基于稀土铕离子荧光标记的磷酸钙纳米材料体内分布与代谢研究

doi:10.15541/jim20240504

摘要/Abstract

摘要： 纳米磷酸钙（nCaP）在药物递送、生物成像、抗菌、促成骨等纳米医学领域具有潜在的应用前景,但其体内分布与代谢规律尚未完全明确,有待深入研究。本研究采用稀土铕离子荧光标记法,以荷瘤裸鼠为模型,探究了两种尺寸nCaP（纳米点NDs：2.5 nm;纳米颗粒NPs：107.8 nm×17.7 nm）在肝、脾、肺、肾、肿瘤的分布与代谢。结果显示,裸鼠尾静脉注射200 μL浓度为1.5 mg/mL的两种nCaP,发现4 h后CaP NPs主要分布在肝脏和脾脏中,分别占比65.70%和29.32%,在肺脏占比3.83%,而在肾脏和肿瘤中含量仅占比0.84%和0.32%,表明大尺寸CaP NPs更容易被网状内皮（RES）系统中的吞噬细胞捕获;不同的是,与CaP NPs相比,CaP NDs在肝脏、脾脏和肺脏的积聚显著减少了89.40%、87.00%和88.89%,而在肾脏和肿瘤部位的蓄积分别提升3.70倍和3.06倍,表明尺寸的减小有利于CaP NDs被肾小球滤出并增强其肿瘤靶向能力。CaP NDs在肝、脾、肺中的清除率（CLz）分别是CaP NPs的6.60倍、4.14倍和2.40倍,是肾脏的40.34%,这表明尺寸的减小有助于CaP NDs被肝脏、脾脏和肺脏内的吞噬细胞迅速代谢,但存在肾小管的重吸收;在肿瘤中CaP NDs的CLz值为CaP NPs的8.13%,表明小尺寸CaP NDs表现出显著增强的肿瘤靶向和滞留能力。进一步,对荷瘤裸鼠初步建立了包含尺寸因素的nCaP生理药代动力学模型,对CaP NDs和CaP NPs在肿瘤部位分布的预测拟合度分别达到0.925和0.827。本研究可为nCaP体内分布与代谢规律的揭示及其医学应用提供支撑。

关键词: 纳米磷酸钙, 尺寸效应, 荧光标记, 组织分布, 生理药代动力学模型

Abstract: Nano-calcium phosphate (nCaP) has potential applications in nanomedicine fields such as drug delivery, bioimaging, antibacterial treatment, and bone formation promotion. However, its distribution and metabolic patterns within the body are not yet fully understood and require further in-depth research. This study employs a rare earth europium ion fluorescence labeling method and uses tumor-bearing mice as a model to investigate the distribution and metabolism of two sizes of nCaP (nanodots NDs: 2.5 nm; nanoparticles NPs: 107.8 nm×17.7 nm) in the liver, spleen, lung, kidney, and tumor tissue. The results showed that after tail vein injection of 200 μL with a concentration of 1.5 mg/mL nCaP into tumor-bearing nude rats for 4 h, CaP NPs were primarily distributed in the liver and spleen, accounting for 65.70% and 29.32%, respectively, with 3.83% in the lung, while their content in the kidney and tumor was only 0.84% and 0.32%. This suggests that larger CaP NPs are more easily captured by phagocytes within the reticuloendothelial system (RES). In contrast, compared to CaP NPs, accumulation of CaP NDs in the liver, spleen, and lung decreased significantly by 89.40%, 87.00%, and 88.89%, respectively, while their accumulation in the kidney and tumor increased by 3.70 times and 3.06 times. This indicates that smaller particle size facilitates CaP NDs in glomerular filtration for urinary excretion and enhances their tumor-targeting capability. The clearance rates (CLz) of CaP NDs in the liver, spleen, and lung were 6.60-flod, 4.14-flod, and 2.40-flod higher than that of CaP NPs, respectively, and 40.34% in the kidney, This indicating that reduced size of CaP NDs facilitates rapid metabolism by phagocytes in the liver, spleen, and lung but also results in reabsorption in the renal tubules. In tumor, the CLz of CaP NDs was 8.13%, much higher than that of CaP NPs, suggesting that the smaller CaP NDs exhibit significantly enhanced tumor targeting and retention capability. In the meantime, a physiologically based pharmacokinetic (PBPK) model incorporating particle size factors was preliminarily established for tumor-bearing mice to simulate the distribution of nano-calcium phosphate. The model's predictive fit for CaP NDs and CaP NPs in tumor sites reached 0.952 and 0.894, respectively. This study provides a promising support for understanding in vivo distribution and metabolic patterns of nCaP and applicating potential in medical.

Key words: nano-calcium phosphate, size effect, fluorescent labeling, tissue distribution, physiologically based pharmacokinetic model

中图分类号:

TQ174

汤新丽, 丁自友, 陈俊锐, 赵刚, 韩颖超. 基于稀土铕离子荧光标记的磷酸钙纳米材料体内分布与代谢研究[J]. 无机材料学报, DOI: 10.15541/jim20240504.

TANG Xinli, DING Ziyou, CHEN Junrui, ZHAO Gang, HAN Yingchao. In vivo Distribution and Metabolism of Calcium Phosphate Nanomaterials Based on Fluorescent Labeling with Rare Earth Europium Ions[J]. Journal of Inorganic Materials, DOI: 10.15541/jim20240504.

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