Dihydrocaffeic Acid-Decorated Iron Oxide Nanomaterials Effectively Inhibit Human Calcitonin Aggregation

Abstract

To date, more than 30 human peptides or proteins have been found to form amyloid fibrils, most of which are associated with human diseases. However, currently, no cure for amyloidosis exists. Therefore, development of therapeutic strategies to inhibit amyloid formation is urgently required. Although the role of some amyloidogenic proteins has not been identified in certain diseases, their self-assembling behavior largely affects their bioactivity. Human calcitonin (hCT) is a hormone peptide containing 32 amino acids and is secreted by the parafollicular cells of the thyroid gland in the human body. It can regulate the concentration of calcium ions in the blood and block the activity of osteoclasts. Therefore, calcitonin has also been considered a therapeutic peptide. However, the aggregation of hCT hinders this process, and hCT has been replaced by salmon calcitonin in drug formulations. Recently, iron oxide nanomaterials have been developed as potential materials for various applications owing to their high biocompatibility, low toxicity, and ease of functionalization. In this study, nanoparticles (NPs) were prepared using a simple chemical coprecipitation method. We first demonstrated that dopamine-conjugated Fe 3 O 4 inhibited hCT aggregation, similar to what we found when carbon dots were used as core materials in the previous study. Later, we continued to simplify the preparation process, that is, the mixing of dihydrocaffeic acid (DCA) and iron oxide NPs, to maintain their stability and inhibitory effect against hCT aggregation. Furthermore, DCA-decorated Fe 3 O 4 can dissociate preformed hCT amyloid fibrils. This appears to be one of the most promising ways to stabilize hCT in solution and may be helpful for amyloidosis treatment.

Synthesis of Fe3O4-Chlorophyllin Nanoparticles for Preventing Amyloid Formation by Human Calcitonin

“…Dihydrocaffeic acid forms stable complexes with iron-oxide nanoparticles through its catechol and carboxylic acid ligands via an adsorption mechanism, and it achieves better efficacy than bare ironoxide nanoparticles. 30 In our past examinations, the appropriate concentration of both nanomaterials to achieve an effective inhibitory effect on 64 μM hCT was approximately 200 μg/mL. Herein, we found that the required concentration of porphyrin derivative-coated nanoparticles was even lower than that of the first two generations of nanomaterials, suggesting that Fe 3 O 4 -Chl/Fe would be more suitable for drug formulation.…”

“…In our previous study, we showed that dopamine and dihydrocaffeic acid, but not their oxidized forms, can inhibit hCT amyloid formation. 30 In addition to molecules extracted from plants, heme, a porphyrin ring complexed with ferrous iron particularly found in mammals, has been shown to suppress amyloid aggregation. 49 The porphyrin macrocycle has been demonstrated as an essential component that contributes to the inhibitory effect of heme.…”

“…40 Although whether it is still more sensitive than ThT in detecting hCT amyloids was not understood, we demonstrated that Bis-ANS distinguishes hCT monomers and fibrils in a previous study. 30 Here, we added Bis-ANS and Nile red to hCT samples after 12 h of incubation. We observed that Bis-ANS exhibited a strong increase in fluorescence at 500 nm for hCT fibrils.…”

“…Recent data suggest that nanomaterials are potential inhibitors of amyloid formation and can be a therapeutic approach in amyloidosis. − We and others have previously demonstrated that appropriate particle surface functionalization allows nanomaterials to interact with proteins and block protein aggregation. , Porphyrins and their derivatives are excellent biological ligands. The most common examples are heme, chlorophylls, and bacteriochlorophylls.…”

Post-thyroidectomy hypocalcemia and related complications

“…Calcitonin, a polypeptide consisting of 32 amino acids, is synthesized by the parafollicular cells of the thyroid gland (Giannetta et al, 2020;Shen, Wu, Zhang, & Tu, 2022). It induces a decrease in calcemia, inhibiting bone resorption by osteoclasts and increasing renal excretion of this ion (Xie et al, 2020).…”