S4-3
The Development and Industrilization Road of MRI Contrast Agents
Shian-Jy (Jassy) Wang1, Wen-Yuan Hsieh1, Chih-Lung Chen1, Hsin-Hsin Shen1, Chien Ho2, Li Liu2
1. Industrial Technology Research Institute, Hsinchu, Taiwan
2. Carnegie Mellon University, Pittsburgh, PA, USA |
The newly developed iTrast-001 is a biocompatible USPIO system composed of an iron oxide nanoparticle core with a monolayer polyethyleneglycol (PEG) coating. The PEG coating provides four major important functions for iTrast-001, it avoids aggregation, enhances solubility, insure homogeneity in aqueous medium and provides crucial tissue and cell selectivity. The PEG monolayer coating combines with the larger particle core size (compared to the commercial products) enhance MR images contrast of the iTrast-001 to be better than the commercial products. The good uptake of iTrast-001 by immune cells and strong contrast enhancement propel the organ transplant rejection tracing and lymph node metastasis imaging to become the first two clinical indications of the iTrast-001.
FEATURES and ADVANTAGES
1. core particle size is in the range of 10-15 nm (TEM image).
2. hydrodynamic particle diameter is in the range of 70~90 nm with polydispersity index within 0.1~0.3 measured by Dynamic light scattering.
3. strong effect on both T1 and T2 proton relaxation times shortening (r1 and r2 relaxivities in water are 18.6 ± 1.3 and 205 ± 10.5 (mM•s)-1, respectively).
4. good biocompatibility without cytotoxicity effect based on in vitro (cell viability) and in vivo (acute toxicity) experiments.
5. excellent MR imaging contrast in both liver and brain perfusion in mice (in vivo MRI) compare the Resovist��, a known clinical product.
6. good macrophage labeling for organ-transplant immuno-rejection tracking by MR imaging
7. preclinical studies including rat and dog acute toxicity, geno-toxicity and PK/TK studies were completed. The Investigational New Drug (IND) application was filed and obtained in Taiwan.
8. good solubility in aqueous environment, up to 25 mg/mL of Fe in concentration, without aggregation for more than 2 year when stored at 4℃
Preliminary MRI imaging data from our in vivo studies suggested that iTrast-001 is a suitable MRI contrast agent for hepatoma diagnosis (liver imaging), immune response detection (heart transplant in rat and kidney transplant in both rat and pig) and cancer metastasis detection (lymph node imaging) with sensitivity (r2/r1 ratio) improvement over existing marketed agents. The clinical phase I trial for iTrast-001 is scheduled to launch in 2014. The clinical goal is to provide a reliable and early diagnostic tool for organ transplant rejection diagnosis.
There are about 3800 patients in average worldwide per year to receive heart transplant in the last decade, based on the data published from the International Society for Heart and Lung Transplantation (ISHLT). There are more than 37 thousands patients worldwide in 2010 had the kidney transplants, gradually increased during the last decade. It is important to monitor patients for the acute immuno-rejection after transplantation. The iTrast-001 is suitable for the immuno-rejection monitoring process with the high imaging contrast and good immune cell labeling. The estimated market size per year for the patient cost with imaging procedure for immuno-rejection monitoring is around 100 million US dollars.
* iTrastR is the registered trademark for Industrial Technology Research Institute |
