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In this research, we studied the effect of polypeptide composition and topology on the hydrogelation of star-shaped block copolypeptides based on hydrophilic, coil poly(L-lysine)20 (s-PLL20) tethered with a hydrophobic, sheet-like polypeptide segment, which is poly(L-phenylalanine) (PPhe), poly(L-leucine) (PLeu), poly(L-valine) (PVal) or poly(L-alanine) (PAla) with a degree of polymerization (DP) about 5. We found that the PPhe, PLeu, and PVal segments are good hydrogelators to promote hydrogelation. The hydrogelation and hydrogel mechanical properties depend on the arm number and hydrophobic polypeptide segment, which are dictated by the amphiphilic balance between polypeptide blocks and the hydrophobic interactions/hydrogen bonding exerted by the hydrophobic polypeptide segment. The star-shaped topology could facilitate their hydrogelation due to the branching chains serving as multiple interacting depots between hydrophobic polypeptide segments. The 6-armed diblock copolypeptides have better hydrogelation ability than 3-armed ones and s-PLL-b-PPhe exhibits better hydrogelation ability than s-PLL-b-PVal and s-PLL-b-PLeu due to the additional cation–π and π–π interactions. This study highlights that polypeptide composition and topology could be additional parameters to manipulate polypeptide hydrogelation.

Nanoparticles (NPs) are the focus of research efforts that aim to develop successful drug delivery systems for the brain. Polypeptide nanocarriers are versatile platforms and combine high functionality with good biocompatibility and biodegradability. The key to the efficient brain delivery of NPs is the specific targeting of cerebral endothelial cells that form the blood–brain barrier (BBB). We have previously discovered that the combination of two different ligands of BBB nutrient transporters, alanine and glutathione, increases the permeability of vesicular NPs across the BBB. Our aim here was to investigate whether the combination of these molecules can also promote the efficient transfer of 3-armed poly(l-glutamic acid) NPs across a human endothelial cell and brain pericyte BBB co-culture model. Alanine and glutathione dual-targeted polypeptide NPs showed good cytocompatibility and elevated cellular uptake in a time-dependent and active manner. Targeted NPs had a higher permeability across the BBB model and could subsequently enter midbrain-like organoids derived from healthy and Parkinson’s disease patient-specific stem cells. These results indicate that poly(l-glutamic acid) NPs can be used as nanocarriers for nervous system application and that the right combination of molecules that target cerebral endothelial cells, in this case alanine and glutathione, can facilitate drug delivery to the brain.

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To study the self-assembly and hydrogel formation of the star-shaped graft copolypeptides with asymmetric topology, star-shaped poly(L-lysine) with various arm numbers were synthesized by using asymmetric polyglycerol dendrimers (PGDs) as the initiators and 1,1,3,3-tetramethylguanidine (TMG) as an activator for OH groups, followed by deprotection and grafting with indole or phenyl group on the side chain. The packing of the grafting moiety via non-covalent interactions not only facilitated the polypeptide segments to adopt more ordered conformations but also triggered the spontaneous hydrogelation. The hydrogelation ability was found to be correlated with polypeptide composition and topology. The star-shaped polypeptides with asymmetric topology exhibited poorer hydrogelation ability than those with symmetric topology due to the less efficient packing of the grafted moiety. The star-shaped polypeptides grafted with indole group on the side chain exhibited better hydrogelation ability than those grafted with phenyl group with the same arm number. This report demonstrated that the grafted moiety and polypeptide topology possessed the potential ability to modulate the polypeptide hydrogelation and hydrogel characteristics.

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