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Fatemeh Ostadhossein1 Santosh Kumar Misra1 Dipanjan Pan1

1, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States

Although infective endocarditis (IE) is relatively rare, it represents a severe infectious disease. Timely diagnosis of this fatal disease is of high importance though remained elusive to date. The first line of diagnosis, echocardiography (EE), suffers from limitations e.g. low sensitivity for vegetation (60-70%). One promising method is multi-slice CT with improved sensitivity over EE. The most common pathogen involved in the IE, Staphylococcus aureus (S. aureus) is notoriously reported in 36% of cases. Failing of the current therapies due to antibacterial drug resistance, low penetration of antibiotic into the vegetation and non-specific interaction of serum protein with drug are compelling reasons to seek new therapies for IE treatment. A property of traceable therapeutics would make it a better choice and preferential regime. In this regard, contrast agents are used to improve the sensitivity and enhance the tissue visualization on X-ray/CT.
Herein, we introduce a novel NP for the early diagnosis, therapy and follow-up of IE utilizing raspberry shaped hollow Hafnium oxide nanoparticles coated with a layer of silver nanoparticles (HfOx-Ag-NP). The NPs were synthesized by a surfactant free template assisted synthesis. Resorcinol and formaldehyde (RF) formed the inner core initially. The hafnium oxide was subsequently grown alongside with the secondary RF polymer through a sol- gel chemistry in one pot. The template was removed in the next step via calcination at 550 °C to obtain hollow raspberry shaped HNPs (~100 nm). The Ag NPs were grown on the rough outermost layer utilizing the silver mirror reaction. TEM and SEM confirmed the proper dendritic formation of NPs. Besides, Ag NP deposition was verified by EDS where the co-localization of Hf and Ag was observed.
The X-ray attenuation of the NPs compared with calcium showed significant enhancement. The Hounsfield unit (HU) as a measure of x-ray attenuation was calculated to be ~10 for 180 mM of Ca whereas for HfOx-Ag-NPs, HU was ~1790. Furthermore, these NPs demonstrated a 30% increase in HU compared with the conventional iodine based contrast agent (iohexol).
It was found that HfOx-Ag-NP could enhance the adhesion to the bacterial membrane through hydrophobic interactions of hairy features of HfOx NPs. In addition, surface decorated Ag NPs could synergistically boost the bacterial killing efficiency due to added antibacterial effects of Ag. Anti-bacterial property of HfOx-Ag-NP were established by OD decrease, colony count and live-dead assays. Studies also showed the effect in blood samples to mimick the physiological conditions and found to effectively suppress the growth and kill S. aureus. Overall, this is the first report on the application of CT contrast agents for the detection of IE using intrinsic property of Hf-NPs alongside with their therapeutic efficiency for bacterial eradication.

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