The in vivo stability and biodegradability of nanocarriers crucially determine therapeutic efficacy as well as safety when used for drug delivery. This study aims to evaluate optimized in vitro techniques predictive for in vivo nanocarrier behavior. Polymeric biodegradable nanogels based on hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2-azidoethyl)methacrylamide) and with various degrees of PEGylation and crosslinking densities are prepared. Three techniques are chosen and refined for specific in vitro evaluation of the nanocarrier performance: (1) fluorescence single particle tracking (fSPT) to study the stability of nanogels in human plasma, (2) tangential flow filtration (TFF) to study the degradation and filtration of nanogel degradation products, and (3) fluorescence fluctuation spectroscopy (FFS) to evaluate and compare the degradation behavior of nanogels in buffer and plasma. fSPT results demonstrate that nanogels with highest PEGylation content show the least aggregation. The TFF results reveal that nanogels with higher crosslink density have slower degradation and removal by filtration. FFS results indicate a similar degradation behavior in human plasma as compared to that in phosphate buffered saline. In conclusion, three methods can be used to compare and select the optimal nanogel composition, and these methods hold potential to predict the in vivo performance of nanocarriers.
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