Synthesis and Preliminary <i>in Vivo</i> Evaluation of Well-Dispersed Biomimetic Nanocrystalline Apatites Labeled with Positron Emission Tomographic Imaging Agents

Abstract

In recent years, biomimetic synthetic apatite nanoparticles (AP-NPs), having chemical similarity with the mineral phase of bone, have attracted a great interest in nanomedicine as potential drug carriers. To evaluate the therapeutic perspectives of AP-NPs through the mechanisms of action and organs they interact with, the noninvasive monitoring of their <i>in vivo</i> behavior is of paramount importance. To this aim, here the feasibility to radiolabel AP-NPs (“naked” and surface-modified with citrate to reduce their aggregation) with two positron emission tomographic (PET) imaging agents ([¹⁸F]­NaF and ⁶⁸Ga-NO2AP^BP) was investigated. [¹⁸F]­NaF was used for the direct incorporation of the radioisotope into the crystal lattice, while the labeling by surface functionalization was accomplished by using ⁶⁸Ga-NO2AP^BP (a new radio-metal chelating agent). The labeling results with both tracers were fast, straightforward, and reproducible. AP-NPs demonstrated excellent ability to bind relevant quantities of both radiotracers and good <i>in vitro</i> stability in clinically relevant media after the labeling. <i>In vivo</i> PET studies in healthy Wistar rats established that the radiolabeled AP-NPs gave significant PET signals and they were stable over the investigated time (90 min) since any tracer desorption was detected. These preliminary <i>in vivo</i> studies furthermore showed a clear ability of citrated versus naked AP-NPs to accumulate in different organs. Interestingly, contrary to naked AP-NPs, citrated ones, which unveiled higher colloidal stability in aqueous suspensions, were able to escape the first physiological filter, i.e., the lungs, being then accumulated in the liver and, to a lesser extent, in the spleen. The results of this work, along with the fact that AP-NPs can be also functionalized with targeting ligands, with therapeutic agents, and also with metals for a combination of different imaging modalities, make AP-NPs very encouraging materials for further investigations as theranostic agents in nanomedicine