pH‐Switchable Vesicles from a Serine‐Derived Guanidiniocarbonyl Pyrrole Carboxylate Zwitterion in DMSO

Abstract

This work describes a new type of vesicles that can be reversibly opened and closed by changing the protonation state of a self-assembling zwitterion. Vesicles are interesting nanomaterials with potential applications such as delivery systems for drug targeting. For this purpose, however, external control of vesicle formation is required. To date, vesicle formation has often been based on the self-assembly of amphiphilic macromolecules such as lipid derivatives or block copolymers. [1,2] Recently, vesicle formation from other types of building blocks, such as shape-persistent macrocyles, cyclodextrins, or small peptides has also been reported. [3] Most of these molecules are still classical amphiphiles and their self-assembly is mainly driven by hydrophobic or aromatic interactions.We have recently introduced a new type of vesicle forming-molecule, namely a self-complementary guanidiniocarbonyl pyrrole carboxylate zwitterion derived from alanine. We have shown by NOESY NMR studies in combination with TEM and AFM experiments that, in DMSO, the zwitterion forms ion-paired dimers that then further aggregate into hollow vesicles of approximately 40-50 nm diameter.[4] We have also used this special type of hydrogen-bond-assisted ion-pair formation between the guanidiniocarbonyl pyrrole cation [5] and a carboxylate unit for the construction of other types of nanostructures such as dimers, [6] loops, [7] and supramolecular polymers.[8] As the guanidiniocarbonyl pyrrole moiety has an approximate pK a value of 6-7, ion-pair formation with a carboxylate (pK a ca. 3-5) only occurs within a narrow pH range. This restriction offers the possibility to deliberately turn the ion-pair formation on or off by changing the pH from neutral to slightly acidic or basic.[9] We therefore wanted to explore whether we can also trigger vesicle formation by using pH as an external signal.[10] To test this hypothesis, we have synthesized a serine-derived guanidiniocarbonyl pyrrole carboxylate zwitterion 3 and studied its vesicle formation on surface with AFM as well as in solution by using dynamic light scattering (DLS) and a pulsed field gradient (PFG)-based NMR method. The latter method allows us to selectively detect the solvent molecules encapsulated in the vesicles and also to quantify the permeability of the vesicle membranes.[11] We show herein that vesicle formation of 3 can indeed be switched on and off in a controlled manner by reversible changes of its protonation state. Furthermore, we found that the vesicles are rather impermeable and the measured exchange rate of solvent molecules across the membrane is very small.The synthesis of the serine-derived guanidiniocarbonyl pyrrole carboxylate zwitterion 3 is shown in Scheme 1. l-serine methyl ester hydrochloride 2 was coupled with the Boc-protected guanidinocarbonyl pyrrole carboxylic acid 1 [12] using PyBOP in a mixture of CH 2 Cl 2 and DMF as the coupling reagent (67 % yield). The Boc group was cleaved with TFA, and the methyl ester was subsequently hydrolyzed with LiOH to produce ...

A Supramolecular Gel from a Quadruple Zwitterion that Responds to Both Acid and Base

“…This provides a simple way of turning the aggregation on or off by either protonation or deprotonation of the zwitterion. [18] The gels in DMSO, therefore, exhibit dual pH dependence; they transform into sols by the addition of either acid or base. Furthermore, these pH-triggered gel-sol transitions are completely reversible; by neutralizing the excess acid or base, the original gels are restored (Scheme 1).…”

A Journey through 12 Years of Interacting Molecules: From Artificial Amino Acid Receptors to the Recognition of Biomolecules and Switchable [nl]Nanomaterials

“…62 At neutral pH, vesicles form in DMSO solution. The vesicles completely disaggregate upon the addition of acid or base and reform again upon neutralization of the solution.…”

“…One of the first examples in which we checked the ability to switch our nanoassemblies by changing the pH was based on a serine-derived zwitterion (Figure 23). 62 At neutral pH, vesicles form in DMSO solution. The vesicles completely disaggregate upon the addition of acid or base and reform again upon neutralization of the solution.…”

Two‐Component Self‐Assembly: Hierarchical Formation of pH‐Switchable Supramolecular Networks by π–π Induced Aggregation of Ion Pairs

“…[9] It requires balancedn oncovalenti nteractions between at least two different molecules to ensureasufficient degree of cooperative aggregation (polymerization).H owever,t his approach allows for the regulation of the microscopic structure andm acroscopic properties by tuning the molarr atio of the two components, in contrastt o single-components elf-assembly. [10] Furthermore, the components might possess functionalities that respond to external stimulus [11] such as temperature, [12] metal ions, [13] light, [14,15] pH, [16][17][18] or solvent, [19] which allow for switching back and forth betweendifferent types of nanostructures.For designing an ovel supramolecular architecture, al arge variety of chemical functionalities is available. [20] We have recentlyd eveloped af lexible tetra-cation based on our guanidiniocarbonyl pyrrole anion binding motif, [21] which efficiently underwent two-component molecular assemblyw ith Na 4 EDTA in a1:1 ratio to form supramolecular polymers baseds olelyo n ion-pair interactions.…”

“…[9] It requires balancedn oncovalenti nteractions between at least two different molecules to ensureasufficient degree of cooperative aggregation (polymerization).H owever,t his approach allows for the regulation of the microscopic structure andm acroscopic properties by tuning the molarr atio of the two components, in contrastt o single-components elf-assembly. [10] Furthermore, the components might possess functionalities that respond to external stimulus [11] such as temperature, [12] metal ions, [13] light, [14,15] pH, [16][17][18] or solvent, [19] which allow for switching back and forth betweendifferent types of nanostructures.…”