Orotracheal administration of contrast agents: a new protocol for brain tumor targeting

Abstract

The development of new non-invasive diagnostic and therapeutic approaches is of paramount importance in order to improve the outcome of patients with glioblastoma (GBM). In this work we investigated a completely non-invasive pre-clinical protocol to effectively target and detect brain tumors through the orotracheal route, using ultra-small nanoparticles (USRPs) and MRI. A mouse model of GBM was developed. In vivo MRI acquisitions were performed before and after intravenous or orotracheal administration of the nanoparticles to identify and segment the tumor. The accumulation of the nanoparticles in neoplastic lesions was assessed ex vivo through fluorescence microscopy. Before the administration of contrast agents, MR images allowed the identification of the presence of abnormal brain tissue in 73% of animals. After orotracheal or intravenous administration of USRPs, in all the mice an excellent co-localization of the position of the tumor with MRI and histology was observed. The elimination time of the USRPs from the tumor after the orotracheal administration was approximately 70% longer compared with intravenous injection. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify and longitudinally monitor the development of GBMs. The absence of ionizing radiation and high resolution of MRI, along with the complete non-invasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge, this is the first time that the advantages of a needle-free orotracheal administration route have been demonstrated for the investigation of the pathomorphological changes due to GBMs.

Orotracheal manganese‐enhanced MRI (MEMRI): An effective approach for lung tumor detection

“…Altogether, these toxicity data from the literature and the non-detectable accumulation of ionic Mn in the brain and liver following orotracheal administration, observed in vivo using a T 1 -weighted UTE MRI sequence, which has been shown previously to be very sensitive to the detection of changes caused by positive contrast agents in the brain, 49 are extremely encouraging with regard to the safety of the orotracheal protocol with low-dose Mn 2+ administration. Nevertheless, further ex vivo studies will be required in the future to quantitatively evaluate the exact amount of Mn accumulation (currently under the detection threshold of MRI) in brain after the orotracheal administration of MnCl 2 to exclude any possible toxic effect.…”

“…Overall, these results support the growing interest in drug and contrast agent delivery via the airways to target and diagnose several diseases of the lungs, 18,53,54 but also of other organs. 49,55 The bulk of the literature seems to suggest that direct pulmonary administration is an effective, simple and reliable route for lung and systemic delivery of drugs. [56][57][58] Further studies are needed to shed light on this efficient and promising administration route.…”

Gadolinium-Based Nanoparticles and Radiation Therapy for Multiple Brain Melanoma Metastases: Proof of Concept before Phase I Trial

“…This phenomenon has previously been reported in brain tumor-bearing animals when the blood brain barrier is damaged. 17 , 22 , 38 Based on the imaging investigations performed on B16F10 brain metastases (Fig 4 c-f), the therapeutic irradiation was performed five days after tumor implantation and at 3.5 hours post IV injection of AGuIX® for highest tumor to healthy tissue ratio. As summarized in Figure 5 c and Table 2 , the pathology is very aggressive without any animals surviving for more than 14 days after tumor implantation for the control group.…”

Ultrasmall AGuIX theranostic nanoparticles for vascular-targeted interstitial photodynamic therapy of glioblastoma

“…An NP called AGuIX was used; it is composed of gadolinium chelates, DOTAGA, 2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, covalently grafted to a polysiloxane core; its synthesis and properties have already been presented in the literature. 36,[44][45][46][47][48] A PS, a tetraphenylporphyrin (TPP) and a peptide (KDKPPR) targeting the NRP-1 receptor overexpressed by tumor angiogenic vessels were then grafted on the surface of this particle. The choice of the AGuIX NPs was driven by several points.…”