Info
Background:
Intrapulmonary drug delivery is an increasingly utilized therapeutic strategy because it enables local targeting, noninvasive administration, and reduces systemic side effects 1,2. Current imaging approaches for pulmonary drug delivery remain limited by low spatial resolution and long acquisition times 3. Spectral photon-counting CT (SPCCT) enables ultra-high-resolution material-specific imaging, making it particularly attractive to evaluate the lungs and the biodistribution of exogenous inhaled agents 4–6. Dextran-coated cerium oxide nanoparticles (Dex-CeNP) are a preclinically validated contrast agent with antioxidant properties7 but they have not been explored for lung applications.
Hypothesis/Objective:
The present study aims to evaluate the biodistribution of intrapulmonary Dex-CeNP using SPCCT in preclinical animal models.
Methods:
Dex-CeNP were synthesized by precipitation of cerium salts in the presence of dextran 7,and administrated using two techniques: intratracheal instillation and nebulization. 7 Sprague-Dawley rats received Dex-CeNP by intratracheal instillation (1.5mL/kg, 26 mgCe/mL), and 3 NZW rabbits underwent passive nebulization (1.5mL/kg in the reservoir, 10 mgCe/mL) (Fig A). Acquisitions were performed using a clinical SPCCT prototype with lung acquisition protocols (45–60 mAs) and high-resolution reconstruction parameters (voxel-size: 0.28³ mm³ and 0.32³ mm³) at different timepoints. Two-basis material decomposition was applied, yielding a water density map and a spectral density map representative of cerium. Lungs were semi automatically segmented and subdivided into 10 sub-anatomical regions (Fig S1). Relative quantity of cerium in each region, defined as regional cerium quantity (mg) divided by total lung cerium quantity (mg) and expressed as a percentage. These relative quantities were analyzed along left-to-right, ventral-to-dorsal, and apico-basal gradients. We calculated the contrast-enhanced fraction (CEF) defined as contrast-enhanced volume (mL) divided by total lung volume (mL) and expressed as a percentage. Longitudinal pharmacokinetic and histopathological studies were performed in rats. Statistical analyses were performed on R (4.5.3). Aligned rank-transform ANOVA was used to compare regional quantities of cerium (art function in ARTool package). A linear mixed effects model (lmer function in LME4 package) was used to determine if pharmacokinetic decay modeling was appropriate.
Results:
Dex-CeNPs were successfully synthesized, with a core diameter of 4.8±1.2 nm and a hydrodynamic diameter of 17.5±0.7 nm (Figure B and S2). Intrapulmonary Dex-CeNP administration was tolerated in both species, with no mortality observed over 1-week in rats and 5-weeks in rabbits. Histopathologic analysis confirmed the absence of significant lung injury after 1 week in rats. (Fig. S3). SPCCT enabled ultra-high-resolution morphological lung imaging, spectral cerium imaging and 3D visualization of drug biodistribution (Figure C). Regional biodistribution patterns differed between instillation and nebulization models across all anatomical planes (Fig. D; P<0.001). The left/right lung drug biodistribution was 45%/55% vs 35%/65% for instillation and nebulization, respectively (P= 0.0009). The ventral/dorsal drug distribution was more homogenous after instillation compared to nebulization (30%/30% vs. 10%/50%; P=8.2×10-10). CEF was 68.6% post-instillation and 45.6% post-nebulization. In rats, time-dependent decay was observed only using spectral images for quantifying cerium on spectral images (P<0.001). The area under the curve was 36mg·h/mL with a signal half-life of 80h (Fig. S4).
Conclusion:
SPCCT enabled noninvasive quantification and spatial mapping of intrapulmonary Dex-CeNP delivery in vivo. This study establishes a framework for quantitative evaluation of radio-opaque pulmonary agents using SPCCT, including assessment of lung morphology, global and regional deposition, and pharmacokinetics.
Image/Figure:
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Image/Figure Caption:
A. Schematic of dextran-coated cerium oxide nanoparticle (Dex-CeNP) function as intrapulmonary contrast for spectral photon-counting CT (SPCCT) imaging.
B. Transmission electron microscopy images of Dex-CeNPs. Scale bar is 50 nanometers.
C1-C6. SPCCT images of Dex-CeNP instillation in rats (C1-C3) and nebulization in rabbits (C3-C6). (C1, C4) Coronal ultra-high resolution CT. (C2, C4) Coronal spectral images of cerium density. (C3, C6) 3D-renderings of cerium distribution inside the total lung volume (shown in grey).
D1-D3. SPCCT-derived regional lung distribution of Dex-CeNP for two administration methods: instillation and nebulization. Relative cerium mass, defined as the cerium amount in a sub-compartment relative to the total cerium amount in the lungs, was determined for each anatomical plane: the axial plane which describes (D1) left-to-right lung gradient. The sagittal plane which describes the (D2) ventral-dorsal lung gradient. And the coronal plane which describes the (D3) apico-basal lung gradient.
Author
Salma Marouan
CREATIS UMR 5220 UCBL