Tuning the Cross-Linking Density and Cross-Linker in Core Cross-Linked Polymeric Micelles and Its Effects on the Particle Stability in Human Blood Plasma and Mice

Core cross-linked polymeric micelles (CCPMs) are designedto improvethe therapeutic profile of hydrophobic drugs, reduce or completelyavoid protein corona formation, and offer prolonged circulation times,a prerequisite for passive or active targeting. In this study, wetuned the CCPM stability by using bifunctional or trifunctional cross-linkersand varying the cross-linkable polymer block length. For CCPMs, amphiphilicthiol-reactive polypept(o)ides of polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine) [pSar-b-pCys(SO2Et)] were employed. While the pCys(SO2Et) chain lengths varied from X ( n ) = 17 to 30, bivalent (derivatives of dihydrolipoicacid) and trivalent (sarcosine/cysteine pentapeptide) cross-linkershave been applied. Asymmetrical flow field-flow fraction (AF4) displayedthe absence of aggregates in human plasma, yet for non-cross-linkedPM and CCPMs cross-linked with dihydrolipoic acid at [pCys(SO2Et)](17), increasing the cross-linking density orthe pCys(SO2Et) chain lengths led to stable CCPMs. Interestingly,circulation time and biodistribution in mice of non-cross-linked andbivalently cross-linked CCPMs are comparable, while the trivalentpeptide cross-linkers enhance the circulation half-life from 11 to19 h.