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

Abstract

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.

Structured Macroporous Hydrogels: Progress, Challenges, and Opportunities

“…Finally, Kharlampieva and co-workers also used an LbL deposition in order to coat sacrificial mesoporous Mn 2 O 3 particles with poly (methacrylic acid) (PMAA) and poly (vinylpyrrolidone) (PVP). [49,50] The Mn 2 O 3 particles were dissolved in HCl to facilitate removal, following which the hollow hydrogel capsules were loaded with doxorubicin for targeted intracellular drug delivery to HeLa cells. [49] Porogen-based techniques, while widely used, do present significant limitations.…”

“…[49,50] The Mn 2 O 3 particles were dissolved in HCl to facilitate removal, following which the hollow hydrogel capsules were loaded with doxorubicin for targeted intracellular drug delivery to HeLa cells. [49] Porogen-based techniques, while widely used, do present significant limitations. Complete removal of the degraded polymer fractions from the gel network ultimately remains challenging Figure 1.…”

Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes

“…In the case of non-porous templates, LbL assembly leads to hydrogel capsules with an interior cavity and nanothin walls, while alternating deposition of polymers inside porous templates results in nano-porous particles of interconnected macromolecular networks [37–40]. In the spirit of this concept we have recently demonstrated the synthesis of temperature- and pH-responsive nano-porous hydrogel microcapsules [41–43] and microparticles [37,38] of cubical shape. The cubic poly(methacrylic acid) (PMAA) hydrogel microparticles in this study were produced by sequential LbL infiltration of PMAA and poly(N-vinylpyrrolidone) (PVPON) inside 2 μm porous cubic templates [37,38].…”

Carbohydrate polymer based pH-sensitive IPN microgels: Synthesis, characterization and drug release characteristics

“…Over the past decades, different polymeric therapeutics have begun to make a vital contribution for tumor targeting in cancer therapy. In cancer drug delivery, different polymer based hydrogels have been designed and demonstrated as drug carrier systems [4] [5] [6,7] [8]. Among the several polymeric systems developed, systems containing biodegradable polymers have been used for localized drug delivery to control therapeutic drug level over a period of months, since the degradation of polymer is slow [9].…”