Order-Order Morphological Transitions for Dual Stimulus Responsive Diblock Copolymer Vesicles

Abstract

A series of non-ionic poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) (PGMA-PHPMA) diblock copolymer vesicles has been prepared by reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of HPMA at 70 °C at low pH using a carboxylic acid-based chain transfer agent. The degree of polymerization (DP) of the PGMA block was fixed at 43, and the DP of the PHPMA block was systematically varied from 175 to 250 in order to target vesicle phase space. Based on our recent work describing the analogous PGMA-PHPMA diblock copolymer worms [Lovett J. R.; Angew. Chem.2015, 54, 1279-1283], such diblock copolymer vesicles were expected to undergo an order-order morphological transition via ionization of the carboxylic acid end-group on switching the solution pH. Indeed, irreversible vesicle-to-sphere and vesicle-to-worm transitions were observed for PHPMA DPs of 175 and 200, respectively, as judged by turbidimetry, transmission electron microscopy (TEM), and dynamic light scattering (DLS) studies. However, such morphological transitions are surprisingly slow, with relatively long time scales (hours) being required at 20 °C. Moreover, no order-order morphological transitions were observed for vesicles comprising longer membrane-forming blocks (e.g., PGMA₄₃-PHPMA_225-250) on raising the pH from pH 3.5 to pH 6.0. However, in such cases the application of a dual stimulus comprising the same pH switch immediately followed by cooling from 20 to 5 °C, induces an irreversible vesicle-to-sphere transition. Finally, TEM and DLS studies conducted in the presence of 100 mM KCl demonstrated that the pH-responsive behavior arising from end-group ionization could be suppressed in the presence of added electrolyte. This is because charge screening suppresses the subtle change in the packing parameter required to drive the morphological transition.

Figure 1

(a) Synthesis of a HOOC-PGMA₄₃ macro-CTA via RAFT solution polymerization of GMA using a 4-cyano-4-(2-phenylethanesulfanylthiocarbonyl)sulfanylpentanoic acid (PETTC) RAFT agent and its subsequent chain extension with HPMA via RAFT aqueous dispersion polymerization to prepare a series of HOOC-PGMA₄₃–PHPMA_X diblock copolymer vesicles at pH 3.5 (where X = 175–250). (b) Illustration of the irreversible vesicle-to-sphere or vesicle-to-worm order–order transitions that occur when the terminal carboxylic acid on the PGMA stabilizer block becomes ionized as a result of a pH switch.

Figure 2

DMF GPC curves obtained for a HOOC-PGMA₄₃ macro-CTA (black curve) and the corresponding HOOC-PGMA₄₃–PHPMA_X diblock copolymer vesicles (where X = 175–250). In all cases high blocking efficiencies (>95%) and low final copolymer polydispersities (M_w/M_n < 1.20) were obtained.

Figure 3

TEM images (recorded after dilution to 0.10% w/w solids using an aqueous solution of either pH 3.5 or pH 6.0) and corresponding digital photographs obtained for HOOC-PGMA₄₃–PHPMA_X diblock copolymer nano-objects: (a) at pH 3.5 and (b) at pH 6.0.

Figure 4

Variation of intensity-average hydrodynamic particle diameter (measured by dynamic light scattering) and zeta potential with dispersion pH (starting at pH 3.5) recorded at 25 °C for 0.1% w/w aqueous dispersions of (a) HOOC-PGMA₄₃–PHPMA₁₇₅ vesicles, (b) HOOC-PGMA₄₃–PHPMA₂₀₀ vesicles, (c) HOOC-PGMA₄₃–PHPMA₂₂₅ vesicles, and (d) HOOC-PGMA₄₃–PHPMA₂₅₀ vesicles.

Figure 5

Change in transmittance % at a fixed wavelength of 450 nm for 0.10% w/w aqueous dispersions of HOOC-PGMA₄₃–PHPMA_175–250 nano-objects over 20 h at 20 °C after a pH switch from pH 3.5 to pH 9.0 using KOH.

Figure 6

(a) Variation of the hydrodynamic particle diameter measured by dynamic light scattering with dispersion pH recorded for 0.1% w/w aqueous dispersions of HOOC-PGMA₄₃–PHPMA₁₇₅ diblock copolymer vesicles starting at pH 3.5 in the absence of salt (open blue circles) and in the presence of 100 mM KCl (closed red circles). TEM images obtained for HOOC-PGMA₄₃–PHPMA₁₇₅ diblock copolymer nano-objects in the presence of 100 mM KCl salt at (b) pH 3.5 and (c) pH 6.0 and in the absence of salt at (d) pH 3.5 and (e) pH 6.0.

Figure 7

Variation of the storage modulus (G′, denoted by full circles) and loss modulus (G″, denoted by open circles) for a 10% w/w aqueous dispersion of HOOC-PGMA₄₃–PHPMA₂₀₀ diblock copolymer nano-objects as a function of temperature, after a pH switch from 3.5 to 6.0 to induce a vesicle-to-worm transition. In each case, the blue data represent decreasing temperature and the red data represent increasing temperature. Conditions: 1.0 rad s^–1 angular frequency at an applied strain of 1.0%.

Figure 8

TEM images (for grids prepared at 5 °C after dilution to 0.10% w/w copolymer at pH 3.5) and corresponding digital photographs obtained for HOOC-PGMA₄₃–PHPMA_X diblock copolymer nano-objects for X = 175, 200, 225, or 250.

Figure 9

Representative TEM images obtained for HOOC-PGMA₄₃-PHPMA_X dispersions after dilution at 5 °C to dilution to 0.10% w/w copolymer at pH 6.5 and (inset) the corresponding digital photographs of their visual appearance at 10% w/w copolymer.