小窝
纳米颗粒
纳米技术
肺
内皮
化学
材料科学
膜
医学
内科学
生物化学
作者
Tapas R. Nayak,Adrián Chrastina,J. L. Valencia,Robert Yedidsion,Tim Buss,Brittany Cederstrom,Jim Koziol,Michael D Levin,Bogdan Olenyuk,Jan E. Schnitzer
标识
DOI:10.1101/2024.09.01.610705
摘要
Abstract Modern medicine seeks precision targeting, imaging and therapy to maximize efficacy and avoid toxicities. Nanoparticles (NPs) have tremendous, yet unmet clinical potential to carry and deliver imaging and therapeutic agents systemically with tissue precision. But their size contributes to unwanted rapid scavenging by the reticulo-endothelial system (RES) and poor penetration of key endothelial cell (EC) barriers, both limiting target-tissue uptake, safety and efficacy. Here, we discover the extraordinary yet size-dependent ability of the EC caveolae pumping system (CPS) to deliver NPs rapidly and specifically into lungs. Gold and dendritic NPs are conjugated to aminopeptidase-P2 antibodies targeting caveolae of lung microvascular endothelium. SPECT-CT imaging and biodistribution analyses reveal that rat lungs extract most of the intravenously injected dose within minutes to achieve rapid blood clearance, high lung tissue concentrations well beyond peak blood levels, and precision lung imaging and targeting. Active transcytosis by caveolae greatly outperforms passive transvascular delivery and can even outpace RES scavenging. These results reveal how much ECs can both limit and promote tissue penetration of NPs and the power and limitations of the CPS. This study provides a new retargeting paradigm for small NPs to avoid RES uptake and achieve unprecedented rapid precision nanodelivery for future diagnostic and therapeutic applications.
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