Esterase-Cleavable 2D Assemblies of Magnetic Iron Oxide Nanocubes: Exploiting Enzymatic Polymer Disassembling To Improve Magnetic Hyperthermia Heat Losses

Here, we report a nanoplatform based on iron oxide nanocubes (IONCs) coated with a bioresorbable polymer
that, upon exposure to lytic enzymes, can be disassembled increasing the heat performances in comparison with the initial
clusters. We have developed two-dimensional (2D) clusters by exploiting benchmark IONCs as heat mediators for magnetic
hyperthermia and a polyhydroxyalkanoate (PHA) copolymer, a biodegradable polymer produced by bacteria that can be
digested by intracellular esterase enzymes. The comparison of magnetic heat performance of the 2D assemblies with 3D
centrosymmetrical assemblies or single IONCs emphasizes the benefit of the 2D assembly. Moreover, the heat losses of 2D
assemblies dispersed in water are better than the 3D assemblies but worse than for single nanocubes. On the other hand, when
the 2D magnetic beads (2D-MNBs) are incubated with the esterase enzyme at a physiological temperature, their magnetic heat
performances began to progressively increase. After 2 h of incubation, specific absorption rate values of the 2D assembly double
the ones of individually coated nanocubes. Such an increase can be mainly correlated to the splitting of the 2D-MNBs into
smaller size clusters with a chain-like configuration containing few nanocubes. Moreover, 2D-MNBs exhibited nonvariable heat
performances even after intentionally inducing their aggregation. Magnetophoresis measurements indicate a comparable
response of 3D and 2D clusters to external magnets (0.3 T) that is by far faster than that of single nanocubes. This feature is
crucial for a physical accumulation of magnetic materials in the presence of magnetic field gradients. This system is the first
example of a nanoplatform that, upon exposure to lytic enzymes, such as those present in a tumor environment, can be
disassembled from the initial 2D-MNB organization to chain-like assemblies with clear improvement of the heat magnetic losses
resulting in better heat dissipation performances. The potential application of 2D nanoassemblies based on the cleavable PHAs
for preserving their magnetic losses inside cells will benefit hyperthermia therapies mediated by magnetic nanoparticles under
alternating magnetic fields.