Tuning the pH‐Switch of Supramolecular Polymer Carriers for siRNA to Physiologically Relevant pH

Abstract

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...

Supramolecular copolymers predominated by alternating order: Theory and application

“…In this section we rationalize the experimental observations on the copolymerization of positively and negatively charged comonomers [25][26][27] on the basis of our theoretical insights. As briefly discussed in section I, the comonomer species with complementary charges contain three identical amphiphilic oligopeptide arms that possess a C 3 symmetry.…”

“…Recently, some of us [25][26][27] have developed a strategy to construct supramolecular copolymers using positively and negatively charged monomeric building blocks with C 3 symmetry, containing three identical peptide arms. These arms contain amphiphilic oligopeptides, based on alternating sequences of hydrophobic phenylalanine or methionine and charged lysine or glutamic acid residues and form rod-like assemblies via a combination of electrostatic interactions, hydrogen bonding and hydrophobic shielding.…”

“…25 The self-assembly is regulated via tuning the pH of the aqueous solutions. 25,27 By changing the charged state of the monomeric building blocks, pH drives the self-assembly into homopolymers of a neutral monomer or into copolymers when both monomer species carry complementary charges. A schematic representa- Chemical structures of the cationic dendritic peptide monomer (A, blue) and the anionic complementary monomer (B, green), and a schematic representation of the self-assembly into alternating supramolecular copolymers.…”

Orthogonally Stimulated Assembly/Disassembly of Depsipeptides by Rational Chemical Design

“…Hence, significant efforts have been directed towards the design of oligopeptides to allow a higher level of control of β‐sheet formation . Hydrophilic amino acids within the sequence, such as lysine or glutamic acid, can be leveraged to promote or inhibit intermolecular interactions depending on their protonation state . On the other hand, depsipeptides, in which a serine residue within the peptide sequence is connected through an ester bond instead, have shown exceptional promise for amyloid fibril formation by an external pH stimulus…”

From Polymers to Functional Biomaterials

“…The authors designed histidine enriched dendritic peptide amphiphiles, which self‐assembled into nanorods. Most importantly the alternating histidine and phenylalanine peptide trimers allow the assembly/disassembly at physiologically relevant pH and are able to complex siRNA, which is released after disintegration of the supramolecular structure …”