Doctor of Philosophy
Dr. Jamal Zweit
Dr. Nicholas Farrell
COPPER SULFIDE MANGANESE NANOPARTICLES FOR MULTIMODALITY IMAGING AND THERAPY
By Ali S. Gawi Ermi, MSc
Inorganic nanoparticles (NPs) are compatible with metal-based multi-modality molecular imaging and targeted therapy. Copper sulfide nanoparticles (CuS NPs) are attractive photoacoustic and photothermal agents and are amenable to incorporation of radionuclides and paramagnetic elements to facilitate image-guided therapy. The aim of this work is to develop manganese (Mn)- doped CuS NP, intrinsically radiolabeled with radionuclides such as (Zirconium-89 (89Zr), Copper-64/67 (64/67Cu) and Manganese-52/55 (52/55Mn)). This novel approach combines Photoacoustic (PA), Positron emission tomography (PET), Single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) in one platform. Potentially, such a platform can also accommodate therapeutic radionuclides and enable image-guided radionuclide therapy as well as photothermal therapy (PTT). In this study, two radionuclides were intrinsically incorporated into CuS-Mn NPs, 89Zr for PET imaging and 67Cu for SPECT imaging and potential radiotherapy. Doping of Mn into CuS NPs (CuS-Mn NPs) provided an enhanced T1/T2 MRI contrast. The CuS NP has a high absorption in the NIR region suitable for PA imaging and exhibits high photo-thermal conversion efficiency, adequate for PTT.
A hydrothermal method was developed for the synthesis of 89Zr/67Cu labeled CuS-Mn NP, by reacting Sodium Sulfide (Na2S) with Copper Chloride (CuCl2)/ Manganese Chloride (MnCl2) in aqueous solution under existence of organic/polymeric ligand as a coating. 89Zr or 67Cu was doped into NPs during the synthesis. Hydrodynamic (HD) size of the NPs was measured by dynamic light scattering (DLS). Reaction yields were assessed by inductively coupled plasmaoptical emission spectrometry (ICP-OES) and gamma counting. Multispectral Optoacoustic Tomography (MSOT) signal was assessed as a function of NPs concentration. Animal PET imaging and biodistribution were done at 30 min, 2 h, and 24 h post intravenous (i.v.) injection. Stability of radiolabeled NPs in water, plasma and urine was evaluated by radio-high performance liquid chromatograph (radio HPLC). Relaxivity characterization was done to study the enhancement of MRI signal by CuS-Mn NP. Animal MRI was performed in mice before and 2 h after injection of CuS-Mn NPs and T1 and T2 weighted MRI images were acquired.
The reaction yield of CuS-Mn NPs ranged from 80-90% as measured by ICP. The radiolabeling yield of [89Zr]-CuS-Mn NP was > 63%. When labeling with the same chemical element as the copper core, the radiolabeling yield of [67Cu]-CuS-Mn NP was almost quantitative. Doping with Mn reduced HD size from 20 nm to ≈ 5 nm, as measured by size distribution DLS. In a phantom study, the MR contrast signal was enhanced two-fold following injection of CuS-Mn NP compared to the bulk molecule MnCl2. The photoacoustic signal response was linear across a NPs concentration ranging from 0.11 µg/ml to 10µg/ml of CuS-Mn NPs.
PET imaging of [89Zr]-CuS-Mn NP showed rapid renal clearance within less than 30 min post injection. This rapid clearance has been facilitated by the ultra-small size (≈3-5nm) of the NP being below the glomerular filtration rate. Enhancement of MRI images was demonstrated in liver and kidney at 2 hours post injection of the NP. CuS-Mn NP increased signal intensity and contrast following i.v. injection into mice, with the signal intensity decreased over time.
Studies were also conducted with [67Cu]-CuS-Mn NPs, which have a larger size distribution of 10-30 nm. Biodistribution of [67Cu]-CuS-Mn NPs showed rapid liver and spleen uptake due to phagocytosis of larger particle size. Such accumulation resulted in increased hepatobiliary clearance compared to the small NPs which are cleared more through the kidney.
The synthesis and intrinsic radiolabeling of CuS-Mn NPs, using either 89Zr or 67Cu has been demonstrated. The feasibility of multi-modal capability with PET, MRI and PA imaging has been demonstrated. This novel approach of intrinsically labelled radio-nanoparticles can be expanded to incorporate a number of radionuclides and the platform can be modified to carry targeting molecules, enabling the potential of target-specific imaging and therapy (Theranostics).
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