THE ORGAN TARGETABILITY OF SMALL AND LARGE ALBUMIN MICROSPHERES CONTAINING FREE AND HSA CONJUGATED METHOTREXATE

The organ-targeting ability of [H-3]methotrexate ([H-3]MTX), [H-3]MTX-human serum albumin (HSA) conjugates, and small (mean volume diameter, 10.0 mum) and large (mean volume diameter, 22.4 mum) size hydrophilic albumin microspheres (HAMs) containing different ratios of [H-3]MTX-HSA conjugates to [H-3]MTX was evaluated after i.v. administration of the compounds, equivalent to 150 nCi via the tail vein of mice. The total radioactivity in the lung increased immediately in a few minutes after i.v. injection of the both small and large HAMs, and then declined for up to 3-4 weeks, apparently reaching a plateau thereafter. However, the radioactivity in the liver, spleen and kidney increased slowly during the rapid decrease in radioactivity in the lung. This suggested that the small and large HAMs administered could be entrapped rapidly in the lung through mechanical filtration because of their large size and slowly redistributed to the liver, spleen and kidney due to either the HAMs being degraded enough for the size to allow passage through the capillary beds of the lung and/or the release of [H-3]MTX or [H-3]MTX-HSA conjugates from the HAMs. The highest value of AUQ was obtained for the liver and lung from small (including [H-3]MTX-HSA conjugates) and large HAMs, respectively, and suggested that the small (including [H-3]MTX-HSA conjugates) and large HAMs have a better targeting ability to the liver and lung, respectively, than that of MTX or MTX-HSA conjugates. This is consistent with the higher value of r(e)* for the liver and lung from the small and large HAMs, respectively. Greater selectivity for the liver and lung from the small and large HAMs, respectively, is indicated by a t(e)* value greater than unity. The greater targeting efficiency of the small and large HAMs for the liver and lung is indicated by higher values of T(e)*. However, the liver targeting efficiency of the small HAMs appeared to be similar to that of [H-3]MTX-HSA conjugates.