pH-Triggered reversible morphological inversion of orthogonally-addressable poly(3-acrylamidophenylboronic acid)-block-poly(acrylamidoethylamine) micelles and their shell crosslinked nanoparticles

Abstract

Functionally-responsive amphiphilic core-shell nanoscopic objects, capable of either complete or partial inversion processes, were produced by the supramolecular assembly of pH-responsive block copolymers, without or with covalent crosslinking of the shell layer, respectively. A new type of well-defined, dual-functionalized boronic acid- and amino-based diblock copolymer poly(3-acrylamidophenylboronic acid)(30)-block-poly(acrylamidoethylamine)(25) (PAPBA(30)-b-PAEA(25)) was synthesized by sequential reversible addition-fragmentation chain transfer (RAFT) polymerization and then assembled into cationic micelles in aqueous solution at pH 5.5. The micelles were further cross-linked throughout the shell domain comprised of poly(acrylamidoethylamine) by reaction with a bis-activated ester of 4,15-dioxo-8,11-dioxa-5,14-diazaoctadecane-1,18-dioic acid, upon increase of the pH to 7, to different cross-linking densities (2%, 5% and 10%), forming well-defined shell cross-linked nanoparticles (SCKs) with hydrodynamic diameters of ca. 50 nm. These smart micelles and SCKs presented switchable cationic, zwitterionic and anionic properties, and existed as stable nanoparticles with high positive surface charge at low pH (pH = 2, zeta potential ~ +40 mV) and strong negative surface charge at high pH (pH = 12, zeta potential ~ -35 mV). (1)H NMR spectroscopy, X-ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS), transmission electron microscopy (TEM), atomic force microscopy (AFM), and zeta potential, were used to characterize the chemical compositions, particle sizes, morphologies and surface charges. Precipitation occurred near the isoelectric points (IEP) of the polymer/particle solutions, and the IEP values could be tuned by changing the shell cross-linking density. The block copolymer micelles were capable of full reversible morphological inversion as a function of pH, by orthogonal protonation of the PAEA and hydroxide association with the PAPBA units, whereas the SCKs underwent only reptation of the PAPBA chain segments through the crosslinked shell of PAEA as the pH was elevated. Further, these nanomaterials also showed D-glucose-responsive properties.

Fig. 1

GPC traces of pinacol-protected PAPBA₃₀, 3, and PAPBA₃₀-b-PAEANBoc₂₅, 6.

Fig. 2

¹H NMR spectra (300 MHz, D₂O) of PAPBA₃₀-b-PAEA₂₅, 1, as amphiphilic micellar assemblies and czaSCKs at 2%, 5% and 10% cross-linking density at pH 2 (upper four spectra) and at pH 12 (lower four spectra). Trimethylsilyl propanoic acid-d₄ (TSP) was used as an internal standard.

Fig. 3

Zeta potential changes of micelles as a function of pH, for samples having the pH adjusted from acidic to basic (red circles) and basic to acidic (black squares). Error bars represent standard deviations of 5 runs. The pH change of each data point during the measurements was less than ± 0.1.

Fig. 4

Volume-based hydrodynamic diameter (D_h)_v change as a function of pH. Error bars represent standard deviations of 5 runs. The pH change of each data point during the measurements was less than ± 0.1.

Fig. 5

Zeta potential and (D_h)_v changes for czaSCKs at 2%, 5% and 10% cross-linking densities as a function of pH. Error bars represent standard deviations of 5 runs. The pH change of each data point during the measurements was less than ± 0.1.

Fig. 6

TEM images for non-cross-linked micelles and czaSCKs deposited from aqueous solutions at different pH values onto carbon-coated copper grids and allowed to dry under ambient conditions: a) non-cross-linked micelles at pH 2; b) non-cross-linked micelles at pH 7.3; c) non-cross-linked micelles at pH 10.5; d) 2% cross-linked czaSCKs at pH 2; e) 5% cross-linked czaSCKs at pH 2; f) 10% cross-linked czaSCKs at pH 2; g) 2% cross-linked czaSCKs at pH 12; h) 5% cross-linked czaSCKs at pH 12; i) 10% cross-linked czaSCKs at pH 12. Samples imaged as a,b,c,e,f,g,h were negatively stained by uranyl acetate; d and i were stained by phosphotungstic acid.

Fig. 7

Tapping-mode AFM images for 10 % czaSCKs drop deposited from aqueous solutions at pH 2 a) and pH 12 b) onto freshly-cleaved mica and allowed to dry under ambient conditions.

Fig. 8

Zeta potential changes of non-cross-linked micelles as a function of pH with a) 5 eq of D-glucose; b) 15 eq of D-glucose.

Scheme 1

Synthesis of PAPBA₃₀-b-PAEA₂₅ by sequential RAFT polymerizations and acidolysis.

Scheme 2

pH-triggered reversible morphology and charge inversion of micelles and SCKs.