Barry Allen

Biodistribution of ultra small superparamagnetic iron oxide nanoparticles in BALB mice

Recently ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles (NPs) have been widely used for medical applications. One of their important applications is using these particles as MRI contrast agent. While various research works have been done about MRI application of USPIOs, there is limited research about their uptakes in various organs. The aim of this study was to evaluate the biodistribution of dextran coated iron oxide NPs labelled with 99mTc in various organs via intravenous injection in Balb/c mice. The magnetite NPs were dispersed in phosphate buffered saline and SnCl2 which was used as a reduction reagent. Subsequently, the radioisotope 99mTc was mixed directly into the reaction solution. The labeling efficiency of USPIOs labeled with 99mTc, was above 99xa0%. Sixty mice were sacrificed at 12 different time points (From 1xa0min to 48xa0h post injections; five mice at each time). The percentage of injected dose per gram of each organ was measured by direct counting for 19 harvested organs of the mice. The biodistribution of 99mTc-USPIO in Balb/c mice showed dramatic uptake in reticuloendothelial system. Accordingly, about 75 percent of injected dose was found in spleen and liver at 15xa0min post injection. More than 24xa0% of the NPs remain in liver after 48xa0h post-injection and their clearance is so fast in other organs. The results suggest that USPIOs as characterized in our study can be potentially used as contrast agent in MR Imaging, distributing reticuloendothelial system specially spleen and liver.

Monoclonal antibody conjugated magnetic nanoparticles could target MUC-1-positive cells in vitro but not in vivo

MUC1 antigen is recognized as a high-molecular-weight glycoprotein that is unexpectedly over-expressed in human breast and other carcinomas. In contrast, C595 a monoclonal antibody (mAb) against the protein core of the human urinary epithelial machine, is commonly expressed in breast carcinomas. The aim of this study was to conjugate ultra-small super paramagnetic iron oxide nanoparticles (USPIO) with C595 mAb, in order to detect in vivo MUC1 expression. A dual contrast agent (the C595 antibody-conjugated USPIO labeled with 99mTc) was prepared for targeted imaging and therapy of anti-MUC1-expressing cancers. The C595 antibody-conjugated USPIO had good stability and reactivity in the presence of blood plasma at 37u2009°C. No significant differences were observed in immunoreactivity results between conjugated and nonconjugated nanoparticles. The T1 and T2 measurements show >79 and 29% increments (for 0.02u2009mg/ml iron concentrations) in T1 and T2 values for USPIO-C595 in comparison with USPIO, respectively. The nanoprobes showed the interesting targeting capability of finding the MUC1-positive cell line in vitro. However, we found disappointing in vivo results (i.e. very low accumulation of nanoprobes in the targeted site while >80% of the injected dose per gram was taken up by the liver and spleen), not only due to the coverage of targeting site by protein corona but also because of absorption of opsonin-based proteins at the surface of nanoprobes.

A comparative evaluation of Ac225 vs Bi213 as therapeutic radioisotopes for targeted alpha therapy for cancer

The Ac225:Bi213 generator is the mainstay for preclinical and clinical studies of targeted alpha therapy for cancer. Both Ac225 (four alpha decays) and Bi213 (one alpha decay) are being used to label targeting vectors to form the alpha immunoconjugate for cancer therapy. This paper considers the radiobiological and economic aspects of Ac225 vs Bi213 as the preferred radioisotope for preclinical and clinical TAT. The in vitro and in vivo evidence and the role of DNA repair processes is examined. The maximum tolerance dose and therapeutic gain are endpoints for comparison. Ac225 has the higher therapeutic gain, when normalised to equal alpha production. However, the slow repair of double strand breaks reduces this advantage. Comparisons are made for the specific energy deposition in targeted and non-targeted cells, for endothelial cells by direct or indirect targeting, the need for sparing agents to save critical organs and cost considerations for preclinical and clinical trials and clinical use. Overall, Ac225 is found to have the better or equal performance to Bi213 at a much lower cost.

Global comparison of targeted alpha vs targeted beta therapy for cancer: In vitro, in vivo and clinical trials

Targeted therapy for cancer is a rapidly expanding and successful approach to the management of many intractable cancers. However, many immunotherapies fail in the longer term and there continues to be a need for improved targeted cancer cell toxicity, which can be achieved by radiolabelling the targeting vector with a radioisotope. Such constructs are successful in using a gamma ray emitter for imaging. However, traditionally, a beta emitter is used for therapeutic applications. The new approach is to use the short range and highly cytotoxic alpha radiation from alpha emitters to achieve improved efficacy and therapeutic gain. This paper sets out to review all experimental and theoretical comparisons of efficacy and therapeutic gain for alpha and beta emitters labelling the same targeting vector. The overall conclusion is that targeted alpha therapy is superior to targeted beta therapy, such that the use of alpha therapy in clinical settings should be expanded.

SU-E-J-03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

PURPOSEnThe purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors.nnnMETHODSnBecause of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 based microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes (211 At, 213 Bi, 223 Ra and 225 Ac) and 6 beta emitters (32 P, 33 P, 67 Cu, 90 Y, 131 I and 177 Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters.nnnRESULTSnWe show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors.nnnCONCLUSIONnThe results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development.