Abstract
Nanotechnology in the field of drug delivery comes with great benefits due to the unique physicochemical properties of newly developed nanocarriers. However, they may come as well with severe toxicological side effects because of unwanted accumulation in organs outside of their targeted site of actions. Several studies showed an unintended accumulation of various nanocarriers in female sex organs, especially in the ovaries. Some led to inflammation, fibrosis, or decreasing follicle numbers. However, none of these studies investigated ovarian accumulation in context to both reproductive aging and particle size. Besides the influences of particle size, the biodistribution profile may be altered as well by reproductive aging because of reduced capacities of the reticuloendothelial system (RES), changes in sex steroid hormone levels as well as altering ovarian stromal blood flow. This systematic investigation of the biodistribution of intravenously (i.v) injected nanoemulsions revealed significant dependencies on the two parameters particle size and age starting from juvenile prepubescent to senescent mice. Using fluorescent in vivo and ex vivo imaging, prepubescent mice showed nearly no accumulation of nanoemulsion in their uteri and ovaries, but high accumulations in the organs of the RES liver and spleen independently of the particle size. In fertile adult mice, the accumulation increased significantly in the ovaries with an increased particle size of the nanoemulsions by nearly doubling the portion of the average radiant efficiency (PARE) to ~10% of the total measured signal of all excised organs. With reproductive aging and hence loss of fertility in senescent mice, the accumulation decreased again to moderate levels, again independently of the particle size. In conclusion, the ovarian accumulation of these nanocarriers depended on both the age plus the particle size during maturity.
Highlights
Nanosized drug-delivery systems (DDS) are increasingly used as drug carriers, diagnostics, or theranostic agents
The mouse with the smallest Devm was chosen as the representative mouse. This in vivo study showed a significant accumulation of nanoemulsions in the ovaries of female mice, which depended on both the particle size and the age of the mice
After puberty and in the most fertile life period, the ovarian accumulation of the nanoemulsions increased to a remarkable extent in adult mice at an age of 13–39 weeks
Summary
Nanosized drug-delivery systems (DDS) are increasingly used as drug carriers, diagnostics, or theranostic agents. Besides the unintended release of active pharmaceutical ingredients through an unwanted ovarian accumulation of the DDS, some nanoparticles were reported to cause toxic harms already by themselves: Some led to inflammation, congestion, extravasations of red blood cells, fibrosis, and apoptosis in ovarian cells of rats [2,8] and others decreased the number of follicles in the ovaries after i.v. application in female mice [2,9] None of these studies investigated both the influence of particle size and aging effects on the accumulation of nanoparticles in ovarian tissue. Solely the formulations NE25 and NE100 led to a visible accumulation in the ovaries, which were with a respective age of 64 and 49 weeks younger than the other senescent mice for the formulations NE50 and NE150 at respective ages of 85 and 80 weeks
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