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. 2015 Dec 1:11:2388-2399.
doi: 10.3762/bjoc.11.260. eCollection 2015.

Size-controlled and redox-responsive supramolecular nanoparticles

Raquel Mejia-Ariza #  1 , Gavin A Kronig #  1 , Jurriaan Huskens  1
Affiliations

Size-controlled and redox-responsive supramolecular nanoparticles

Raquel Mejia-Ariza et al. Beilstein J Org Chem. .

Abstract

Control over the assembly and disassembly of nanoparticles is pivotal for their use as drug delivery vehicles. Here, we aim to form supramolecular nanoparticles (SNPs) by combining advantages of the reversible assembly properties of SNPs using host-guest interactions and of a stimulus-responsive moiety. The SNPs are composed of a core of positively charged poly(ethylene imine) grafted with β-cyclodextrin (CD) and a positively charged ferrocene (Fc)-terminated poly(amidoamine) dendrimer, with a monovalent stabilizer at the surface. Fc was chosen for its loss of CD-binding properties when oxidizing it to the ferrocenium cation. The ionic strength was shown to play an important role in controlling the aggregate growth. The attractive supramolecular and repulsive electrostatic interactions constitute a balance of forces in this system at low ionic strengths. At higher ionic strengths, the increased charge screening led to a loss of electrostatic repulsion and therefore to faster aggregate growth. A Job plot showed that a 1:1 stoichiometry of host and guest moieties gave the most efficient aggregate growth. Different stabilizers were used to find the optimal stopper to limit the growth. A weaker guest moiety was shown to be less efficient in stabilizing the SNPs. Also steric repulsion is important for achieving SNP stability. SNPs of controlled particle size and good stability (up to seven days) were prepared by fine-tuning the ratio of multivalent and monovalent interactions. Finally, reversibility of the SNPs was confirmed by oxidizing the Fc guest moieties in the core of the SNPs.

Keywords: host–guest interactions; nanoparticles; self-assembly; stimulus-responsive; supramolecular chemistry.

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Figures

Figure 1
Figure 1
Microcalorimetric titrations of a) CD-PEI (CD concentration of 0.088 mM, cell) with Ad-TEG (1.1 mM, burette) and b) Ad-TEG (1.1 mM, cell) with CD (10 mM; burette). H = host (CD from CD-PEI or native CD) and G = guest (Ad from Ad-TEG). Experimental binding curve (markers) and best fit to a 1:1 model (line).
Figure 2
Figure 2
ITC titration of Fc-PEG (1.03 mM; cell) with native CD (10 mM; burette). H = host and G = guest. Experimental binding curve (markers) and best fit to a 1:1 model (line).
Scheme 1
Scheme 1
a) Schematic representation of the supramolecular nanoparticle (SNP) self-assembly and redox-triggered disassembly of the host–guest complex. b) Chemical structures of the building blocks used here. c) Binding of Fc by CD and subsequent dissociation upon oxidation of Fc.
Figure 3
Figure 3
Size determination of SNPs prepared from CD-PEI and Fc8-PAMAM: SEM images (a–c) of the resulting SNPs as a function of the [Fc]/[CD] ratio (in Fc and CD moieties from Fc8-PAMAM and CD-PEI, respectively) in aqueous solution (without salt) (a: 0, b: 0.5 and c: 1) used during supramolecular assembly keeping constant the total concentration using [CD] = 100 µM and d) d by DLS and size by HRSEM.
Figure 4
Figure 4
DLS size determination of SNPs prepared from CD-PEI and Fc8-PAMAM by increasing the [Fc]/[CD] ratio (in Fc and CD moieties from Fc8-PAMAM and CD-PEI, respectively) at different salt concentrations (0–0.2 M NaCl) keeping constant the total concentration using [CD] = 100 µM after: a) 20 min and b) 3 h.
Figure 5
Figure 5
Hydrodynamic diameter, d, of SNPs prepared from CD-PEI and Fc8-PAMAM or Ad8-PAMAM measured by DLS as a function of the [guest]/([guest] + [CD]) ratio for: a) CD-PEI and Fc8-PAMAM [CD + Fc] = 50 µM (in CD and Fc moieties), I = 0.4 M NaCl, with 2 mM native CD measured after 10 min, and b) CD-PEI and Ad8-PAMAM [CD + Ad] = 200 µM (in CD and Ad moieties), I = 0.2 M NaCl, with 2.0 mM native CD measured after 6 min.
Figure 6
Figure 6
DLS size determinations of SNPs prepared from CD-PEI, Fc8-PAMAM, in the absence or presence of a monovalent stopper, for two [Fc]/[CD] ratios (in Fc and CD moieties from Fc8-PAMAM and CD-PEI, respectively) keeping constant both [CD] = [Fc] + [stopper] = 100 uM (where [stopper] is the concentration of the monovalent stopper), using 0.2 M NaCl and different stoppers: Ad-PEG, mPEG (no guest moiety), Fc-PEG, Ad-TEG and without stabilizer after: a) 20 min and b) 4 h.
Figure 7
Figure 7
Size determinations of SNPs prepared from CD-PEI, Fc8-PAMAM and Ad-PEG: SEM images (a–c) of the resulting SNPs by increasing [Fc]/[CD] ratios (in Fc and CD moieties from Fc8-PAMAM and CD-PEI, respectively) using 0.2 M NaCl (a: 0.375, b: 0.50 and c: 0.625) used during supramolecular assembly using [CD] = 100 μM and CD:(Ad + Fc) stoichiometry, and DLS data (d–f) after: d) 20 min, e) 4 h and f) 7 days.
Figure 8
Figure 8
DLS size determination before (red) and after the addition of the oxidant agent Ce4+ (green) for as-prepared SNPs: a) [CD] = 100 µM (in CD moieties from CD-PEI) [Fc] = 50 µM (in Fc moieties from Fc8-PAMAM) and [Ad] = 50 µM (from Ad-PEG) and b) [CD] = 100 µM and [Ad] = 37.5 µM (in Ad moieties from Ad8-PAMAM) and [Ad] = 62.5 µM (from Ad-PEG) (control) in 0.2 M NaCl. 10 equiv of Ce4+relative to Fc was added to the SNPs. Experimental d measurements (markers) and trendlines (line, guide to the eye).
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