The effect of particle size on the biodistribution of low-modulus ...

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The effect of particle size on the biodistribution of low-modulus ...

42 T.J. Merkel et al. / Journal ong>ofong> Controlled Release 162 (2012) 37–44Fig. 3. Semi-log plot showing the biodistribution ong>ofong> highly deformable ong>particleong>s ong>ofong> different ong>sizeong>s in mice over the course ong>ofong> 5 days as measured by the percent ong>ofong> total fluorescencerecovered. ong>Theong> fluorescent signal from the ong>particleong>s in each whole tissue examined is shown for ong>particleong>s with diameters ong>ofong> (A) 0.78 μm, (B) 3.8 μm, (C) 6.4 μm and (D) 8.9 μm. Lineshave been added to connect the data points for clarity only. Four mice were examined per time-point, with error bars representing one standard deviation.possible that these smaller ong>particleong>s were more rapidly recognized andphagocytosed by macrophages in the liver and spleen, leading to theirmore rapid clearance from the circulation. ong>Theong> shorter circulation timeong>ofong> the 3.79 μm ong>particleong>s also lends support to this argument, as thesemicroong>particleong>s would be expected to more readily avoid sequestrationin the fenestrations in the spleen that might entrap the 6.4 μm ong>particleong>sdue to their marginally smaller ong>sizeong>, while still large enough to avoidprimary clearance in the liver. Further work will be required to fully understandthe different mechanisms ong>ofong> clearance that act on these highlydeformable ong>particleong>s as ong>particleong> ong>sizeong> varies.4. ConclusionsParticles with extremely high levels ong>ofong> deformability, characterizedby a Young's modulus ong>ofong> 6.5 kPa, are able to avoid or escape filtrationwhen injected intravascularly in mice. Evidence ong>ofong> avoidance is clearfrom the long (>30 h) elimination half-lives ong>ofong> all but the largest ong>ofong>these ong>particleong>s. Escape from clearance tissues is also clearly seen, asthese ong>particleong>s tended to accumulate into the spleen over time, reachinga maximum value then decreasing. ong>Theong> decrease in accumulation in thespleen correlated with an increase in the concentration ong>ofong> ong>particleong>s in theblood, presumably due to the release ong>ofong> some ong>ofong> the physically entrappedong>particleong>s. This was seen most dramatically in the largest ong>ofong> the microgelsstudied (8.9 μm), where the ong>particleong> concentration decreased for the firsthour ong>ofong> the study before increasing at the 3 and 7 hour time points, presumablyduetotheescapeong>ofong>ong>particleong>sfromthelungsandspleen,whichresulted in a corresponding decrease in ong>particleong> accumulation. Finally,higher circulation persistence and slower clearance were seen for deformableong>particleong>s that resembled red blood cells in ong>sizeong> than for bothlarger and smaller ong>particleong>s, indicating that this combination ong>ofong> ong>sizeong>,shape and deformability results in ong>particleong>s that are better adapted tothe avoidance ong>ofong> natural clearance mechanisms in the body.ong>Theong> results presented here demonstrate the importance ong>ofong> ong>sizeong>and deformability for determining the biodistribution and circulationpersistence ong>ofong> hydrogel ong>particleong>s. This information is expected to havea large impact on the design ong>ofong> hydrogel ong>particleong>s for therapeutic ordiagnostic applications and to provide a foundation for the use ong>ofong>such highly deformable ong>particleong>s for drug delivery.

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