鞘内注射健康小鼠后中枢神经系统中纳米颗粒的命运。,Scientific Reports

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鞘内注射健康小鼠后中枢神经系统中纳米颗粒的命运。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-08-29 , DOI: 10.1038/s41598-019-49028-w
K T Householder _{1,

2,

3} , S Dharmaraj _{1,

2,

3} , D I Sandberg _{1,

4} , R J Wechsler-Reya ₅ , R W Sirianni _{1,

2,

3}

Affiliation

脑脊液（CSF）在脑室中产生，并在脑和脊髓的蛛网膜下腔（SAS）内循环，并在该处与实质的间质液交换。脑脊液进入整个中枢神经系统（CNS）使其成为一种有吸引力的药物输送介质。但是，鞘内（IT）疗法很少进入临床，部分原因是分布有限和清除迅速。鉴于纳米颗粒（NP）载体在延长循环和改善全身给药剂的递送方面的成功，我们寻求评估IT注射的NP在中枢神经系统内的分布。我们将荧光的100 nm聚乙二醇化NPs注入健康小鼠的大水罐，并研究它们在大脑和脊髓中的分布。我们的数据表明，NPs可以通过SAS在整个神经轴上快速分布，并且具有可复制的，解剖学上定义的传递方式。NPs在软脑膜内的保留时间超过3周，显示偏爱腹面且对CNS实质的渗透极小。NP的清除发生在整个筛状板进入鼻粘膜中，小部分的NP定位在神经根离开脊柱的位置。较大的10 µm颗粒也能够通过SAS，但分布不广泛。这些研究证明了NPs能够沿神经网络实现广泛的输送，并强调了IT管理是将纳米药物输送到蛛网膜下腔的潜在重要途径。

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Fate of nanoparticles in the central nervous system after intrathecal injection in healthy mice.

Cerebrospinal fluid (CSF) is produced in the cerebral ventricles and circulates within the subarachnoid space (SAS) of the brain and spinal cord, where it exchanges with interstitial fluid of the parenchyma. The access of CSF to the entire central nervous system (CNS) makes it an attractive medium for drug delivery. However, few intrathecal (IT) therapies have reached the clinic due, in part, to limited distribution and rapid clearance. Given the success of nanoparticle (NP) carriers in prolonging circulation and improving delivery of systemically administered agents, we sought to evaluate the distribution of IT injected NPs within the CNS. We administered fluorescent, 100 nm PEGylated-NPs into the cisterna magna of healthy mice and studied their distribution along the brain and spinal cord. Our data demonstrate that NPs are capable of distributing rapidly through the SAS along the entire neuraxis with reproducible, anatomically defined patterns of delivery. NPs were well retained within the leptomeninges for over 3 weeks, showing preference for ventral surfaces and minimal penetration into the CNS parenchyma. Clearance of NPs occurred across the cribriform plate into the nasal mucosa, with a small fraction of NPs localizing with nerve roots exiting the spinal column. Larger 10 µm particles were also capable of moving through the SAS but did not achieve as widespread distribution. These studies demonstrate the ability of NPs to achieve widespread delivery along the neuraxis and highlight IT administration as a potentially significant route of administration for delivery of nanomedicine to the subarachnoid space.

更新日期：2019-08-29

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