Protease-Mediated T1 Contrast Enhancement of Multilayered Magneto-Gadolinium Nanostructures for Imaging and Magnetic Hyperthermia.

In this work, we constructed a multifunctional composite nanostructure for combined magnetic hyperthermia therapy and magnetic resonance imaging based on T1 and T2 signals. First, iron oxide nanocubes with a benchmark heating efficiency for magnetic hyperthermia were assembled within an amphiphilic polymer to form magnetic nanobeads. Next, poly(acrylic acid)-coated inorganic sodium gadolinium fluoride nanoparticles were electrostatically loaded onto the magnetic nanobead surface via a layer-by-layer approach by employing a positively charged enzymatic-cleavable biopolymer. The positive-negative multilayering process was validated through the changes occurring in surface ζ-potential values and structural characterization by transmission electron microscopy (TEM) imaging. These nanostructures exhibit an efficient heating profile, in terms of the specific absorption rates under clinically accepted magnetic field conditions. The addition of protease enzyme mediates the degradation of the surface layers of the nanostructures with the detachment of gadolinium nanoparticles from the magnetic beads and exposure to the aqueous environment. Such a process is associated with changes in the T1 relaxation time and contrast and a parallel decrease in the T2 signal. These structures are also nontoxic when tested on glioblastoma tumor cells up to a maximum gadolinium dose of 125 µg mL-1, which also corresponds to a iron dose of 52 µg mL-1. Nontoxic nanostructures with such enzyme-triggered release mechanisms and T1 signal enhancement are desirable for tracking tumor microenvironment release with remote T1-guidance and magnetic hyperthermia therapy actuation to be done at the diseased site upon verification of magnetic resonance imaging (MRI)-guided release.

Highly Emitting Perovskite Nanocrystals with 2-Year Stability in Water through an Automated Polymer Encapsulation for Bioimaging.

Lead-based halide perovskite nanocrystals are highly luminescent materials, but their sensitivity to humid environments and their biotoxicity are still important challenges to solve. Here, we develop a stepwise approach to encapsulate representative CsPbBr3 nanocrystals into water-soluble polymer capsules. We show that our protocol can be extended to nanocrystals coated with different ligands, enabling an outstanding high photoluminescence quantum yield of ∼60% that is preserved over two years in capsules dispersed in water. We demonstrate that this on-bench strategy can be implemented on an automated platform with slight modifications, granting access to a faster and more reproducible fabrication process. Also, we reveal that the capsules can be exploited as photoluminescent probes for cell imaging at a dose as low as 0.3 µgPb/mL that is well below the toxicity threshold for Pb and Cs ions. Our approach contributes to expanding significantly the fields of applications of these luminescent materials including biology and biomedicine.

Magnetic nanoparticles and clusters for magnetic hyperthermia: optimizing their heat performance and developing combinatorial therapies to tackle cancer.

Magnetic hyperthermia (MHT) is a therapeutic modality for the treatment of solid tumors that has now accumulated more than 30 years of experience. In the ongoing MHT clinical trials for the treatment of brain and prostate tumors, iron oxide nanoparticles are employed as intra-tumoral MHT agents under a patient-safe 100 kHz alternating magnetic field (AMF) applicator. Although iron oxide nanoparticles are currently approved by FDA for imaging purposes and for the treatment of anemia, magnetic nanoparticles (MNPs) designed for the efficient treatment of MHT must respond to specific physical-chemical properties in terms of magneto-energy conversion, heat dose production, surface chemistry and aggregation state. Accordingly, in the past few decades, these requirements have boosted the development of a new generation of MNPs specifically aimed for MHT. In this review, we present an overview on MNPs and their assemblies produced via different synthetic routes, focusing on which MNP features have allowed unprecedented heating efficiency levels to be achieved in MHT and highlighting nanoplatforms that prevent magnetic heat loss in the intracellular environment. Moreover, we review the advances on MNP-based nanoplatforms that embrace the concept of multimodal therapy, which aims to combine MHT with chemotherapy, radiotherapy, immunotherapy, photodynamic or phototherapy. Next, for a better control of the therapeutic temperature at the tumor, we focus on the studies that have optimized MNPs to maintain gold-standard MHT performance and are also tackling MNP imaging with the aim to quantitatively assess the amount of nanoparticles accumulated at the tumor site and regulate the MHT field conditions. To conclude, future perspectives with guidance on how to advance MHT therapy will be provided.

Uncovering the Magnetic Particle Imaging and Magnetic Resonance Imaging Features of Iron Oxide Nanocube Clusters.

Multifunctional imaging nanoprobes continue to garner strong interest for their great potential in the detection and monitoring of cancer. In this study, we investigate a series of spatially arranged iron oxide nanocube-based clusters (i.e., chain-like dimer/trimer, centrosymmetric clusters, and enzymatically cleavable two-dimensional clusters) as magnetic particle imaging and magnetic resonance imaging probes. Our findings demonstrate that the short nanocube chain assemblies exhibit remarkable magnetic particle imaging signal enhancement with respect to the individually dispersed or the centrosymmetric cluster analogues. This result can be attributed to the beneficial uniaxial magnetic dipolar coupling occurring in the chain-like nanocube assembly. Moreover, we could effectively synthesize enzymatically cleavable two-dimensional nanocube clusters, which upon exposure to a lytic enzyme, exhibit a progressive increase in magnetic particle imaging signal at well-defined incubation time points. The increase in magnetic particle imaging signal can be used to trace the disassembly of the large planar clusters into smaller nanocube chains by enzymatic polymer degradation. These studies demonstrate that chain-like assemblies of iron oxide nanocubes offer the best spatial arrangement to improve magnetic particle imaging signals. In addition, the nanocube clusters synthesized in this study also show remarkable transverse magnetic resonance imaging relaxation signals. These nanoprobes, previously showcased for their outstanding heat performance in magnetic hyperthermia applications, have great potential as dual imaging probes and could be employed to improve the tumor thermo-therapeutic efficacy, while offering a readable magnetic signal for image mapping of material disassemblies at tumor sites.

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.