Polymer particles that switch shape in response to a stimulus

Abstract

Particle engineering for biomedical applications has unfolded the roles of attributes such as size, surface chemistry, and shape for modulating particle interactions with cells. Recently, dynamic manipulation of such key properties has gained attention in view of the need to precisely control particle interaction with cells. With increasing recognition of the pivotal role of particle shape in determining their biomedical applications, we report on polymeric particles that are able to switch their shape in real time in a stimulus-responsive manner. The shape-switching behavior was driven by a subtle balance between polymer viscosity and interfacial tension. The balance between the two forces was modulated by application of an external stimulus chosen from temperature, pH, or chemical additives. The dynamics of shape switch was precisely controlled over minutes to days under physiological conditions. Shape-switching particles exhibited unique interactions with cells. Elliptical disk-shaped particles that are not phagocytosed by macrophages were made to internalize through shape switch, demonstrating the ability of shape-switchable particles in modulating interaction with cells.

Fig. 1.

Design of stimulus-responsive shape-switchable PLGA particles. (A) Mechanism of shape switch. The balance between viscosity of polymer (μ) and interfacial tension (σ) between the particle and surrounding media determines the extent and dynamics of shape switch. When the interfacial tension overwhelms the polymer viscosity, an ED undergoes shape switch to a sphere in response to temperature (T), environmental pH, and chemicals (C). (B) Shape switching of PLGA particles (see also Movie S1). PLGA-ester EDs [molecular mass ∼5.2 kDa, T_g(mid) = 28 °C, AR = 5, switched in deionized water at 37 °C] (Left: 0 min; Center: 2 min; Right: 5 min). (Scale bar: 5 μm.) (C) For Newtonian fluids, shape switching can be described by the quasi-steady Stokes equation, and the scaling factor for shape switch (τ) is given by Eq. 1.

Fig. 2.

Shape switching via temperature-induced change of polymer viscosity. (A) SEM images of shape-switching PLGA particles with different molecular masses. PLGA-ester EDs [Top, molecular mass 29.8 kDa, T_g(mid) = 40 °C, AR = 5.5 (scale bar: 5 μm)]; [Middle, molecular mass 52.7 kDa, T_g(mid) = 43 °C, AR = 5.5 (scale bar: 5 μm)]; and [Bottom, molecular mass 29.8 kDa, T_g(mid) = 40 °C, AR = 4 (scale bar: 500 nm)] were incubated at their mid-T_gs. (Scale bar: 5 μm.) (B) AR of the EDs decreased nearly exponentially to 1 (sphere) in a molecular-mass-dependent manner at their mid-T_g (closed squares: molecular mass 29.8 kDa; open squares: molecular mass 52.7 kDa). Higher molecular mass particles went through slower shape switch (T_1/2) because of their higher viscosity. (C) Temperature-responsive shape switching of PLGA-ester EDs (molecular mass 29.8 kDa). Whereas shape switch slowly occurred at onset T_g (32 °C), the T_1/2 remarkably decreased at a temperature 10 °C above mid-T_g. (D) Size-dependent shape switch of PLGA-ester EDs (molecular mass 29.8 kDa). The T_1/2 increased as the initial sphere’s particle size increased.

Fig. 3.

pH-induced shape switch of PLGA particles. (A) The shape-switching study was performed in a buffer solution at pH 7.4 at 37 °C by using PLGA-acid EDs [molecular mass 4.1 kDa, T_g(mid) = 27 °C, AR = 4]. There was no detectable shape switch at pH 7.4 because of low interfacial tension of hydrophilic surface originating from ionized acid end groups. Shape switch occurred upon pH reduction, which led to protonation of the acid end and exhibited a near-exponential decrease of AR. Data are shown as mean ± SEM (n > 30). (B) The T_1/2 of PLGA-acid EDs (molecular mass 4.1 kDa) depended strongly on pH. The T_1/2 gradually increased as pH increased from 3.0 to 4.5 and abruptly increased above pH 5.0. (C) Whereas PLGA-acid EDs showed over 10,000-fold increase of T_1/2 from pH 4 to 7.4, PLGA-ester ED [molecular mass 6.5 KDa, T_g(mid) = 28 °C, AR = 4] switched shape quickly (T_1/2 < 1 min) at both pHs, indicating that there was negligible change in the interfacial tension on PLGA-ester particles by pH.

Fig. 4.

Chemical-induced shape switch. PLGA-acid EDs [molecular mass 4.1 kDa, T_g(mid) = 27 °C, AR = 4] were incubated at pH 7.4 and 37 °C. Cationic Azure C possessing a hydrophobic group was used as a trigger for shape switch. (A) PLGA-acid particles, whose shape remained the same, started switching shape upon exposure to Azure C (2 femtomoles per particle), indicating that Azure C binds to particles and reduces the interfacial tension. AR decreased nearly exponentially. Data are shown as mean ± SEM (n > 30). (b) The Azure C-induced shape switch was concentration-dependent up to 5 femtomole per particle, above which the effect seemed to have saturated. (C) Fold difference in the characteristic switch time between Azure C-treated and nontreated EDs. The degree of shape switch by Azure C was higher at high pH than at low pH because of greater availability of Azure C binding sites (i.e., ionized end carboxylic acids) on the particles at higher pH.

Fig. 5.

Time-lapse video microscopy clips of shape-dependent phagocytosis by macrophage. (A) A shape-switching PLGA-ester ED (mixture of two PLGAs, AR = 5) was initially attached on a macrophage and not phagocytosed. The macrophage then quickly internalized the particle once shape switched to near-sphere shape. (B) Macrophage spread on a PLGA-acid ED [molecular mass 4.1 kDa, T_g(mid) = 27 °C, AR = 5], which do not switch shape at pH 7.4, but could not complete phagocytosis. All particles were opsonized with mouse IgG before the experiments. (Scale bar: 10 μm.)