Rapid short-pulses of focused ultrasound and microbubbles deliver a range of agent sizes to the brain.
Rapid short-pulses of focused ultrasound and microbubbles deliver a range of agent sizes to the brain.
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DOI：
10.1038/s41598-023-33671-5
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发表时间：
2023-04-28
影响因子：
4.6
通讯作者：
Morse, Sophie V.
中科院分区：
文献类型：
--
作者：
Chang, William Lim Kee;Chan, Tiffany G.;Raguseo, Federica;Mishra, Aishwarya;Chattenton, Dani;de Rosales, Rafael T. M.;Long, Nicholas J.;Morse, Sophie V.
聚焦超声和微泡可以非侵入性地局部递送治疗剂和成像剂穿过血脑屏障。统一的治疗和最小的不良生物效应对于实现可靠的剂量和安全地常规使用该技术至关重要。为了实现这些目标，我们以前设计了一个快速的短脉冲超声序列，并用它来提供一个3 kDa的模型代理小鼠大脑。我们观察到均匀分布的交付和血脑屏障关闭在10分钟内。然而，许多治疗剂和显像剂大于3 kDa，例如抗体片段和反义寡核苷酸。在这里，我们评估的可行性，使用快速短脉冲提供更高分子量的模型代理。3，10和70 kDa的葡聚糖被成功地传递到小鼠的大脑，随着药剂大小的增加，剂量降低，分布更不均匀。观察到内源性白蛋白（66.5 kDa）的极轻微外渗，而未检测到免疫球蛋白（~ 150 kDa）和PEG化脂质体（97.9 nm）。该研究表明，快速短脉冲是通用的，并且在0.35 MPa的声压下，可以递送尺寸高达8 nm（70 kDa葡聚糖）和11 nm（免疫球蛋白）之间的流体动力学直径的治疗剂和成像剂。增加声压可以延长快速短脉冲的使用，以递送超过该阈值的药剂，而对安全性几乎没有影响。这项研究证明了使用快速短脉冲递送高分子量治疗剂和成像剂的潜力。
Focused ultrasound and microbubbles can non-invasively and locally deliver therapeutics and imaging agents across the blood–brain barrier. Uniform treatment and minimal adverse bioeffects are critical to achieve reliable doses and enable safe routine use of this technique. Towards these aims, we have previously designed a rapid short-pulse ultrasound sequence and used it to deliver a 3 kDa model agent to mouse brains. We observed a homogeneous distribution in delivery and blood–brain barrier closing within 10 min. However, many therapeutics and imaging agents are larger than 3 kDa, such as antibody fragments and antisense oligonucleotides. Here, we evaluate the feasibility of using rapid short-pulses to deliver higher-molecular-weight model agents. 3, 10 and 70 kDa dextrans were successfully delivered to mouse brains, with decreasing doses and more heterogeneous distributions with increasing agent size. Minimal extravasation of endogenous albumin (66.5 kDa) was observed, while immunoglobulin (~ 150 kDa) and PEGylated liposomes (97.9 nm) were not detected. This study indicates that rapid short-pulses are versatile and, at an acoustic pressure of 0.35 MPa, can deliver therapeutics and imaging agents of sizes up to a hydrodynamic diameter between 8 nm (70 kDa dextran) and 11 nm (immunoglobulin). Increasing the acoustic pressure can extend the use of rapid short-pulses to deliver agents beyond this threshold, with little compromise on safety. This study demonstrates the potential for deliveries of higher-molecular-weight therapeutics and imaging agents using rapid short-pulses.
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