
Kanakia, Shruti, "Graphene Based High Performance Magnetic Resonance Imaging Contrast Agent" (2015). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2856.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2856