Internalization of Red Blood Cell-Mimicking Hydrogel Capsules with pH-Triggered Shape Responses

Abstract

We report on naturally inspired hydrogel capsules with pH-induced transitions from discoids to oblate ellipsoids and their interactions with cells. We integrate characteristics of erythrocytes such as discoidal shape, hollow structure, and elasticity with reversible pH-responsiveness of poly(methacrylic acid) (PMAA) to design a new type of drug delivery carrier to be potentially triggered by chemical stimuli in the tumor lesion. The capsules are fabricated from cross-linked PMAA multilayers using sacrificial discoid silicon templates. The degree of capsule shape transition is controlled by the pH-tuned volume change, which in turn is regulated by the capsule wall composition. The (PMAA)15 capsules undergo a dramatic 24-fold volume change, while a moderate 2.3-fold volume variation is observed for more rigid PMAA–(poly(N-vinylpyrrolidone) (PMAA–PVPON)5 capsules when solution pH is varied between 7.4 and 4. Despite that both types of capsules exhibit discoid-to-oblate ellipsoid transitions, a 3-fold greater swelling in radial dimensions is found for one-component systems due to a greater degree of the circular face bulging. We also show that (PMAA–PVPON)5 discoidal capsules interact differently with J774A.1 macrophages, HMVEC endothelial cells, and 4T1 breast cancer cells. The discoidal capsules show 60% lower internalization as compared to spherical capsules. Finally, hydrogel capsules demonstrate a 2-fold decrease in size upon internalization. These capsules represent a unique example of elastic hydrogel discoids capable of pH-induced drastic and reversible variations in aspect ratios. Considering the RBC-mimicking shape, their dimensions, and their capability to undergo pH-triggered intracellular responses, the hydrogel capsules demonstrate considerable potential as novel carriers in shape-regulated transport and cellular uptake.

Intracellular Degradable Hydrogel Cubes and Spheres for Anti-Cancer Drug Delivery

“…This agrees with previous reports on PMAA-based micro/ nanogels 16,23,54 and hydrogel capsules 36,59 where cross-linker type and synthesis method did not affect the cytocompatibility of the delivery systems.…”

Loading Capacity versus Enzyme Activity in Anisotropic and Spherical Calcium Carbonate Microparticles

“…Alteration of biological responses was reported for particles with similar compositions, but with different geometries [12][13][14] entering the bio-distribution pathways [15][16][17] . Not only were capsules produced by various anisotropic shapes, but they were also shown to change shape in the case of hydrogel-based containers 13,18,19 . Inhalation is viewed as a particularly important area of medical application of anisotropic particles because of their favourable hydrodynamic properties.…”

Photo‐Cross‐Linked Dual‐Responsive Hollow Capsules Mimicking Cell Membrane for Controllable Cargo Post‐Encapsulation and Release

“…The design of artificial cell membrane was among the first subject to be studied2, 3, 4, 5, 6, 7, 8 for selective uptake and release of (bio)molecules and particles as key characteristics of cellular compartments controlling intra‐ and intercellular signaling processes.…”