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

Abstract

Core cross-linked polymeric micelles (CCPMs) are designed to improve the therapeutic profile of hydrophobic drugs, reduce or completely avoid protein corona formation, and offer prolonged circulation times, a prerequisite for passive or active targeting. In this study, we tuned the CCPM stability by using bifunctional or trifunctional cross-linkers and varying the cross-linkable polymer block length. For CCPMs, amphiphilic thiol-reactive polypept(o)ides of polysarcosine-<i>block</i>-poly(<i>S</i>-ethylsulfonyl-l-cysteine) [pSar-<i>b</i>-pCys(SO₂Et)] were employed. While the pCys(SO₂Et) chain lengths varied from <i>X</i>_<i>n</i> = 17 to 30, bivalent (derivatives of dihydrolipoic acid) and trivalent (sarcosine/cysteine pentapeptide) cross-linkers have been applied. Asymmetrical flow field-flow fraction (AF4) displayed the absence of aggregates in human plasma, yet for non-cross-linked PM and CCPMs cross-linked with dihydrolipoic acid at [pCys(SO₂Et)]₁₇, increasing the cross-linking density or the pCys(SO₂Et) chain lengths led to stable CCPMs. Interestingly, circulation time and biodistribution in mice of non-cross-linked and bivalently cross-linked CCPMs are comparable, while the trivalent peptide cross-linkers enhance the circulation half-life from 11 to 19 h.