Optimized magnetic nanoparticle labels for ultra-sensitive sepsis diagnostics

DESCRIPTION (provided by applicant): MagneSensors' program is aimed at developing next generation magnetic nanoparticle labels tailored specifically for ultra-sensitive magnetic assays. These magnetic nanoparticles will be used to detect bacteria leading to sepsis, where there is a strong need for reliable diagnostic tests that are sensitive, specific, and fast. The project takes advantage of an innovative magnetic detection platform where magnetic nanoparticles are attached to antibodies that bind with high specificity to surface antigens on target bacteria. An extremely sensitive magnetic sensor, consisting of a patented high temperature superconducting quantum interference device (SQUID), quantitatively measures the number of magnetic labels bound to thebacteria, and hence the number of bacteria in a sample. These optimized magnetic nanoparticles will enable high sensitivity detection in whole blood using a simple mix and measure format, which is not possible with competing methods. Moreover, the tests can be automated for high throughput and low cost. There is a major emphasis on high sensitivity to enable diagnosis of the pathogen at the earliest possible stage. While the initial focus is on a proof-of-concept for the detection of E. coli O157:H7, theplatform is applicable to a wide range of bacteria. Sepsis is the tenth-leading cause of death in the U.S. and the second-leading cause of death in non- coronary intensive care unit patients. Existing diagnostic tests are inadequate and there is a large market opportunity available for superior tests, as the health care problem is significant. Note that while competing amplified nucleic acid tests can achieve the necessary sensitivity, there are many challenges to achieving it on clinical specimens. Drawbacks include false positives due to contamination as well as longer turnaround times and other issues that hamper its reliable use for the clinical diagnosis of life threatening infections. The Phase I aims are: 1) to synthesize magnetic nanoparticle labelsthat have over 50X larger signal (compared to currently used magnetic nanoparticles) and which are stable in blood, and 2) demonstrate sensitive detection of bacteria to 250 CFU/ml in a 45-minute, mix and measure assay in whole blood. In Phase II the sensitivity will be improved further to lt 50 CFU/ml in as little as 15-20 minutes total assay time, and include additional relevant organisms such as S. aureus along with testing on clinical samples. Magnetic nanoparticles with a larger magnetic signal will besynthesized by increasing the overall volume of the magnetic core as well as the size of the magnetite crystals comprising the core. Minimal aggregation and non-specific binding are critical for stability in whole blood, which is necessarily more difficult for powerful magnetic nanoparticles due to their larger attractive forces. To achieve this stability, we will modify the nanoparticle surface using a method we have developed and successfully employed in prior work. PUBLIC HEALTH RELEVANCE: Sepsisis the tenth-leading cause of death in the U.S., the second-leading cause of death in non-coronary intensive care unit patients, and costs the health care system over 17 billion annually. The ensuing overuse of antibiotics has further resulted in antibiotic-resistant strains of bacteria, significantly increasing the risk of sepsis from hospital-acquired infections, particularly those from post-operative wound, trauma, and the urinary tract. The proposed effort is ultimately focused on rapid, ultra-sensitive diagnostic tests for bacteria that lead to sepsis, enabling the pathogen to be identified at the earliest possible stage to permit timely treatment with the correct antibiotic.