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Shape and responsiveness of nanoengineered delivery carriers are crucial characteristics for rapid and efficient delivery of therapeutics. We report on a novel type of micrometer-sized hydrogel particles of controlled shape with dual pH- and redox-sensitivity for intracellular delivery of anticancer drugs. The cubical and spherical poly(methacrylic acid) (PMAA) networks with disulfide links are obtained by cross-linking PMAA with cystamine within hydrogen-bonded multilayers of PMAA/poly(vinylpyrrolidone) (PMAA/PVPON) on sacrificial mesoporous templates. The pH-triggered hydrogel swelling/shrinkage not only affords effective doxorubicin entrapment but also efficient endosomal/lysosomal escape, and redox-triggered degradation provides drug release into the cytosolic space. The hydrogels degrade rapidly to low molecular weight chains in the presence of the typical intracellular concentration of glutathione, which should ensure a rapid renal clearance in vivo. Particle shape is found to affect internalization at the initial step of cell-particle interactions. Drug-loaded spherical particles are found to be 12% more cytotoxic than the corresponding cubes within the first 10 h of cell incubation suggesting more rapid internalization of spheres. Both doxorubicin-loaded hydrogel cubes and spheres demonstrate 50% and 90% cytotoxicity when incubated with HeLa cancer cells for 24 and 48 h, respectively. The presented approach integrates the advantages of pH-sensitivity, enzymatic degradation, and shape-regulated internalization for novel types of "intelligent" three-dimensional networks with programmable behavior for use in controlled delivery of therapeutics.

We demonstrated a simple and facile approach to fabricate biocompatible monodisperse hollow microparticles of controlled geometry. The hemispherical, spherical, and cubical microparticles are obtained by drying multilayer capsules of hydrogen-bonded poly(N-vinylpyrrolidone)/tannic acid (PVPON/TA)n. Drying spherical capsules results in hemispherical particles if 15 < n < 20. This shape transformation is controlled by capsule stiffness, which is regulated by the layer number, capsule diameter, and PVPON molecular weight. Cubical and spherical hollow particles maintaining their three-dimensional shapes in the dry state are obtained if n ≥ 25.5. A 17-fold stiffness increase is required to lead from totally collapsed (PVPON/TA)5.5 to dried self-supporting (PVPON/TA)25.5 particles of 2 μm in dimensions. All hollow particles could be further resuspended in aqueous solutions while retaining their shapes upon rehydration. The cell growth and viability studies using human cancer cells revealed noncytotoxic properties of the (PVPON/TA) multilayer particles. Both spherical and hemispherical capsules were internalized by macrophages with the uptake of the hemispherical particles per cell two times more efficient. The method presented here allows for a robust preparation of biocompatible shaped particles whose shape and dimensions can be easily tuned by controlling capsule size and wall thickness. The reported structures can be potentially useful for biomedical applications such as shape-controlled cellular uptake and flow dynamics.