The ability to reversibly cross-link proteins and peptides grants the amino acid cysteine its unique role in nature as well as in peptide chemistry. We report a novel class of S-alkylsulfonyl-l-cysteines and N-carboxy anhydrides (NCA) thereof for peptide synthesis. The S-alkylsulfonyl group is stable against amines and thus enables its use under Fmoc chemistry conditions and the controlled polymerization of the corresponding NCAs yielding well-defined homo- as well as block co-polymers. Yet, thiols react immediately with the S-alkylsulfonyl group forming asymmetric disulfides. Therefore, we introduce the first reactive cysteine derivative for efficient and chemoselective disulfide formation in synthetic polypeptides, thus bypassing additional protective group cleavage steps.
Thereby, one of the main goals of liposomes is to protect the entrapped drug while also reducing its off-site toxicity, as shown for multiple formulations. [5][6][7][8] To this end, increasing on-target tissue concentration is a key aspect which can be achieved both by nontargeted and targeted liposomes. [9][10][11][12] In this regard, a crucial point is the prolongation of systemic circulation lifetime. It is well-known that upon injection the majority of conventional (plain) liposomes are cleared rapidly from the blood stream by cells of the mononuclear phagocyte system. [13][14][15] To enhance circulation times, a variety of approaches to modify the surface of liposomes emerged, [16][17][18] yet ultimately polyethylene glycol (PEG) established itself as gold standard in the early 1990s aiming at decreasing opsonization. [19][20][21] PEGylation not only reduces but also alternates the recognition of nanoparticles by complement factors and opsonins, resulting in a decreased nanoparticle recognition and clearance by macrophages. [22,23] Manipulating opsonization, including the reduction of complement activation thus is one of the main goals in preventing rapid clearance.Today, surface modifications of liposomes are mostly realized with amphiphilic lipid-polymer conjugates like 1,2-distearoyl-snglycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-mPEG2k). [24,25] Despite the benefits and being considered mostly nonimmunogenic, phospholipid-PEG conjugates have also demonstrated some drawbacks over the Circulation lifetime is a crucial parameter for a successful therapy with nanoparticles. Reduction and alteration of opsonization profiles by surface modification of nanoparticles is the main strategy to achieve this objective. In clinical settings, PEGylation is the most relevant strategy to enhance blood circulation, yet it has drawbacks, including hypersensitivity reactions in some patients treated with PEGylated nanoparticles, which fuel the search for alternative strategies. In this work, lipopolysarcosine derivatives (BA-pSar, bisalkyl polysarcosine) with precise chain lengths and low polydispersity indices are synthesized, characterized, and incorporated into the bilayer of preformed liposomes via a post insertion technique. Successful incorporation of BA-pSar can be realized in a clinically relevant liposomal formulation. Furthermore, BA-pSar provides excellent surface charge shielding potential for charged liposomes and renders their surface neutral. Pharmacokinetic investigations in a zebrafish model show enhanced circulation properties and reduction in macrophage recognition, matching the behavior of PEGylated liposomes. Moreover, complement activation, which is a key factor in hypersensitivity reactions caused by PEGylated liposomes, can be reduced by modifying the surface of liposomes with an acetylated BA-pSar derivative. Hence, this study presents an alternative surface modification strategy with similar benefits as the established PEGylation of nanoparticles, but with the potential...
Secondary structure formation differentiates polypeptides from most of the other synthetic polymers, and the transitions from random coils to rod-like α-helices or β-sheets represent an additional parameter to direct self-assembly and the morphology of nanostructures. We investigated the influence of distinct secondary structures on the self-assembly of reactive amphiphilic polypept(o)ides. The individual morphologies can be preserved by core cross-linking via chemoselective disulfide bond formation. A series of thiol-responsive copolymers of racemic polysarcosine- block -poly( S -ethylsulfonyl- dl -cysteine) (pSar- b -p( dl )Cys), enantiopure polysarcosine- block -poly( S -ethylsulfonyl- l -cysteine) (pSar- b -p( l )Cys), and polysarcosine- block -poly( S -ethylsulfonyl- l -homocysteine) (pSar- b -p( l )Hcy) was prepared by N -carboxyanhydride polymerization. The secondary structure of the peptide segment varies from α-helices (pSar- b -p( l )Hcy) to antiparallel β-sheets (pSar- b -p( l )Cys) and disrupted β-sheets (pSar- b -p( dl )Cys). When subjected to nanoprecipitation, copolymers with antiparallel β-sheets display the strongest tendency to self-assemble, whereas disrupted β-sheets hardly induce aggregation. This translates to worm-like micelles, solely spherical micelles, or ellipsoidal structures, as analyzed by atomic force microscopy and cryogenic transmission electron microscopy, which underlines the potential of secondary structure-driven self-assembly of synthetic polypeptides.
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