Acute toxicity of intravenously administered microfabricated silicon dioxide drug delivery particles in mice: preliminary findings.

BACKGROUND AND OBJECTIVE: Microfabricated particles with nanosized features may serve an important role in the next generation of drug delivery vehicles. Microfabrication (micro-electromechanical systems) technologies offer the promise of both structural elements (e.g., pores, reservoirs) and electromechanical features (e.g., timers, valves, actuators) built into a single particle. In order to serve as carriers to deliver drugs to systemic sites of action, such as tumors, the particles must be safe to administer intravenously. An acute safety study was performed in a mouse model, using intravenous injection of solid silicon dioxide particles created to simulate the size and shape of potential targeted drug delivery vehicles. DESIGN: Two-micron thick, square and circular, parallelepiped-shaped particles were produced with varying sizes of 2 microm, 5 microm and 10 microm using microfabrication techniques and injected into groups of mice (six mice per group) over a range of doses. End-points included acute lethality, clinical signs of toxicity and weight loss. Sections of major organs were sampled for histological examination. RESULTS: At dose levels of 1 x 10(8) particles per mouse, circular particles of 2 microm and 5 microm showed no signs of acute toxicity. Similar results were obtained with the 2 microm and 5 microm square silicon dioxide particles; however, 14-day necropsy indicates fewer 5 microm circular particles in the lung than 5 microm square particles, indicating that the shape of the particles may impact on safety. Acute lethality was observed for 10 microm particles; none of the mice injected with the 10 microm particles survived except at very low dose levels of 6 x 10(5) particles per mouse. CONCLUSIONS: Solid silicon particles greater than 5 microm in their largest dimension are cleared in the lungs and are not safe for intravenous delivery. Particles of 2-5 microm in size do not lodge predominantly in the lung and do not cause acute toxicity, but accumulate in organs such as the liver and spleen. Possible chronic toxicities associated with organ uptake of such non-biodegradable particles have yet to be addressed.

The development of immunoassays to four biological threat agents in a bidiffractive grating biosensor.

A critical need exists for a field deployable biosensor to detect environmental infectious agents in collected air samples rapidly, with sensitivity and specificity approaching that of standard laboratory procedures. The ideal sensor would analyze unknown samples in minutes, have programmable operation for unattended sample analysis, and be capable of multiple agent analysis for a number of agents. The goal of this project was to further the development of the bidiffractive grating biosensor (BDG) created through collaboration between Battelle Memorial Institute (BMI), Hoffman LaRoche (HLR), and the Naval Medical Research Command (NMRC). This manuscript details the development, optimization, and evaluation of this device as a potential field deployable biosensor. Well-characterized immunochemical reagents developed by the Biological Defense Research Department (BDRD) at NMRI were employed to develop assays in the BDG. These results were compared to those obtained with antigen capture enzyme linked immunosorbent assays (ELISAs). Four separate antigens were evaluated: Staphylococcus aureus enterotoxin B (SEB), ricin (RIC), Francisella tularensis (FT), and Clostridium botulinum toxin (BOT).