We describe the efficient synthesis of block copolypeptides, polypeptoids as well as block copolypept(o)ides by chemical ligation techniques.

In this work, the synthesis of polypeptoid-block-polypeptide copolymers (block copolypept(o)ides) based on bifunctional initiators is described, which introduces a distinct chemical entity at the connection between both blocks. With a view towards redox-sensitive block copolypept(o)ides, a cystamine-based initiator was used to synthesize polysarcosine macroinitiators with degrees of polymerization (Xn) between 100 and 200 displaying monomodal molecular weight distributions and dispersities (Đ) around 1.1 as determined by size exclusion chromatography. Block copolypept(o)ides with a poly(γ-t-butyloxycarbonyl-L-glutamate) (PGlu(O(t) Bu)) block (Xn = 25 or 50) were synthesized by controlled N-carboxyanhydride polymerization. Resulting block copolymers possess monomodal molecular weight distributions, dispersities around 1.2 and were applied to degradation studies. While block copolypept(o)ides are stable at 10 × 10(-6) M, they degrade over time at GSH concentrations of 10 × 10(-3) and 100 × 10(-3) M. Furthermore, these disulfide-containing block copolymers form PeptoMicelles, which degrade at intracellular GSH concentrations while remaining stable at extracellular GSH levels.

Star-like polymers are one of the smallest systems in the class of core crosslinked polymeric nanoparticles. This article reports on a versatile, straightforward synthesis of three-arm star-like polypept(o)ide (polysarcosine-block-polylysine) polymers, which are designed to be either stable or degradable at elevated levels of glutathione. Polypept(o)ides are a recently introduced class of polymers combining the stealth-like properties of the polypeptoid polysarcosine with the functionality of polypeptides, thus enabling the synthesis of materials completely based on endogenous amino acids. The star-like homo and block copolymers are synthesized by living nucleophilic ring opening polymerization of the corresponding N-carboxyanhydrides (NCAs) yielding polymeric stars with precise control over the degree of polymerization (X = 25, 50, 100), Poisson-like molecular weight distributions, and low dispersities (Đ = 1.06-1.15). Star-like polypept(o)ides display a hydrodynamic radius of 5 nm (μ < 0.05) as determined by dynamic light scattering (DLS). While star-like polysarcosines and polypept(o)ides based on disulfide containing initiators are stable in solution, degradation occurs at 100 × 10 m glutathione concentration. The disulfide cleavage yields the respective polymeric arms, which possess Poisson-like molecular weight distributions and low dispersities (Đ = 1.05-1.12). Initial cellular uptake and toxicity studies reveal that PeptoStars are well tolerated by HeLa, HEK 293, and DC 2.4 cells.

Aqueous supramolecular polymers [4] have recently entered the field of biomed ical applications [5] and several systems have been disclosed for regenerative medi cine or drug delivery, using host-guest pairs, [6] peptide amphiphiles, [7] ureido pyrimidineone, [8] and benzenetricarbox amide (BTA) [9] scaffolds. We here focus on the use of 1D supramolecular polymers, with a nanorodlike morphology, based on new dendritic oligo(histidine-alt-phenyla lanine) peptide synthons. These combine high robustness and fidelity in the self assembly with stimuliresponsive proper ties toward pHvalues of the surrounding medium. We have previously reported C 3 symmetrical nonaphenylalanine supra molecular building monomers equipped with dendritic tetraethylene glycol chains, with binding affinities of up to 7 × 10 7 m −1 in water. [10] In order to introduce pHswitchable properties into the supramolecular polymeriza tion, we changed the peripheral dendritic tetraethylene glycol chains for dendritic carboxylic acids in the amphiphilic mono mers that are highly charged and thus molecularly dissolved at neutral pH and selfassemble into anisotropic supramolecular polymers by acidifying the aqueous medium. [11] These sys tems were not applicable when aiming for a pHtriggered dis assembly of supramolecular constructs upon lowering the pH. To this end we have disclosed an ampholytic supramolecular copolymer design, whereby the multicomponent coassembly of anionic oligo(glutamic acid-alt-phenylalanine) and cationic oligo(lysine-alt-phenylalanine) peptide synthons leads to alter nating copolymer formation. [12] The pHstability window of these copolymers could be tuned by a supramolecular engi neering approach, using mismatched comonomer pairs which shifts the pHtriggered disassembly of the copolymers from pH 4.2 to 5.8. [13] In this case however the pHtriggered glutamic acid monomer that is released upon disassembly of the copol ymers leads to the formation of homopolymers, in a process that is driven by charge regulation. [2c,12b,13] Thus, we here aim to develop a facile pHresponsive supramolecular polymeriza tion using an oligo(histidine-alt-phenylalanine) peptide syn thon, that operates in a physiologically relevant pH window, and where the functional and structural dendritic comonomers can be mixed at will, without significantly shifting the pHtriggered disassembly. The hydrophobic-hydrophilic shift upon protona tion of histidine containing amphiphiles under slightly acidic pH-triggered ReleaseThe 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 supramolecula...