Aerosolized In Vivo 3D Localization of Nose-to-Brain Nanocarrier Delivery Using Multimodality Neuroimaging in a Rat Model—Protocol Development

Abstract

The fate of intranasal aerosolized radiolabeled polymeric micellar nanoparticles (LPNPs) was tracked with positron emission tomography/computer tomography (PET/CT) imaging in a rat model to measure nose-to-brain delivery. A quantitative temporal and spatial testing protocol for new radio-nanotheranostic agents was sought in vivo. LPNPs labeled with a zirconium 89 (89Zr) PET tracer were administered via intranasal or intravenous delivery, followed by serial PET/CT imaging. After 2 h of continuous imaging, the animals were sacrificed, and the brain substructures (olfactory bulb, forebrain, and brainstem) were isolated. The activity in each brain region was measured for comparison with the corresponding PET/CT region of interest via activity measurements. Serial imaging of the LPNPs (100 nm PLA–PEG–DSPE+89Zr) delivered intranasally via nasal tubing demonstrated increased activity in the brain after 1 and 2 h following intranasal drug delivery (INDD) compared to intravenous administration, which correlated with ex vivo gamma counting and autoradiography. Although assessment of delivery from nose to brain is a promising approach, the technology has several limitations that require further development. An experimental protocol for aerosolized intranasal delivery is presented herein, which may provide a platform for better targeting the olfactory epithelium.

In Vitro Evaluation of Nasal Aerosol Depositions: An Insight for Direct Nose to Brain Drug Delivery

“…A quantitative temporal and spatial testing protocol for new radio-nanotherapeutic agents was also investigated in vivo. Intranasal aerosolized radiolabeled polymeric micellar nanoparticles were tracked with positron emission tomography/computer tomography (PET/CT) imaging in a rat model to measure NTBDD quantitatively [ 121 ].…”

Radiolabeled Aminopyrazoles as Novel Isoform Selective Probes for pJNK3 Quantification

“…50 As shown in Figure 4C, (±)-F3 showed insignificant permeability compared with standards, which supports the observed poor brain uptake in the biodistribution study. Future efforts to overcome this obstacle may include advanced methods of compound formulation that rely on carrier strategies (e.g., lipid nanocarriers) to improve BBB penetration, 51 non-standard routes of probe administration, 52 or the employment of alternative pJNK3-selective scaffolds.…”

Intranasal Pathway for Nanoparticles to Enter the Central Nervous System

“…44,45 In fact, radio-labeling was utilized to explore the distribution of small molecules and nanoparticles intranasally administered on account of the outstanding sensitivity of radioactive detection techniques, but the low spatial imaging resolution hardly reflects the delivery pathway, which can easily be overcome by MRI. 46 According to the anatomical structure of rat brain, the nasal mucosa where nanoparticles are administered directly connects olfactory bulb and pons via olfactory nerve and trigeminal nerve, respectively. 24 It is therefore reasonable to speculate that the Fe 3 O 4 @PEG NPs are transported into the brain along these nerves.…”

“…However, the temporal variations are asynchronous for these three brain regions. The olfactory bulb starts to show an increased signal approximately 5 min postadministration, while pons and cerebellum present increased signals at around 15 min postadministration, indicating Fe 3 O 4 @PEG NPs need different times to reach different brain regions, which provides an important evidence on the route taken by the PEGylated particles to enter the brain. , In fact, radio-labeling was utilized to explore the distribution of small molecules and nanoparticles intranasally administered on account of the outstanding sensitivity of radioactive detection techniques, but the low spatial imaging resolution hardly reflects the delivery pathway, which can easily be overcome by MRI …”