Nose-to-brain/spinal cord delivery kinetics of liposomes with different surface properties
Nose-to-brain/spinal cord delivery kinetics of liposomes with different surface properties
复制标题
DOI：
10.1016/j.jconrel.2022.03.017
复制
发表时间：
2022-03-29
影响因子：
10.8
通讯作者：
Suzuki, Toyofumi
中科院分区：
文献类型：
--
作者：
Kurano, Takumi;Kanazawa, Takanori;Suzuki, Toyofumi
通过鼻-脑递送的脂质体给药有望成为有效将药物递送至中枢神经系统的策略。有效的鼻-脑递送和以这种方式施用的药物的动力学取决于脂质体的性质。然而，缺乏关于哪种脂质体适用于此目的的基本知识。在此，对鼻内给药的脂质体（带正电荷、中性和带负电荷，有或没有聚乙二醇[PEG]修饰;粒径< 100 nm）进行定性研究，以阐明其在脑和脊髓中的动力学。此外，进行定量研究，以确定它们在大脑和脊髓的每个部分的分布。通过两个实验研究了脂质体表面电荷和PEG修饰对鼻内给药后动力学和分布的影响。在鼻内给予荧光标记的脂质体后，通过离体观察进行定性评价。中性PEG修饰的脂质体在给药后60 min分布于整个脑和脊髓，荧光强度随时间增加。相比之下，非PEG修饰的中性脂质体在嗅球中显示出特别强的荧光，并且荧光定位在大脑的前部。给药后60 min，带正电荷的脂质体在脑外侧部和腰髓周围显示低荧光。在全脑和脊髓中观察到低荧光，在给药120分钟后在嗅球中观察到强荧光。带负电荷的脂质体在给药后60 min未显示荧光，但在给药后120 min在整个脑和脊髓中观察到低荧光。我们定量放射性同位素标记的脂质体鼻内给药后，在脑和脊髓中的放射性。与其他脂质体相比，中性脂质体在脑和脊髓中的药物浓度-时间曲线下面积（AUC 60 -120）分布最高。与带负电荷的脂质体相比，带正电荷的脂质体在嗅球和前脑中的分布更高，而带负电荷的脂质体在后脑和球脊髓束中的分布更高。此外，鼻内给药90 min后，与非PEG修饰的中性脂质体相比，PEG修饰的中性脂质体在脑和脊髓中的分布显著增强。这些结果表明，表面电荷和PEG修饰强烈影响鼻-脑递送动力学的效率，并且PEG修饰的中性脂质体是用于将药物递送至脑和脊髓的宽区域的优良载体。
The administration of liposomes via nose-to-brain delivery is expected to become a strategy for efficient drug delivery to the central nervous system. Efficient nose-to-brain delivery and the kinetics of drugs administered in this manner depend on the properties of liposomes. However, there is a lack of basic knowledge of which liposomes are suitable for this purpose. Here, a qualitative study of intranasally administered liposomes (positively charged, neutral, and negatively charged, with or without polyethylene glycol [PEG] modification; particle size < 100 nm) was performed to elucidate their dynamics in the brain and spinal cord. Additionally, a quantitative investigation was performed to ascertain their distribution in each part of the brain and spinal cord. The effects of liposome surface charge and PEG modification on the kinetics and distribution post intranasal administration were investigated via two experiments. Qualitative evaluation was performed via ex vivo observation after intranasal administration of fluorescently labeled liposomes. Neutral PEG-modified liposomes were distributed throughout the brain and spinal cord 60 min after administration, and the fluorescence intensity increased with time. By contrast, non-PEG-modified neutral liposomes showed particularly strong fluorescence in the olfactory bulb, and the fluorescence was localized in the anterior part of the brain. Positively charged liposomes showed low fluorescence around the lateral part of the brain and lumbar spinal cord 60 min after administration. Low fluorescence was observed in the whole brain and spinal cord, with strong fluorescence being observed in the olfactory bulb after 120 min of administration. Negatively charged liposomes showed no fluorescence at 60 min after administration, but low fluorescence was observed throughout the brain and spinal cord 120 min after administration. We quantified the radioactivity in the brain and spinal cord after intranasal administration of radioisotope-labeled liposomes. Neutral liposomes showed the highest distribution by area under the drug concentration-time curve (AUC60-120) in the brain and spinal cord compared to other liposomes. Compared with negatively charged liposomes, positively charged liposomes had a higher distribution in the olfactory bulb and forebrain, while negatively charged liposomes had a higher distribution in the hindbrain and bulbospinal tract cord. In addition, the distribution of PEG-modified neutral liposomes in the brain and spinal cord was significantly enhanced compared to that of non-PEG-modified neutral liposomes after 90 min of intranasal administration. These results indicate that surface charge and PEG modification strongly affect the efficiency of nose-to brain delivery kinetics, and that PEG-modified neutral liposomes are excellent carriers for drug delivery to a wide area of the brain and spinal cord.