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... Show moreCore 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-block-poly(S-ethylsulfonyl-l-cysteine) [pSar-b-pCys(SO2Et)] were employed. While the pCys(SO2Et) chain lengths varied from Xn = 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. Show less
Holm, R.; Douverne, M.; Weber, B.; Bauer, T.; Best, A.; Ahlers, P.; ... ; Barz, M. 2019
The size control of nanomedicines for tumor diagnosis and therapy is of high importance, since it enables or disables deep and sufficient tumor penetration. Amphiphilic star-shaped block copolypept... Show moreThe size control of nanomedicines for tumor diagnosis and therapy is of high importance, since it enables or disables deep and sufficient tumor penetration. Amphiphilic star-shaped block copolypept(o)ides offer substantial promise to precisely adjust the hydrophobic core and the hydrophilic corona, independent of each other, and therefore simultaneously control the size dimension in the interesting size range from 10 to 30 nm. To gain access to core-shell structures of such sizes, 3-arm and 6-arm PeptoStars, based on poly(gamma-tert-butyloxycarbonyl-L-glutamate)-b-polysarcosine (pGlu(OtBu)-b-pSar), were prepared via controlled living ring-opening polymerization (ROP) of the corresponding N-carboxyanhydrides. Moreover, size exclusion chromatography (SEC) proves the presence of well-defined star shaped polymers with molecular weights from 38 to 88 kg/mol with low polymer dispersities of 1.16 to 1.23. By varying the alpha-helical peptide core and maintain a constant polysarcosine corona, hydrodynamic size analyses revealed the importance of using a sufficiently large and dense hydrophilic shielding corona to prevent aggregation of the hydrophobic core and obtain uniform-sized spherical-shaped particles with hydrodynamic diameters below 24 nm. Fluorescence correlation spectroscopy (FCS) additionally demonstrates the absence of protein adsorption in human plasma for 6-arm polypept(o)ide stars and thus confirms polysarcosine as stealthlike material. Show less
Otter, R.; Henke, N.A.; Berac, C.; Bauer, T.; Barz, M.; Seiffert, S.; Besenius, P. 2018
We report the synthesis of ABA' triblock peptide-polysarcosine-peptide conjugates featuring two complementary phenylalanine-histidine pentapeptide strands A/A'. These sequences encode for... Show moreWe report the synthesis of ABA' triblock peptide-polysarcosine-peptide conjugates featuring two complementary phenylalanine-histidine pentapeptide strands A/A'. These sequences encode for antiparallel beta-sheet formation into folded conjugates, which promote the self-assembly into polysarcosine-shielded core-shell nanorods. These do not cause aggregation of serum proteins in human blood plasma underlining an enhanced stability. Show less
The preparation of histidine enriched dendritic peptide amphiphiles and their self-assembly into multicomponent pH-switchable supramolecular polymers is reported. Alternating histidine and... Show moreThe preparation of histidine enriched dendritic peptide amphiphiles and their self-assembly into multicomponent pH-switchable supramolecular polymers is reported. Alternating histidine and phenylalanine peptide synthons allow the assembly/disassembly to be adjusted in a physiologically relevant range of pH 5.3-6.0. Coassembly of monomers equipped with dendritic tetraethylene glycol chains with monomers bearing peripheral primary amine groups leads to nanorods with a tunable cationic surface charge density. These surface functional supramolecular polycations are able to reversibly bind short interfering RNA (siRNA). The nanorod-like supramolecular polymers, their complexation with siRNA, and the pH-triggered assembly/disassembly of the supramolecular carriers are characterized via circular dichroism spectroscopy, gel electrophoresis, as well as transmission electron microscopy. Multicomponent supramolecular polymers represent a modular and promising strategy for applications as responsive carrier vehicles, codelivery strategies, and gene therapy. Show less
